Sickle Cell Anemia - References

Blood 1999 Sep 1;94(5):1555-1560

Sickle Cell Acute Chest Syndrome: Pathogenesis and Rationale for Treatment.

Stuart MJ, Setty BN

Department of Pediatrics and the Cardeza Foundation for Hematologic Research, Thomas Jefferson University, Philadelphia, PA.

Acute chest syndrome (ACS) is a leading cause of death in sickle cell disease (SCD). Our previous work showed that hypoxia enhances the ability of sickle erythrocytes to adhere to human microvessel endothelium via interaction between very late activation antigen-4 (VLA4) expressed on sickle erythrocytes and the endothelial adhesion molecule vascular cell adhesion molecule-1 (VCAM-1). Additionally, hypoxia has been shown to decrease the production of nitric oxide (NO) which inhibits VCAM-1 upregulation. Based on these observations, we hypothesize that during ACS, the rapidly progressive clinical course that can occur is caused by initial hypoxia-induced pulmonary endothelial VCAM-1 upregulation that is not counterbalanced by production of cytoprotective mediators, including NO, resulting in intrapulmonary adhesion. We assessed plasma NO metabolites and soluble VCAM-1 in 36 patients with SCD and 23 age-matched controls. Patients with SCD were evaluated at baseline (n = 36), in vaso-occlusive crisis (VOC; n = 12), and during ACS (n = 7). We observed marked upregulation of VCAM-1 during ACS (1,290 +/- 451 ng per mL; mean +/- 1 SD) with values significantly higher than controls (P <.0001) or patients either in steady state or VOC (P <.01). NO metabolites were concomitantly decreased during ACS (9.2 +/- 1.5 nmol/mL) with values lower than controls (22.2 +/- 5.5), patients during steady state (21.4 +/- 5.5), or VOC (14.2 +/- 1.2) (P <.0001). Additionally, the ratio of soluble VCAM-1 to NO metabolites during ACS (132.9 +/- 46.5) was significantly higher when compared with controls (P <.0001) or patients either in steady state or VOC (P <.0001). Although hypoxia enhanced in vitro sickle erythrocyte-pulmonary microvessel adhesion, NO donors inhibited this process with concomitant inhibition of VCAM-1. We suggest that in ACS there is pathologic over expression of endothelial VCAM-1. Our investigations also provide a rationale for the therapeutic use in ACS of cytoprotective modulators including NO and dexamethasone, which potentially exert their efficacy by an inhibitory effect on VCAM-1 and concomitant inhibition of sickle erythrocyte-endothelial adhesion.

PMID: 10477680

Blood 1999 Sep 1;94(5):1550-1554

Safety of Hydroxyurea in Children With Sickle Cell Anemia: Results of the HUG-KIDS Study, a Phase I/II Trial.

Kinney TR, Helms RW, O'Branski EE, Ohene-Frempong K, Wang W, Daeschner C, Vichinsky E, Redding-Lallinger R, Gee B, Platt OS, Ware RE

Duke Pediatric Sickle Cell Program, Duke Children's Hospital, Durham, NC; the Department of Biostatistics and Frank Porter Graham Child Development Center, University of North Carolina at Chapel Hill, Chapel Hill, NC; Comprehensive Sickle Cell Center, The Children's Hospital of Philadelphia, Philadelphia, PA; St Jude Children's Research Hospital, Memphis, TN; Pitt Memorial Hospital, East Carolina University, Greenville, NC; Sickle Cell Center of Northern California, Oakland Children's Hospital, Oakland, CA; the University of North Carolina Pediatric Sickle Cell Program, University of North Carolina at Chapel Hill, Chapel Hill, NC; and the Department of Medicine, Children's Hospital, Harvard Medical School, Boston, MA.

Previous studies have determined the short-term toxicity profile, laboratory changes, and clinical efficacy associated with hydroxyurea (HU) therapy in adults with sickle cell anemia. The safety and efficacy of this agent in pediatric patients with sickle cell anemia has not been determined. Children with sickle cell anemia, age 5 to 15 years, were eligible for this multicenter Phase I/II trial. HU was started at 15 mg/kg/d and escalated to 30 mg/kg/d unless the patient experienced laboratory toxicity. Patients were monitored by 2-week visits to assess compliance, toxicity, clinical adverse events, growth parameters, and laboratory efficacy associated with HU treatment. Eighty-four children were enrolled between December 1994 and March 1996. Sixty-eight children reached maximum tolerated dose (MTD) and 52 were treated at MTD for 1 year. Significant hematologic changes included increases in hemoglobin concentration, mean corpuscular volume, mean corpuscular hemoglobin, and fetal hemoglobin parameters, and decreases in white blood cell, neutrophil, platelet, and reticulocyte counts. Laboratory toxicities typically were mild, transient, and were reversible upon temporary discontinuation of HU. No life-threatening clinical adverse events occurred and no child experienced growth failure. This Phase I/II trial shows that HU therapy is safe for children with sickle cell anemia when treatment was directed by a pediatric hematologist. HU in children induces similar laboratory changes as in adults. Phase III trials to determine if HU can prevent chronic organ damage in children with sickle cell anemia are warranted.

PMID: 10477679

Mt Sinai J Med 1999 Sep;66(4):282-285

Resolving Conflicts: Misconceptions and Myths in the Care of the Patient with Sickle Cell Disease.

Sutton M, Atweh GF, Cashman TD, Davis WT

Department of Pediatrics, Mount Sinai School of Medicine, New York, NY.

Sickle cell disease is an autosomal recessive disease that primarily affects persons of African ancestry. The hallmark of the disease is hemolytic anemia and vaso-occlusive crisis. Patients often have recurrent and severely painful episodes that necessitate the use of opioids. The reluctance of some health care providers to prescribe narcotics has resulted in adversarial relationships with some patients. The socio-cultural disparity between patients and providers may play a role. However, the lack of knowledge and understanding of the underlying pathophysiology of the disease and pain are the key issues. Education, research and hands-on experience, resulting in changes in attitudes and behaviors, will ultimately lead to a more empathic approach to the sickle cell patient.

PMID: 10477486

Anesth Analg 1999 Sep;89(3):598-603

Fast-track cardiac anesthesia in patients with sickle cell abnormalities.

Djaiani GN, Cheng DC, Carroll JA, Yudin M, Karski JM

Department of Anesthesia, The Toronto Hospital, University of Toronto, Ontario, Canada.

We conducted a retrospective review of 10 patients with sickle cell trait (SCT) and 30 patients (cohort control) without SCT undergoing first-time coronary artery bypass graft surgery with cardiopulmonary bypass. Demographic, perioperative management, and outcome data were collected. Both groups were matched according to age, weight, duration of surgery, and preoperative hemoglobin (Hb) concentration. Distribution of gender, medical conditions, pharmacological treatment, and preoperative left ventricular function were similar between the groups. The comparisons were analyzed in respect to postoperative blood loss and transfusion rates, as well as duration of intubation, intensive care unit, and hospital length of stay (LOS). All patients underwent fast-track cardiac anesthesia. A combination of cold crystalloid and blood cardioplegia was used. The lowest nasopharyngeal temperature was 33 degrees C. There were no episodes of significant hypoxemia, hypercarbia, or acidosis. None of the patients had sickling crisis during the perioperative period. The postoperative blood loss was 687 +/- 135 vs 585 +/-220 mL in the SCT and control groups, respectively. The trigger for blood transfusion during cardiopulmonary bypass was hematocrit <20% and Hb <75 g/L postoperatively. Three SCT patients (30%) and 10 control patients (33%) received a blood transfusion. Median extubation time was 4.0 vs 3.9 h; intensive care unit LOS was 27 vs 28 h; and hospital LOS was 6.0 vs 5.5 days in the SCT and control groups, respectively. There were no intraoperative deaths. One patient in the SCT group died from multiorgan failure 2 mo after surgery. IMPLICATIONS: Fast-track cardiac anesthesia can be used safely in patients with sickle cell trait undergoing first-time coronary artery bypass graft surgery. Extubation time and intensive care unit and hospital length of stay are comparable to those of matched controls, and blood loss and transfusion requirements are not increased. A hematocrit of 20% seems to be a safe transfusion trigger during cardiopulmonary bypass in these patients.

PMID: 10475287, UI: 99402272

Acta Haematol 1999 Aug;102(1):31-37

Levels of Endothelial, Neutrophil and Platelet-Specific Factors in Sickle Cell Anemia Patients during Hydroxyurea Therapy.

Saleh AW, Hillen HF, Duits AJ

Department of Internal Medicine, St. Elisabeth Hospital, Curacao, The Netherlands Antilles.

It has been shown that the clinical course of sickle cell (SS) patients can be ameliorated by administration of hydroxyurea (HU). Induction of hemoglobin F (HbF) is thought to be the mechanism responsible for clinical improvement in some patients. However, HU has a variable effect on HbF production and there exists no good correlation between the extent of HbF increase and clinical response. On the other hand, the degree of adherence of SS to vascular endothelium and neutrophil counts correlate well with clinical severity. Being a cytotoxic drug, used in myeloproliferative diseases, HU may alter proliferation among various cell lines. Moreover, HU has been reported to reduce red blood cell (RBC) adhesion receptor expression in young SS individuals and induces changes in endothelial cells in vitro. It should be conceived that in addition to its effects on HbF production, HU may change the clinical symptoms of SS patients by affecting the degree of adherence of different blood cells, by influencing the activity of endothelium as well as the activity of white blood cells (WBC) and platelets. To analyze whether several of the determinants of adhesion are modulated by HU treatment we studied the levels of endothelial activity (soluble vascular adhesion molecule-1, (sVCAM-1), interleukin-8 (IL-8), fibronectin, neutrophil activity (sL-selectin, sIL-6 receptor-alpha, myeloperoxidase) and platelet activity (von Willebrand factor) in relation to clinical symptoms, hematological data and HbF levels in 8 SS patients before and during 5 months of HU therapy. Steady state sVCAM-1 levels are increased compared to normal controls and a significant decrease is noted during HU treatment, suggesting a decrease in the interactions between RBC and vascular endothelium. The IL-8 levels are comparable to those in normal controls and remain unaffected by HU therapy. Intercurrent infection and crises reveal striking increases in IL-8 which are accompanied by leukocytosis, but otherwise the IL-8 levels do not correlate with hematological data. HU has no demonstrable effect on fibronectin or soluble neutrophil adhesion molecules, but the levels of myeloperoxidase decrease significantly while WBC counts do not, implying a reduction in neutrophil activity which may help attenuate the propagation phase of a vasoocclusive crisis.

PMID: 10473885

AJR Am J Roentgenol 1999 Sep;173(3):788, 792-3

Gastrointestinal/genitourinary case of the day. Liver infarction in a patient with sickle cell anemia, splenic atrophy, and gallstones.

Atkinson DS Jr, Fenlon HM, Kuligowska E

Department of Radiology, Boston Medical Center, and Boston University School of Medicine, MA 02118, USA.

PMID: 10470926, UI: 99397527

Am J Hematol 1999 Sep;62(1):62

A 78-year-old man with sickle-cell anemia.

Koduri PR, Leon M, Honig GR, Lu SJ

Division of Hematology, Cook County Hospital, Chicago, Illinois.

PMID: 10467281

Am J Hematol 1999 Sep;62(1):1-6

Outpatient management of fever in children with sickle cell disease (SCD) in an African setting.

Rahimy MC, Gangbo A, Ahouignan G, Anagonou S, Boco V, Alihonou E

Newborn Screening for Sickle Cell Disease and Comprehensive Clinical Care Programs Health Sciences Faculty, Cotonou, National University of Republic of Benin (West Africa&rpar.

Because hospitalization and intravenous antibiotics for treatment of a potentially fatal bacterial infection in febrile children with sickle cell disease (SCD) are difficult to apply, outpatient treatment has been considered in developed countries for selected patients. Eligibility criteria and procedures may differ in developing countries because of unique economic and social conditions. After clinical evaluation within 36 hr of the onset of a fever exceeding 38.5 degrees C, children with SCD who are being closely followed as a part of a SCD cohort in Cotonou (West Africa), were treated as outpatients. The antibiotic regimen consisted of intramuscular injection of ceftriaxone 50 mg/kg/day for 2 days followed by amoxicillin 25 mg/kg x 3/day x 4 days and oral hyper-hydration. Patients were observed for 6 hr and thereafter discharged with a medical control at day 2, day 8 + day 15. All 60 children included completed their treatment, and none were lost to follow-up. A definite or a presumed bacterial infection was the cause of the febrile episode in 76.7% of cases. An appreciable decrease in fever was observed from day 2 and only 2 patients were hospitalized at day 3, one for abdominal painful crisis and one other for persistent fever without documented infection. No severe bacterial infections, recurrence of febrile episode, nor death were encountered during the follow-up. The cost of this outpatient approach is US $30 per patient as compared to US $140 per patient if the patient had been hospitalized. Outpatient management of febrile episode in children with SCD is feasible and cost-effective in Sub-Saharan African. It requires, however, improved medical education on SCD and immediate medical attention after the onset of fever. Copyright 1999 Wiley-Liss, Inc.

PMID: 10467269

Genet Test 1999;3(2):185-90

Prepregnancy testing for single-gene disorders by polar body analysis.

Verlinsky Y, Rechitsky S, Verlinsky O, Ivachnenko V, Lifchez A, Kaplan B, Moise J, Valle J, Borkowski A, Nefedova J, Goltsman E, Strom C, Kuliev A

Reproductive Genetics Institute, Chicago, IL 60657, USA.

Preventive measures for single-gene disorders are currently based on carrier screening in pregnancy and prenatal diagnosis. Although this has been extremely effective for preventing new cases of common inherited conditions, the major limitation is still termination of 25% of wanted pregnancies following detection of affected fetuses. To overcome this important problem, we developed a method for prepregnancy genetic testing that involves DNA analysis of the first and second polar bodies, which are extruded during maturation and fertilization of oocytes. We offered this option to 28 couples at risk for having children with single-gene disorders. Fifty clinical cycles were performed from these patients for the following conditions: 20 for cystic fibrosis, 18 for thalassemia, 6 for sickle cell disease, 2 each for Gaucher disease and LCHAD (long-chain 3-hydroxyacyl-COA dehydrogenase deficiency), and 1 each for hemophilia B and phenylketonuria. Oocytes obtained from these patients using in vitro fertilization procedures (IVF) were tested by a sequential multiplex nested PCR analysis of the first and second polar body to detect the gene involved simultaneously with linked polimorphic markers. A total of 191 of 399 oocytes with predicted genotype were mutation free and preselected for fertilization and transfer. In all but three cycles, one to three unaffected embryos with predicted unaffected genotypes were transferred, resulting in 20 pregnancies, from which 19 healthy children have been born. The follow-up analysis of embryos resulting from oocytes with predicted affected genotype, confirmed the diagnosis in 97% of cases, demonstrating the reliability of prepregnancy diagnosis of single-gene defects by polar body analysis.

PMID: 10464666, UI: 99393932

J Eur Acad Dermatol Venereol 1999 May;12(3):243-4

Hydroxyurea-induced leg ulcers: is macroerythrocytosis a pathogenic factor?

Velez A, Garcia-Aranda JM, Moreno JC

Section of Dermatology, Hospital Universitario Reina Sofia, Cordoba, Spain.

Hydroxyurea is a common cancer chemotherapy agent that inhibits ribonucleotide reductase, an enzyme essential to DNA synthesis. It is considered the drug of choice in the treatment of chronic myelogenous leukemia and essential thrombocythemia. The occurrence of leg ulcers have been described in 8.5% of patients receiving continuous treatment with hydroxyurea, but the cause of this complication is unknown. We report two additional patients and suggest that macroerythrocytosis, which occurs in almost all the patients taking hydroxyurea, may be a pathogenic factor. Macroerythrocytosis can be considered as an 'acquired' blood dyscrasia, and similar leg ulcers have long been known to occur with certain hereditary blood dyscrasias, such as sickle cell anemia, thalasemia, and spherocytosis.

PMID: 10461646, UI: 99390747

Br J Haematol 1999 Aug;106(2):388-90

Coil embolization of cerebral aneurysms in patients with sickling disorders.

McQuaker IG, Jaspan T, McConachie NS, Dolan G

Department of Haematology, University Hospital, Nottingham, UK.

In patients with sickle cell disease cerebral aneurysm formation is thought to be a complication of recurrent red cell sickling, and multiple aneurysms have been reported in these patients. Management of patients with suspected cerebral aneurysm has traditionally involved cerebral vessel angiography followed by craniotomy and aneurysmal clipping. In patients without sickle cell disease, non-operative intervention in the form of endovascular coil embolization is increasingly being used to ablate aneurysms, but has not thus far been reported in patients with sickle cell disease. We report two patients with sickling disorders who have undergone coil embolization of cerebral aneurysms with good functional and radiological outcomes. These patients illustrate that endovascular coiling is useful in the treatment of cerebral aneurysms associated with sickling disorders, although, as with surgical intervention, preparation with exchange transfusion is appropriate.

PMID: 10460596, UI: 99390187

Pediatr Radiol 1999 Aug 23;29(9):646-661

Imaging of sickle cell disease.

Crowley JJ, Sarnaik S

Department of Pediatric Imaging, Children's Hospital of Michigan, 3901 Beaubien Boulevard, Detroit, MI 48201-2196, USA

Sickle cell disease is an important health care issue in the United States and in certain areas in Africa, the Middle East and India. Although a great deal of progress has been made in understanding the disease at the molecular and pathophysiologic level, specific treatment which is safe and accessible for most patients is still elusive. Going into the next millennium, the management of this disease is still largely dependent on early diagnosis and the treatment of complications with supportive care. Thus, diagnosis and evaluation of the complications of the disease are crucial in directing clinical care at the bedside. Modern imaging modalities have greatly improved, and their application in the patient with the sickling disorders has enhanced the decision - making process. The purpose of this article is to review the clinical aspects of common complications of the disease and to discuss imaging approaches which are useful in their evaluation.http://link.springer-ny.com/link/service/journals/00247/bibs/29n9p646.html

PMID: 10460325

Lancet 1999 Mar 6;353(9155):786-92

6-month efficacy, tolerance, and acceptability of a short regimen of oral zidovudine to reduce vertical transmission of HIV in breastfed children in Cote d'Ivoire and Burkina Faso: a double-blind placebo-controlled multicentre trial. DITRAME Study Group. DIminution de la Transmission Mere-Enfant.

Dabis F, Msellati P, Meda N, Welffens-Ekra C, You B, Manigart O, Leroy V, Simonon A, Cartoux M, Combe P, Ouangre A, Ramon R, Ky-Zerbo O, Montcho C, Salamon R, Rouzioux C, Van de Perre P, Mandelbrot L

Unite INSERM 330, Universite Victor Segalen Bordeaux 2, France. Francois.dabis@dim.u-bordeaux2.fr

BACKGROUND: Zidovudine reduces the rate of vertical transmission of HIV in non-breastfed populations. We assessed the acceptability, tolerance, and 6-month efficacy of a short regimen of oral zidovudine in African populations practising breastfeeding. METHODS: A randomised double-blind placebo-controlled trial was carried out in public clinics of Abidjan, Cote d'Ivoire, and Bobo-Dioulasso, Burkina Faso. Eligible participants were women aged 18 years or older, who had confirmed HIV-1 infection and pregnancy of 36-38 weeks duration, and who gave written informed consent. Exclusion criteria were severe anaemia, neutropenia, abnormal liver function, and sickle-cell disease. Women were randomly assigned zidovudine (n=214; 300 mg twice daily until labour, 600 mg at beginning of labour, and 300 mg twice daily for 7 days post partum) or matching placebo (n=217). The primary outcome was the diagnosis of HIV-1 infection in the infant on the basis of sequential DNA PCR tests at days 1-8, 45, 90, and 180. We compared the probability of infection at a given age in the two groups. Analyses were by intention to treat. FINDINGS: Women were enrolled between September, 1995, and February, 1998, when enrolment to the placebo group was stopped. Analysis was based on 421 women and 400 lifeborn infants. Baseline demographic, clinical, and laboratory characteristics were similar in the two groups. The Kaplan-Meier probability of HIV infection in the infant at 6 months was 18.0% in the zidovudine group (n=192) and 27.5% in the placebo group (n=197; relative efficacy 0.38 [95% CI 0.05-0.60]; p=0.027). Adjustment for centre, period of recruitment, mode of delivery, maternal CD4-cell count, duration of labour, prolonged rupture of membranes, and duration of breastfeeding did not change the treatment effect. The proportions of women taking more than 80% of the planned maximum dose were 75% before delivery, 81% during labour, and 83% post partum, without statistical difference between the groups. No major adverse biological or clinical event was reported in excess among women and children of the zidovudine group. INTERPRETATION: A short course of oral zidovudine given during the peripartum period is well accepted and well tolerated, and provides a 38% reduction in early vertical transmission of HIV-1 infection despite breastfeeding.

Publication Types:

• Clinical trial
• Multicenter study
• Randomized controlled trial

PMID: 10459959, UI: 99387715

Can J Surg 1999 Aug;42(4):289-92

Sickle cell disease of the spine in children.

Roger E, Letts M

Division of Pediatric Orthopedics, Children's Hospital of Eastern Ontario, University of Ottawa.

OBJECTIVE: To determine the incidence of back pain in children admitted with sickle cell disease so as to increase awareness of this disease in black children presenting with back pain or discomfort. DESIGN: A retrospective review. SETTING: The Children's Hospital of Eastern Ontario in Ottawa, a tertiary care, university affiliated centre. PATIENTS: Thirty children were treated for active sickle cell disease between 1990 and 1996. Eleven (5 boys, 6 girls) suffered vascular-occlusive phenomena occurring in bone, referred to as "bony crises," requiring a total of 49 admissions. MAIN OUTCOME MEASURES: Clinical manifestations of spinal involvement by sickle cell disease. MAIN RESULTS: The spine represented the second most common area of bone involvement (26%) exceeded only by the knee (35%). The vertebral level affected was lumbosacral in 66% of cases, followed by thoracic in 22% and cervical in only 12%. Eighty-six percent of the children with spinal pain were anemic upon presentation, 71% had an elevated leukocyte count, 15% were hyponatremic and 15% were hyperkalemic. Minimal physical signs in the spine were noted, other than a local tenderness over the spinous process in 71% and a decreased range of back motion in 17%. CONCLUSIONS: Sickle cell disease is becoming more common in Canada as a result of increasing immigration from African countries and should always be considered as a possible cause of back pain in a black child.

PMID: 10459329, UI: 99388621

Afr J Med Med Sci 1996 Sep;25(3):293-6

Malignant haemangioendothelioma of bone in a HbSC disease patient--a case report.

Shokunbi WA, Campbell OB, Ogunbiyi JO

Department of Haematology, University College Hospital, Ibadan, Nigeria.

We report here a 35-year-old man with sickle cell disease (SCD), who presented in 1989 with pain in the (R) hip of 7 years duration and swelling of the (R) calf of 3 months duration. Clinical examination revealed a hard tender mass in the (R) calf. Histology of the (R) calf mass revealed haemangioendothelioma (HE), similar to the histology of the (R) iliac bone mass obtained in another institution previously. He was treated with external radiotherapy with the 1.25 megavoltage beam to antero-posterior fields of the (R) hemipelvis and (R) calf, with good response. Chemotherapy was subsequently administered using 6 cycles of VAC regime. The patient remained in remission for 12 months. In 1991 he had lymphoedema of (R) lower limb and received further radiotherapy and chemotherapy after an isotope bone scan had revealed disease activity in the (R) hemipelvis, (R) femur and (L) upper tibia. He responded again with complete regression of the lymphoedema and remained well until April 1993 when the lymphoedema recurred. He died while being evaluated for further treatment. Although there is no evidence to suggest that SCD confers any protection from development of neoplasms, the co-existence of SCD with a neoplasm is not common. We consider the occurrence of HE of bone, a rare malignancy, in a HbSC patient worthy of reporting.

PMID: 10457808, UI: 99386258

Afr J Med Med Sci 1996 Sep;25(3):261-4

Periodontal disease in homozygous HBSS adolescent Nigerians.

Arowojolu MO, Savage KO, Aken'ova YA

Department of Preventive Dentistry, University College Hospital, Ibadan, Nigeria.

The association between sickle cell anaemia (SCA) and periodontal disease was assessed in a prospective comparative study over 6 months using 50 adolescents known SCA patients and 50 adolescent non-SCA subjects. Their ages ranged from 11 to 19 years (mean = 15.25 years). The partial mouth recording system was used to determine the gingival index, plaque index, and probing depths of 6 sampled teeth in the mouth. There was no significant difference between the mean plaque and gingival indices of SCA and the control, but the mean probing depth of the SCA subjects was significantly higher than that of the control, notably amongst the females. However, this was of no clinical significance. The periodontal status of the males in the SCA group was similar to that of their female counterpart whereas the males in the control group have poorer status than the females in the same group. These results suggest that SCA does not lead to increased severity in periodontal disease in adolescent Nigerians.

PMID: 10457802, UI: 99386252

N J Med 1999 Aug;96(8):23-5

Sickle cell patients find a brand New World.

Noonan SS

As recently as the 1970s, sickle cell anemia patients had little hope of living past their teen years and little relief from painful crises. With the 1980s came the use of prophylactic penicillin to significantly reduce morbidity and mortality from infection in sickel cell youngsters. One of the sickle cell breakthroughs of the 1990s is the use of hydroxyurea for sickle cell treatment in adult patients. In the future, gene therapy may be the answer to the complex problems sickle cell anemia presents.

PMID: 10457727, UI: 99386177

Biophys Chem 1999 Jul 19;80(1):21-30

Temperature and domain size dependence of sickle cell hemoglobin polymer melting in high concentration phosphate buffer.

Louderback JG, Aroutiounian SK, Kerr WC, Ballas SK, Kim-Shapiro DB

Department of Physics, Wake Forest University, Winston-Salem, NC 27109-7507, USA.

Deoxygenated sickle cell hemoglobin (Hb S) in 1.8 M phosphate buffer, and carbon monoxide (CO) saturated buffer were rapidly mixed using a stopped-flow apparatus. The binding of the CO to the Hb S polymers and the polymer melting was measured by time resolved optical spectroscopy. Polymer melting was associated with decreased turbidity, and CO binding to deoxy-Hb S was monitored by observation of changes in the absorption profile. The reaction temperature was varied from 20 degrees C to 35 degrees C. Polymer domain size at 20 degrees C was also varied. The data for mixtures involving normal adult hemoglobin (Hb A) fit well to a single exponential process whereas it was necessary to include a second process when fitting data involving Hb S. The overall Hb S-CO reaction rate decreased with increasing temperature from 20 degrees C to 35 degrees C, and increased with decreasing domain size. In comparison, Hb A-CO reaction rates increased uniformly with increasing temperature. Two competing reaction channels in the Hb S-CO reaction are proposed, one involving CO binding directly to the polymer and the other involving CO only binding to Hb molecules in the solution phase. The temperature dependence of the contribution of each pathway is discussed.

PMID: 10457594, UI: 99386044

Am J Surg 1999 Jul;178(1):42-5

Is splenectomy for massive splenomegaly safe in children?

Al-Salem AH

Department of Surgery, Qatif Central Hospital, Saudi Arabia.

PURPOSE: To study and analyze the causes, etiology, morbidity, mortality and theraputic value of splenectomy performed for massive splenomegaly in children. METHODS: The medical records of 115 children less than 18 years old who had splenectomy for various hematological disorders were reviewed. Twenty of them had splenectomy for massive splenomegaly (spleen weight > or =1,000 g). The records of these were reviewed for age at operation, gender, hematological diagnosis, indication for splenectomy, operative procedures, postoperative complications, and outcome. RESULTS: Twenty children had splenectomy for massive splenomegaly. There were 16 males and 4 females. Their ages ranged from 4 to 15 years (mean 11.2). Twelve had sickle cell disease, 5 had sickle-beta-thalassemia, 1 had beta-thalassemia major, 1 had thalassemia intermediate, and 1 had chronic myeloid leukemia. The indications for splenectomy were hypersplenism in 11, recurrent splenic sequestration crisis in 8, and splenic abscess in 1. The transfusion requirements in the patient with beta-thalassemia major decreased markedly postoperatively from 18 transfusions/year to only 4 transfusions/year; and for those with hypersplenism, there was a marked improvement in their blood parameters following splenectomy. The patient with thalassemia intermediate required no more blood transfusions. There was no mortality. The immediate postoperative morbidity was 10% for those with massive splenomegaly compared with 6.3% for those with splenomegaly <1,000 g. CONCLUSIONS: With good perioperative management, splenectomy in children with massive splenomegaly is both safe and effective.

PMID: 10456701, UI: 99383701

Clin Pediatr (Phila) 1999 Aug;38(8):459-62

Low frequency of meperidine-associated seizures in sickle cell disease.

Nadvi SZ, Sarnaik S, Ravindranath Y

Department of Pediatrics, Wayne State University School of Medicine, Detroit, MI, USA.

Pain control measures in sickle cell diseases are not uniform. Most clinicians use parenteral morphine or meperidine for severe pain. Reports of seizures associated with meperidine have led to a growing reliance on intravenous morphine, usually with patient-controlled devices. Acceptance of morphine has been poor among patients, and many prefer meperidine. The aim of this retrospective study was to determine the incidence of meperidine-associated seizures in a large, mostly pediatric population with sickling disorders. The results suggest that the incidence of seizures with meperidine is extremely small (0.4% of patients; 0.06% of admissions). The risk of seizures should not dissuade clinicians from using this drug.

PMID: 10456240, UI: 99385199

J Biol Chem 1999 Aug 27;274(35):24742-8

Effects of S-nitrosation on oxygen binding by normal and sickle cell hemoglobin.

Bonaventura C, Ferruzzi G, Tesh S, Stevens RD

Duke University Marine Biomedical Center, Nicholas School of the Environment Marine Laboratory, Beaufort, North Carolina 28516, USA.

S-Nitrosated hemoglobin (SNO-Hb) is of interest because of the allosteric control of NO delivery from SNO-Hb made possible by the conformational differences between the R- and T-states of Hb. To better understand SNO-Hb, the oxygen binding properties of S-nitrosated forms of normal and sickle cell Hb were investigated. Spectral assays and electrospray ionization mass spectrometry were used to quantify the degree of S-nitrosation. Hb A(0) and unpolymerized Hb S exhibit similar shifts toward their R-state conformations in response to S-nitrosation, with increased oxygen affinity and decreased cooperativity. Responses to 2, 3-diphosphoglycerate were unaltered, indicating regional changes in the deoxy structure of SNO-Hb that accommodate NO adduction. A cycle of deoxygenation/reoxygenation does not cause loss of NO or appreciable heme oxidation. There is, however, appreciable loss of NO and heme oxidation when oxygen-binding experiments are carried out in the presence of glutathione. These results indicate that the in vivo stability of SNO-Hb and its associated vasoactivity depend on the abundance of thiols and other factors that influence transnitrosation reactions. The increased oxygen affinity and R-state character that result from S-nitrosation of Hb S would be expected to decrease its polymerization and thereby lessen the associated symptoms of sickle cell disease.

PMID: 10455144, UI: 99386952

Pediatr Nephrol 1999 May;13(4):340-2

Parvovirus glomerulonephritis in a patient with sickle cell disease.

Tolaymat A, Al Mousily F, MacWilliam K, Lammert N, Freeman B

Nemours Children's Clinic and University of Florida/Jacksonville, 32207, USA.

A child with sickle cell disease developed glomerulonephritis 10 days following an aplastic crisis induced by human parvovirus B 19 infection. An initial kidney biopsy showed focal proliferative glomerulonephritis, and 1 year later was compatible with focal and segmental glomerulosclerosis. Renal tissue, tested by polymerase chain reaction, was positive for parvovirus, while the patient's blood was negative. For the first time a direct relationship has been demonstrated between parvovirus infection and glomerulonephritis.

PMID: 10454787, UI: 99314599

Occup Med (Lond) 1999 Jan;49(1):55-6

What are the implications of sickle cell anaemia?

Yardley-Jones A

Sickle Cell Trait is common in certain populations. The vast majority of individuals who possess combinations of these genes which cause variations in haemoglobin are asymptomatic. However, despite advances in treatment, health problems associated with homozygous inheritance can result in work-related performance issues. Such cases require individual risk assessments in relation to their jobs when considering fitness for work, rehabilitation and prevention of symptoms.

PMID: 10451589, UI: 99380888

Trans R Soc Trop Med Hyg 1999 Feb;93 Suppl 1:21-8

Variation of Plasmodium falciparum msp1 block 2 and msp2 allele prevalence and of infection complexity in two neighbouring Senegalese villages with different transmission conditions.

Konate L, Zwetyenga J, Rogier C, Bischoff E, Fontenille D, Tall A, Spiegel A, Trape JF, Mercereau-Puijalon O

Unite d'Immunologie Moleculaire des Parasites, Institut Pasteur, Paris, France.

To investigate the impact of transmission on the development of immunity to malaria and on parasite diversity, longitudinal surveys have been conducted for several years in Dielmo and Ndiop, 2 neighbouring Senegalese villages with holo- and mesoendemic transmission conditions, respectively. We analysed Plasmodium falciparum msp1 block 2 and msp2 genotypes of isolates collected from 58% of the Dielmo villagers during the same week as those studied recently from Ndiop. Allele frequencies differed in both villages, indicating considerable microgeographical heterogeneity of parasite populations. The complexity of the infections, estimated using individual or combined msp1 and msp2 genotyping, in Dielmo was more than double that in Ndiop and it was age-dependent in Dielmo but not in Ndiop. Thus, this study confirmed the influence of age on the complexity of asymptomatic malaria infections in a holoendemic area. The age distribution of complexity in Dielmo substantiates the interpretation that the number of parasite types per isolate reflects acquired antiparasite immunity. This cross-sectional survey also confirms that the sickle cell trait has no impact on complexity but influences the distribution of P. falciparum genotypes.

PMID: 10450422, UI: 99378916

Am J Dermatopathol 1999 Aug;21(4):384-6

Purpura as a cutaneous association of sickle cell disease.

Jones Wu S, Pellegrini AE

Department of Internal Medicine, The Ohio State University College of Medicine, 4731 University Hospitals Clinic, Columbus 43210, USA.

A common chronic feature of sickle cell disease is the presence of painful, punched-out leg ulcers. Other cutaneous findings in patients with homozygous sickle cell disease have not been described in the literature. We present a case of a 50-year-old black woman with sickle cell disease who was admitted for acute onset of arm and hip pain. After admission she deteriorated clinically, with multiorgan failure and mental status changes. Examination of the skin revealed erythematous papules and plaques with scaly centers and purpura on the upper trunk. The clinical differential diagnosis was vasculitis versus sepsis. Skin biopsy of two representative lesions was performed. Hematoxylin- and eosin-stained sections showed a superficial perivascular mixed inflammatory infiltrate with numerous eosinophils and extravasated erythrocytes, some of which exhibited bizarre morphology of sickled red blood cells. These findings indicated that the patient's cutaneous lesions, possibly multifactorial in origin, could be a component of her sickle cell crisis. This case is presented as an unusual one in which evaluation of erythrocyte morphology contributed to patient management and to emphasize the importance of examining erythrocyte morphology as a part of the histologic evaluation of stained tissue.

PMID: 10446783, UI: 99374449

Am J Physiol 1999 Aug;277(2 Pt 2):F271-6

Butyrate increases apical membrane CFTR but reduces chloride secretion in MDCK cells.

Moyer BD, Loffing-Cueni D, Loffing J, Reynolds D, Stanton BA

Department of Physiology, Dartmouth Medical School, Hanover, New Hampshire 03755, USA.

Sodium butyrate and its derivatives are useful therapeutic agents for the treatment of genetic diseases including urea cycle disorders, sickle cell disease, thalassemias, and possibly cystic fibrosis (CF). Butyrate partially restores cAMP-activated Cl(-) secretion in CF epithelial cells by stimulating DeltaF508 cystic fibrosis transmembrane conductance regulator (DeltaF508-CFTR) gene expression and increasing the amount of DeltaF508-CFTR in the plasma membrane. Because the effect of butyrate on Cl(-) secretion by renal epithelial cells has not been reported, we examined the effects of chronic butyrate treatment (15-18 h) on the function, expression, and localization of CFTR fused to the green fluorescent protein (GFP-CFTR) in stably transfected MDCK cells. We report that sodium butyrate reduced Cl(-) secretion across MDCK cells, yet increased apical membrane GFP-CFTR expression 25-fold and increased apical membrane Cl(-) currents 30-fold. Although butyrate also increased Na-K-ATPase protein expression twofold, the drug reduced the activity of the Na-K-ATPase by 55%. Our findings suggest that butyrate inhibits cAMP-stimulated Cl(-) secretion across MDCK cells in part by reducing the activity of the Na-K-ATPase.

PMID: 10444582, UI: 99375155

Br J Haematol 1999 Jul;106(1):178-81

Enhanced adherence of beta-thalassaemic erythrocytes to endothelial cells.

Hovav T, Goldfarb A, Artmann G, Yedgar S, Barshtein G

Department of Biochemistry, Hebrew University-Hadassah Medical School, Jerusalem, Israel.

The adherence of red blood cells (RBC) to endothelial cells (EC), shown to correlate with microvascular occlusion in sickle cell disease and malaria, is considered a major contributor to microcirculatory disorders. In the present study the adherence to EC was markedly enhanced with RBC from beta-thalassaemia major (TM) patients, and even more so with RBC from beta-thalassaemia intermedia (TI) patients (10-fold and 25-fold higher than normal, respectively). It is proposed that enhanced RBC/EC adherence may contribute to the microcirculatory disorders observed in thalassaemia, especially in TI patients who are particularly known to suffer from leg ulcers.

PMID: 10444184, UI: 99373568

East Afr Med J 1999 Apr;76(4):228-32

Antenatal haemoglobin profile at Korle-Bu Teaching Hospital.

Lassey AT, Klufio CA, Annan BD, Wilson JB

Department of Obstetrics and Gynaecology, University of Ghana Medical School, Accra.

OBJECTIVE: To determine the frequency of haemoglobin (Hb) measurement and some socio-demographic characteristics in women attending antenatal clinic. DESIGN: Prospective cross-sectional study. SETTING: Antenatal clinic, Korle-Bu Teaching Hospital. SUBJECTS: Nine hundred and thirty two pregnant mothers attending antenatal clinic at the hospital. Patients with sickle cell disease, thalassaemia, sickling test positive or unknown sickling status were excluded. MAIN OUTCOME MEASURES: Proportion of patients whose records showed various frequencies of Hb determinations and the proportion of those with anaemia at 26 weeks and 34 weeks gestations. RESULTS: One hundred and seventy five (18.8%) patients did not have antenatal Hb measurement; 248 (26.6%) had two, and 251 (26.9%) had more than two measurements. The mean of booking Hb was 10.6 + 1.53 gm/dl. Of the 458 subjects with reliable dates, 293 had their booking Hb measurement at < 26 weeks. For this sub-group the mean was 10.8 +/- 1.43 gm/dl. (22.5% were < 10 gm/dl). For 272 subjects with reliable dates whose last Hb measurement was at > 34 weeks, the mean last Hb was 11.0 +/- 1.37 gm/dl. (last Hb was < 10 gm/dl in 19.1%). Nulliparity and booking antenatal weight < 64.0 kg were significantly associated with Hb < 10 gm/dl at some time during pregnancy. CONCLUSION: Anaemia in pregnancy is common in this urban population. Combined effects of iron-folate supplementation, malaria chemoprophylaxis as well as early booking and a waiver of antenatal care user fees for needy patients are suggested as remedial measures.

PMID: 10442106, UI: 99370694

Presse Med 1999 Jul 3-10;28(24):1283-6

[Intracavernous injections of etilefrin: its efficacy in the treatment of priapism in sickle cell patients].

Gbadoe AD, Akakpo-Vidah A, Tsolenyanu E, Messie K, Atakouma DY, Segbena AY, Vovor A, Tekou HA, Assimadi JK

Service de pediatrie, CHU-Tokoin, Lome-Togo. adama.gbadoe@syfed.tg.refer.org

OBJECTIVE: To date, the treatment of priapism in sickle-cell patients has relied on measures aimed at lowering blood viscosity and acidosis and reducing the level of circulating hemoglobin S (hyperhydration, alkalinization, or exsanguinotransfusion...) Surgical cavernous-venous shunt may be proposed if conservative treatment fails. We examined the efficacy of intracavernous etilefrin injections. PATIENTS AND METHODS: From January 1996 through October 1997 (20 months) we performed 35 consecutive intracavernous injections of an alphastimulant, etilefrin in 7 sickle-cell patients (6 SS, 1 AS) who had experienced one or several episodes of low-flow priapism lasting 2 to 28 hours. RESULTS: Involution of the tumefaction was rapidly achieved in all cases. Tolerance was satisfactory, although some post-injection undesirable effects were reported by certain patients: moderate transient pain (2-5 min) in the retrosternal area, or intense pain in the penis (more intense than the priapism) which lasted 10 to 30 minutes. This work confirmed the earlier reported efficacy of intracavernous injections of etilefrin and suggests that the autonomous nervous system plays an important role in the genesis of this condition in sickle-cell patients. Patients should be informed about the observed undesirable effects which have not been reported previously in the literature. CONCLUSION: Etilefrin can be proposed as first line treatment for priapism in sickle-cell patients (at least in cases lasting less than 24 h). The pathogenic mechanism could involve neuromuscular dysfunction.

PMID: 10442057, UI: 99370645

Semin Cell Dev Biol 1999 Jun;10(3):259-65

Use of somatic cell fusion to reprogram globin genes.

Broyles RH

Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, OK, 73190, USA.

Somatic cell fusion@21S omatic cell fusion, pioneered by Henry Harris and Nils Ringertz over three decades ago,(1-5)has been used to illuminate many interesting cellular processes involving cytoplasmic-nuclear interactions.(6)Cell fusion creates a multinucleated cell surrounded by a single membrane, termed a heterokaryon if the fused cells originate from two or more tissues or species. If heterokaryons are maintained in culture for several days, some will form hybrids, which result when the chromosomes from both nuclei coalesce into one metaphase plate during mitosis, creating hybrid nuclei in the daughter cells. Heterokaryons and cell hybrids have been used to detect gene regulatory factors,(7)to show the extinction of one cellular phenotype and dominance of another,(8, 9)and to confer a new or added property on a recipient cell.(10)It is for the very daunting task of understanding development, with all its cell-specific gene activations and repressions, that cell fusion has been especially useful, particularly for understanding whether gene programming is plastic or irreversible.(11)@91Developmental hemoglobin switching@21During ontogeny, vertebrates of all classes undergo one or more hemoglobin (Hb) switches, typically an early switch from embryonic to fetal or larval Hbs, and a subsequent switch from fetal/larval to adult Hb.(12,13)By investigating these switches, in addition to understanding the mechanisms for gene regulation that lead to the orderly emergence of phenotypic characters, we may reap medical benefits from being able to partially or wholly reverse the fetal-to-adult Hb switch in humans with sickle cell disease or beta-thalassemias. Fetal hemoglobin (HbF), composed of alpha- and gamma-globin chains, when present in sufficient quantities, prevents sickling; and in the beta-thalassemias, the gamma chains replace the absent or markedly reduced beta-globin chains.(14)However, manipulation of a Hb switch may require knowing the correct combination of trans-acting factors and how they interact, problems yet to be elucidated. Copyright 1999 Academic Press.

PMID: 10441537, UI: 99373484

APMIS 1999 Jul;107(7):699-702

Complement haemolytic activity, circulating immune complexes and the morbidity of sickle cell anaemia.

Anyaegbu CC, Okpala IE, Aken'ova AY, Salimonu LS

Department of Haematology, Nnamdi Azikiwe University Hospital, Nnewi, Anambra State, Nigeria.

The aim of this study was to find out if the number of crises and complications of sickle cell anaemia (SCA) relate to complement function, or the levels of circulating immune complexes (CIC), complement factor B (Bf), C3 and C4. In 73 steady-state HbSS patients and 50 HbAA control subjects, we determined the haemolytic activity of the alternative pathway of complement (AP50), of the classical pathway (CH50); and the serum concentrations of Bf, C3, C4 and CIC. By clinical examination of each patient and review of the medical records, we determined the number of complications of SCA which had occurred and the mean number of crises per year over a minimum period of 3 years. The mean+/-SD AP50 for the patients (14+/-2 U/ml) was significantly lower than the control value of 16+/-3 U/ml (p<0.001). AP50 had a significant inverse correlation with the number of crises (r=-0.30, p<0.02). Mean+/-SD CIC in patients (0.45+/-0.38 g/l) was significantly higher than in controls: 0.24+/-0.15 g/l (p<0.002). CIC showed a significant direct correlation with the number of complications of SCA (r=+/-0.28, p<0.02). Mean+/-SD Bf in SCA patients (0.19+/-0.09) was higher than in controls (0.17+/-0.05). The difference reached marginal statistical significance (p=0.049). SCA patients and controls had no significant differences in CH50, C3 and C4. These parameters and Bf did not correlate with either the number of crises or complications. The mechanisms underlying the correlations observed in this study are yet to be fully elucidated.

PMID: 10440069, UI: 99366681

Blood 1999 Aug 15;94(4):1451-9

Altered hematopoiesis in murine sickle cell disease.

Blouin MJ, De Paepe ME, Trudel M

Institut de Recherches Cliniques de Montreal, Molecular Genetics and Development, Faculte de Medecine de L'Universite de Montreal, Montreal, Quebec, Canada.

We investigated the mechanisms of sickle cell disease (SCD) hematopoietic/erythropoietic defects using bone marrow, spleen, and/or peripheral blood from the transgenic SAD mouse model, which closely reproduces the biochemical and physiological disorders observed in human SCD. First, the erythropoietic lineage late precursors (polychromatophilic normoblasts to the intramedullary reticulocytes) of SAD mouse bone marrow were significantly altered morphologically. These anomalies resulted from high levels of hemoglobin polymers and were associated with increased cell fragmentation occurring during medullary endothelial migration of reticulocytes. Secondly, analysis of bone marrow erythropoiesis in earlier stages showed a marked depletion in SAD erythroid burst-forming units (BFU-E; of approximately 42%) and erythroid colony-forming units (CFU-E; of approximately 23%) progenitors, despite a significant increase in their proliferation, suggesting a compensatory mechanism. In contrast to the bone marrow progenitor depletion, we observed (1) a high mobilization/relocation of BFU-E early progenitors ( approximately 4-fold increase) in peripheral blood of SAD mice as well as of colony-forming units-granulocyte-macrophage (CFU-GM) and (2) a 7-fold increase of SAD CFU-E in the spleen. Third, and most importantly, SAD bone marrow multipotent cells (spleen colony-forming units [CFU-S], granulocyte-erythroid-macrophage-megakaryocyte colony-forming units [CFU-GEMM], and Sca(+)Lin(-)) were highly mobilized to the peripheral blood ( approximately 4-fold increase), suggesting that peripheral multipotent cells could serve as proliferative and autologous vehicles for gene therapy. Therefore, we conclude the following. (1) The abnormal differentiation and morphology of late nucleated erythroid precursors result in an ineffective sickle erythropoiesis and likely contribute to the pathophysiology of sickle cell disorders; this suggests that transfer of normal or modified SCD bone marrow cells may have a selective advantage in vivo. (2) A hematopoietic compensatory mechanism exists in SAD/SCD pathology and consists of mobilization of multipotent cells from the bone marrow to the peripheral blood and their subsequent uptake into the spleen, an extramedullary hematopoietic site for immediate differentiation. Altogether, these results corroborate the strong potential effectiveness of both autologous and allogeneic bone marrow transplantation for SCD hematopoietic therapy.

PMID: 10438733, UI: 99369692

Wkly Epidemiol Rec 1999 Jun 11;74(23):177-83

Pneumococcal vaccines. WHO position paper.

Pneumococcal diseases are a major public health problem all over the world. The etiological agent, Streptococcus pneumoniae (the pneumococcus) is surrounded by a polysaccharide capsule. Differences in the composition of this capsule permit the serological differentiation between about 90 capsular types, some of which are frequently associated with pneumococcal disease, others rarely. Invasive pneumococcal infections include pneumonia, meningitis and febrile bacteremia; among the common noninvasive manifestations are otitis media, sinusitis and bronchitis. At least 1 million children die of pneumococcal disease every year, most of these being young children in developing countries. In the developed world, elderly persons carry the major disease burden. Conditions associated with increased risk of serious pneumococcal disease include HIV infection, sickle-cell anaemia and a variety of chronic organ failures. Vaccination is the only available tool to prevent pneumococcal disease. The recent development of widespread microbial resistance to essential antibiotics underlines the urgent need for more efficient pneumococcal vaccines. Immunity following pneumococcal disease is directed primarily against the capsular serotype involved. The currently licensed pneumococcal vaccine is based on the 23 most common serotypes, against which the vaccine has an overall protective efficacy of about 60%-70%. Children aged < 2 years, and persons suffering from various states of immunodeficiency, for example HIV infection, do not consistently develop immunity following vaccination, thus reducing the protective value of the vaccine in some major target groups for pneumococcal disease. However, in the healthy elderly population the polysaccharide vaccine provides relatively efficient protection against invasive pneumococcal disease. Extensive clinical trials are now under way with a new generation of pneumococcal vaccines. These protein-polysaccharide combinations, known as conjugate vaccines, contain 7-11 selected polysaccharides bound to a protein carrier, and induce a T-cell dependent immune response. These vaccines are likely to be protective even in children aged < 2 years, and may reduce pneumococcal transmission through a herd effect.

PMID: 10437429, UI: 99366482

Br J Biomed Sci 1998 Dec;55(4):265-7

Haemorheological changes in sickle cell disease: measurement and significance.

Famodu AA, Halim NK, Odoemene DI, Eneh EE

Department of Haematology, Faculty of Medicine, University of Benin, Benin City, Nigeria.

PMID: 10436543, UI: 99365596

Acta Haematol 1999;101(4):178-84

Sickle-cell disease in Brazzaville, Congo: genetical, hematological, biochemical and clinical aspects.

Mouele R, Boukila V, Fourcade V, Feingold J, Galacteros F

Unite de Recherche en Genetique Moleculaire et Hematologie, INSERM U91, Hopital Henri-Mondor AP. HP, Creteil, France.

Clinical, hematological and molecular features of 116 unrelated sickle-cell anemia patients from Brazzaville were investigated. The mean age of the patients was 9.4 +/- 5.3 years. 232 beta(s)-chromosomes were haplotyped and almost all sickle cell anemia patients (91%) were homozygous for the Bantu haplotype. All hematological indices were similar for males and females. Mean hemoglobin (Hb) concentration was 6.6 +/- 1.4 g/dl. Fetal Hb (HbF) levels were from 1 to 28%, with a mean of 8.8 +/- 5.8%. There was a curvilinear relationship between %HbF and age suggesting that HbF level had a selective effect on the survival of patients. This effect was sex dependent. The (-alpha(3.7)) gene frequency was 0.45 and was not affected by stratification for age. Hematological characteristics of patients with (-alpha/alphaalpha, -alpha/-alpha) and without (alphaalpha/alphaalpha) the -alpha(3.7) alpha-thal-2 deletion showed trends similar to those reported in Jamaican and US sickle cell anemia patients. Hyperbilirubinemia (>38 micromol/l) was common and high lactic dehydrogenase (LDH) concentrations were recorded. Bilirubin concentrations for males and females were similar whereas those for LDH concentration were not. Hepatomegaly and splenomegaly were common. Splenomegaly was strongly associated with the -alpha(3.7) alpha-thal-2 deletion. These clinical and hematological observations indicate a more severe form of hemolytic disease in Congolese SS patients.

PMID: 10436298, UI: 99367273

J Pediatr Gastroenterol Nutr 1999 Aug;29(2):127-31

Effects of red blood cell transfusion on resting energy expenditure in adolescents with sickle cell anemia.

Harmatz P, Heyman MB, Cunningham J, Lee PD, Styles L, Quirolo K, Kopp-Hoolihan L, Ghiron J, Hintz RL, Vichinsky E

Department of Gastroenterology and Nutrition, Children's Hospital Oakland, California 94609, USA.

BACKGROUND: Previous studies indicate that resting energy expenditure is elevated in children with sickle cell anemia, possibly caused in part by hemolysis and increased erythropoietic activity. The purpose of the present investigation was to determine whether erythrocyte transfusion normalizes resting energy expenditure in sickle cell anemia. METHODS: Five adolescents with sickle cell anemia (12-16 years old; 4 boys, 1 girl) were studied before and 1 week after erythrocyte transfusion before elective surgery or at the initial transfusion for growth failure. Resting energy expenditure was measured by indirect calorimetry, and laboratory measures were determined by routine, validated methods. Data comparisons were by nonparametric analysis. RESULTS: After erythrocyte transfusion, total hemoglobin levels increased (difference (D) = 15 g/l; p < 0.05), whereas hemoglobin S (D = -0.36; p < 0.05) and reticulocyte count (D = -0.12; p < 0.05) decreased. Mean pretransfusion resting energy expenditure was elevated to 124% above predicted levels (p < 0.05) and increased further to 134% above prediction (p < 0.05 vs. pretransfusion levels). Plasma triiodothyronine (T3) levels increased (D = 0.17 nmol/l; p < 0.05), reverse T3 (rT3) levels tended to decline (D = -0.04 nmol/l; p = 0.14), and rT3/T3 decreased (D = -0.03; p < 0.05). Plasma insulin-like growth factor-I (IGF-I) levels were low-normal before transfusion and did not change, despite the change in resting energy expenditure. CONCLUSIONS: The results confirm that resting energy expenditure is elevated in patients with sickle cell anemia. However, resting energy expenditure further increased after transfusion, despite decreased erythropoietic activity. A posttransfusion decrease in rT3/T3 may contribute to the increased resting energy expenditure. That there was no change in IGF-I implies that the growth hormone-IGF system is not involved in posttransfusion regulation of resting energy expenditure. Therefore, our data are not consistent with the hypothesis that increased resting energy expenditure in sickle cell anemia is directly related to erythropoietic activity. The mechanisms by which resting energy expenditure increases after transfusion in sickle cell anemia require additional investigation.

PMID: 10435647, UI: 99362000

Prog Urol 1999 Jun;9(3):496-501

[No title available].

Falandry L

Service d'Urologie, Centre Hospitalier Universitaire de Niamey, Niger.

OBJECTIVES: To define, based on the author's experience and the data of the literature, a simple and rigorous practical approach to the management of priapism in developing countries, for which the therapeutic approach is controversial and difficult due to the rarity of this condition. MATERIAL AND METHODS: The reported series is based on 56 cases of priapism in black patients (49 adults and 7 children), observed and treated by the same operator over an 18-year period in Burkina (n = 8) and then in Chad (n = 12), Gabon (n = 19) and Niger (n = 17). The pathophysiology and aetiologies are reviewed. RESULTS: All patients treated surgically underwent various surgical techniques for diversion of the corpora cavernosa. In this group of 51 reported cases, there were 17 successes (33.3%), 5 partial results (9.8%) and 29 failures (56.8%). The overall immediate success rate, resulting in detumescence, was 36/51 (70%). These initial successes almost exclusively concerned patients treated by unilateral cavernoglandular shunt within an interval not exceeding 2 days. Although the long-term results, all treatments combined, were disappointing (56.8% of patients with sufficient follow-up are impotent), creation of a unilateral cavernoglandular fistula to the glans, based on Al Ghorab's technique, appeared to provide the best results with a success rate of 52%, i.e. 13/25 cases of priapism correctly followed. CONCLUSION: Except in the context of sickle-cell anaemia, in which concomitant aetiological treatment can be proposed, only emergency surgery is effective to avoid secondary impotence. The unilateral cavernoglandular shunt is extremely simple and, according to the author, remains the best procedure.

PMID: 10434324, UI: 99363168

Biochim Biophys Acta 1999 Aug 5;1428(2-3):381-7

The reaction of deoxy-sickle cell hemoglobin with hydroxyurea.

Kim-Shapiro DB, King SB, Shields H, Kolibash CP, Gravatt WL, Ballas SK

Department of Physics, Wake Forest University, Winston-Salem, NC, USA.

In addition to its capacity to increase fetal hemoglobin levels, other mechanisms are implicated in hydroxyurea's ability to provide beneficial effects to patients with sickle cell disease. We hypothesize that the reaction of hemoglobin with hydroxyurea may play a role. It is shown that hydroxyurea reacts with deoxy-sickle cell hemoglobin (Hb) to form methemoglobin (metHb) and nitrosyl hemoglobin (HbNO). The products of the reaction as well as the kinetics are followed by absorption spectroscopy and electron paramagnetic resonance (EPR) spectroscopy. Analysis of the kinetics shows that the reaction can be approximated by a pseudo-first order rate constant of 3.7x10(-4) (1/(s.M)) for the disappearance of deoxy-sickle cell hemoglobin. Further analysis shows that HbNO is formed at an observed average rate of 5.25x10(-5) (1/s), three to four times slower than the rate of formation of metHb. EPR spectroscopy is used to show that the formation of HbNO involves the specific transfer of NO from the NHOH group of hydroxyurea. The potential importance of this reaction is discussed in the context of metHb and HbNO being able to increase the delay time for sickle cell hemoglobin polymerization and HbNO's vasodilating capabilities through conversion to S-nitrosohemoglobin.

PMID: 10434057, UI: 99365029

J Emerg Med 1999 Jul-Aug;17(4):625-30

Management of sickle cell pain crisis in the emergency department at teaching hospitals.

Silbergleit R, Jancis MO, McNamara RM

Department of Surgery, University of Michigan, Ann Arbor 48109-0303, USA.

The purpose of this study is to determine the frequency and variety of strategies being used in the Emergency Department (ED) management of sickle cell pain crisis (SCPC). One thousand randomly selected academic emergency physicians received a multiple-choice survey; 549 (55%) completed the survey. Forty-five percent of respondents treat patients with SCPC every week or almost every shift. Twenty percent use protocols for management of SCPC. Respondents consider pain refractory to outpatient treatment if it is persistent after two (23%) or three (53%) doses of parenteral analgesic. Meperidine or morphine is the most common initial analgesic. In the routine management of uncomplicated SCPC, i.v. analgesics, i.v. hydration, oxygen therapy, and complete blood counts are often or always used by 67, 71, 66, and 82% of respondents, respectively. Some patterns in the diagnostic and therapeutic management of patients with SCPC in the ED are identified, but overall practice is highly variable. Some popular elements of care are divergent from those suggested by the scientific literature.

PMID: 10431951, UI: 99358898

Rev Neurol (Paris) 1999 May;155(5):351-6

[No title available].

Lannuzel A, Salmon V, Mevel G, Malpote E, Rabier R, Caparros-Lefebvre D

Service de Neurologie, Centre Hospitalier Universitaire de Pointe-a-Pitre, Faculte Antilles-Guyane, Guadeloupe. lannuzel@ais.gp

Sickle cell disease (homozygotes SS) is known as a risk factor for both ischemic and hemorrhagic stroke, but heterozygotes AS seem to be spared. We carried out a retrospective study to assess the main risk factors and the influence of hemoglobine abnormalities on stroke in Guadeloupe. The percentages of AS, AC, and AA on 295 patients admitted for stroke were compared to the prevalence obtained on 72,000 newborn babies. Ischemic, hemorrhagic stroke and stroke complications represented respectively 83 p. 100, 10 p. 100 and 7 p. 100. Seventy one per 100 of patients had hypertension and 19 p. 100 had an association of diabetes and hypertension. The percentage of heterozygotes AS was significantly lower in the group with ischemic stroke (4 p. 100) in comparison with controls (8.5 p. 100), while AS were more represented in hemorrhagic stroke (16 p. 100). The risk of hemorrhagic stroke was 10 fold higher in AS patients admitted for stroke and the risk of ischemic stroke was reduced by 15 fold. These data suggest that the sickle cell trait could be associated to red cell and/or endothelial specificities which could prevent for ischemic stroke. The influence of AS heterozygotie on the occurrence of stroke needs to be examined in a longitudinal, prospective study.

PMID: 10427598, UI: 99356605

Chest 1999 Jul;116(1 Suppl):92S

Transgenic HbS mouse neutrophils in increased susceptibility to acute lung injury: implications for sickle acute chest syndrome.

Hsu L, McDermott T, Brown L, Aguayo SM

Atlanta Veterans Administration Medical Center and Emory University, GA, USA.

PMID: 10424612, UI: 99351898

An Med Interna 1999 Jun;16(6):325

[Beta thalassemia and hemoglobin S].

Rodriguez-Cuartero A, Garcia-Vera E, Salas-Galan A

Publication Types:

• Letter

PMID: 10422311, UI: 99351211

Arch Pathol Lab Med 1999 Aug;123(8):745-746

Acute Lymphoblastic Leukemia in Sickle Cell Disease.

Sotomayor EA, Glasser L

Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI.

PMID: 10420237

J Biol Chem 1999 Jul 30;274(31):21763-8

Repairing the sickle cell mutation. I. Specific covalent binding of a photoreactive third strand to the mutated base pair.

Broitman S, Amosova O, Dolinnaya NG, Fresco JR

Department of Molecular Biology, Princeton University, Princeton, New Jersey 08544, USA.

A DNA third strand with a 3'-psoralen substituent was designed to form a triplex with the sequence downstream of the T.A mutant base pair of the human sickle cell beta-globin gene. Triplex-mediated psoralen modification of the mutant T residue was sought as an approach to gene repair. The 24-nucleotide purine-rich target sequence switches from one strand to the other and has four pyrimidine interruptions. Therefore, a third strand sequence favorable to two triplex motifs was used, one parallel and the other antiparallel to it. To cope with the pyrimidine interruptions, which weaken third strand binding, 5-methylcytosine and 5-propynyluracil were used in the third strand. Further, a six residue "hook" complementary to an overhang of a linear duplex target was added to the 5'-end of the third strand via a T(4) linker. In binding to the overhang by Watson-Crick pairing, the hook facilitates triplex formation. This third strand also binds specifically to the target within a supercoiled plasmid. The psoralen moiety at the 3'-end of the third strand forms photoadducts to the targeted T with high efficiency. Such monoadducts are known to preferentially trigger reversion of the mutation by DNA repair enzymes.

PMID: 10419490, UI: 99348307

Clin Pediatr (Phila) 1999 Jul;38(7):401-6

Back pain in children who present to the emergency department.

Selbst SM, Lavelle JM, Soyupak SK, Markowitz RI

Division of Emergency Medicine, Children's Hospital of Philadelphia, USA.

The purpose of this study was to identify the causes and epidemiology of back pain in children who present to the emergency department. All children who presented to an urban pediatric emergency department (ED) during a 1-year period with the chief complaint of back pain were examined and evaluated with a uniform questionnaire. This was completed at the time of the ED visit in 48%, and within 48 hours in 52%. During a 1-year period, 225 children with a complaint of back pain were evaluated. The mean age was 11.9 +/- 4 years and 60% were female. Onset was acute (< or = 2 days) in 59%, and chronic (> or = 4 weeks) in only 11.6%. Pain awakened children from sleep in 47%, and caused 52% to miss school or work. The most common diagnoses were direct trauma (25%), muscle strain (24%), sickle cell crises (13%), idiopathic (13%), urinary tract infection (5%), and viral syndrome (4%). Radiographs of the back were rarely helpful. About 5% required hospital admission; one half of these were attributed to sickle cell crises. We conclude that back pain is an uncommon reason for children to present to an emergency department. When present, pediatric back pain is most often musculoskeletal, associated with an acute infectious illness or a traumatic event. Although the etiology is rarely serious, back pain often affects the daily activities of symptomatic children.

PMID: 10416096, UI: 99344585

Rev Paul Med 1999 Jan 7;117(1):38-9

Delayed hemolytic transfusion reaction presenting as a painful crisis in a patient with sickle cell anemia.

Fabron Junior A, Moreira Junior G, Bordin JO

Universidade Federal de Sao Paulo/Escola Paulista de Medicina, Brazil.

CONTEXT: Patients with sickle cell anemia (SCA) are frequently transfused with red blood cells (RBC). Recently we reported that the calculated risk of RBC alloimmunization per transfussed unit in Brazilian patients with SCA is 1.15%. We describe a delayed hemolytic transfusion reaction (DHTR) presenting as a painful crisis in a patient with SCA. CASE REPORT: A 35-year-old Brazilian female with homozygous SCA was admitted for a program of partial exchange transfusion prior to cholecystectomy. Her blood group was O RhD positive and no atypical RBC alloantibody was detected using the indirect antiglobulin technique. Pre-transfusional hemoglobin (Hb) was 8.7 g/dL and isovolumic partial exchange transfusion was performed using 4 units of ABO compatible packed RBC. Five days after the last transfusion she developed generalized joint pain and fever of 39 degrees C. Her Hb level dropped from 12.0 g/dL to 9.3 g/dL and the unconjugated bilirrubin level rose to 27 mmol/L. She was jaundiced and had hemoglobinuria. Hemoglobin electrophoresis showed 48.7% HbS, 46.6% HbA1, 2.7% HbA2, and 2.0% HbF. The patient's extended RBC phenotype was CDe, K-k+, Kp(a-b+), Fy(a-b-), M+N+s+, Le(a+b-), Di(a-). An RBC alloantibody with specificity to the Rh system (anti-c, titer 1:16.384) was identified by the indirect antiglobulin test. The Rh phenotype of the RBC used in the last packed RBC transfusion was CcDEe. The patient was discharged, asymptomatic, 7 days after admission.

PMID: 10413970, UI: 99342375

Biochemistry 1999 Jul 20;38(29):9549-9555

A Biochemical and Biophysical Characterization of Recombinant Mutants of Fetal Hemoglobin and Their Interaction with Sickle Cell Hemoglobin(,).

Larson SC, Fisher GW, Ho NT, Shen TJ, Ho C

Department of Biological Sciences and Center for Light Microscope Imaging and Biotechnology, Carnegie Mellon University, Pittsburgh, Pennsylvania 15213.

Three recombinant mutants of human fetal hemoglobin (Hb F) have been constructed to determine what effects specific amino acid residues in the gamma chain have on the biophysical and biochemical properties of the native protein molecule. Target residues in these recombinant fetal hemoglobins were replaced with the corresponding amino acids in the beta chain of human normal adult hemoglobin (Hb A). The recombinant mutants of Hb F included rHb F (gamma112Thr --> Cys), rHb F (gamma130Trp --> Tyr), and rHb F (gamma112Thr --> Cys/gamma130Trp --> Tyr). Specifically, the importance of gamma112Thr and gamma130Trp to the stability of Hb F against alkaline denaturation and in the interaction with sickle cell hemoglobin (Hb S) was investigated. Contrary to expectations, these rHbs were found to be as stable against alkaline denaturation as Hb F, suggesting that the amino acid residues mentioned above are not responsible for the stability of Hb F against the alkaline denaturation as compared to that of Hb A. Sub-zero isoelectric focusing (IEF) was employed to investigate the extent of hybrid formation in equilibrium mixtures of Hb S with these hemoglobins and with several other hemoglobins in the carbon monoxy form. Equimolar mixtures of Hb A and Hb S and of Hb A(2) and Hb S indicate that 48-49% of the Hb exists as the hybrid tetramer, which is in agreement with the expected binomial distribution. Similar mixtures of Hb F and Hb S contain only 44% hybrid tetramer. The results for two of our recombinant mutants of Hb F were identical to the results for mixtures of Hb F and Hb S, while the other mutant, rHb F (gamma130Trp --> Tyr), produced 42% hybrid tetramer. The sub-zero IEF technique discussed here is more convenient than room-temperature IEF techniques, which require Hb mixtures in the deoxy state. These recombinant mutants of Hb F were further characterized by equilibrium oxygen binding studies, which indicated no significant differences from Hb F. While these mutants of Hb F did not have tetramer-dimer dissociation properties significantly altered from those of Hb F, future mutants of Hb F may yet prove useful to the development of a gene therapy for the treatment of patients with sickle cell anemia.

PMID: 10413533

J Soc Pediatr Nurs 1999 Apr-Jun;4(2):61-73

Practice guidelines for the assessment of children with sickle cell pain.

Beyer JE, Platt AF, Kinney TR, Treadwell M

University of Missouri-Kansas City, USA. beyerj@smtpgate.umkc.edu

ISSUES AND PURPOSE: Pain is the most frequent and important problem for children with sickle cell disease (SCD), but it has been undertreated and understudied. A multidisciplinary group of healthcare providers, academics, and people with SCD and their families met to (1) examine the pain of vaso-occlusive events (VOE) in children and adults with SCD and (2) reach consensus about necessary improvements in care. CONCLUSIONS: Accurate assessment of pain is at the crux of effective care for children with VOE. This requires a trusting interactive relationship among patient, family, and healthcare team. Comprehensive pain assessment is a lifelong process in need of continued updating. PRACTICE IMPLICATIONS: Children with SCD seek treatment from nurses in many settings. Traditional care has been frustrating to both families and care providers. Children and adolescents with SCD pain would benefit from nursing care that considers patients' perspectives about pain and comfort as key determinants for treatment. A unified approach to pain assessment may be a significant factor in improving pain control.

PMID: 10410355, UI: 99338544

Biochim Biophys Acta 1999 Jul 13;1432(2):333-49

NMR study of the sites of human hemoglobin acetylated by aspirin.

Xu AS, Macdonald JM, Labotka RJ, London RE

Laboratory of Structural Biology, National Institute of Environmental Health Sciences, P.O. Box 12233, Research Triangle Park, NC 27709-2233, USA.

Acetylation of hemoglobin by aspirin and other acetylating agents has been used to generate hemoglobin analogs with altered structural and functional properties, and may prove useful in the treatment of sickle cell disease. We have studied the acetylation of human hemoglobin using [1'-(13)C]acetylsalicylic acid in combination with two-dimensional HMQC and HSQC NMR analysis. The spectra of the acetylated hemoglobin exhibit a number of well resolved resonances. Several spectral assignment strategies were used: blocking the 2, 3-DPG binding site non-covalently with inositol hexaphosphate or covalently with a cross-linking agent, selective carbamylation of the N-terminal valine amino groups with cyanate, spin-labeling the hemoglobin at betaCys93, and analysis of a hemoglobin triple mutant: betaV1MH2DeltaK144R, in which betaLys144 is replaced by an arginine residue. These studies support the conclusion that the most rapidly acetylated residue is betaLys82 rather than betaLys144, as previously reported. Further, it is apparent that acetyl betaLys82 can give rise to several resonances due to additional acetylation of betaLys82' or other nearby residues. An additional assignment strategy involving comparison of the chemical shifts of the acetyl resonances observed for adducts of diamagnetic carbonmonoxyhemoglobin with the shifts observed in paramagnetic cyanomethemoglobin provides information about the location of the acetyl derivatives relative to the heme irons. This approach is limited, however, by the lack of well defined structural information for the lysine residues on the protein surface. Additional tentative assignments have also been made, using the above approaches.

PMID: 10407155, UI: 99337480

J Matern Fetal Med 1999 Jul-Aug;8(4):196-9

Extensive spontaneous retroperitoneal hemorrhage: an unusual complication of heparin anticoagulation during pregnancy.

Sherer DM, Dayal AK, Schwartz BM, Oren R, Abulafia O

Department of Obstetrics & Gynecology and Women's Health, Montefiore Medical Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

A 27-year-old patient at 13 weeks' gestation maintained on subcutaneous heparinization due to hemoglobin S and hemoglobin C (SC) sickle cell disease and previous splenic vein thrombosis presented with spontaneous acute onset of severe left lower abdominal and groin pain. The pain, which radiated to the anterior aspect of the thigh, was associated with nausea and vomiting and was exacerbated by extension of the left lower extremity. The patient was hemodynamically stable, yet during the first 24 h of hospitalization a marked decrease in hematocrit from 29% to 22% occurred. Contrast computed tomography (CT) revealed an extensive abdominal-pelvic, retroperitoneal hematoma extending approximately 15 cm in length from above L5 cephalad to below the greater trochanter of the left femur caudally. The retroperitoneal hemorrhage self-tamponaded and did not require surgical management. The dosage of heparin was decreased and maintained with appropriate activated partial prothrombin (aPTT) levels. To our knowledge, this is the first report of a spontaneous retroperitoneal hemorrhage complicating heparin anticoagulation in pregnancy. Unusual hemorrhagic complications of anticoagulation therapy are discussed.

PMID: 10406306, UI: 99332939

Anaesthesia 1999 Jun;54(6):614-6

Amniotic fluid embolism in a patient with SC sickle cell disease.

Sanders GM

Publication Types:

• Letter

PMID: 10404193, UI: 99333666

Med Trop (Mars) 1998;58(4):403-7

[Pleuropulmonary manifestations of salmonellosis].

Hovette P, Camara P, Petrognani R, Donzel C

Service Medicaux, l'Hopital Principal de Dakar, Senegal.

Salmonella infections are widespread particularly in tropical zones. Each year, 12.5 million cases of typhoid fever are reported with an incidence of 540 cases for every 100,000 inhabitants in developing countries versus 0.2 cases in industrialized countries. Pleuropulmonary manifestations constitute the most common extra-intestinal manifestation of salmonella infection. Counts are usually carried out in the digestive tract. Respiratory tract manifestations result from blood-borne diffusion from mesenteric lymph nodes, but gastroenteritis goes unnoticed in 2 of 3 cases. Predisposing factors are frequent including cancer, previous graft placement and immunosuppressant therapy, sickle cell disease, alcohol abuse, and pre-existing pulmonary disease. Clinical manifestations are usually acute but subacute forms cannot be ruled out. Cough is a common symptom observed in 25% of patients with typhoid fever. Pneumonia is uncommon overall (1%) but occurs in 50% of patients with pleural effusion, empyema, lung abscess, or bronchopleural fistula. A few cases of adult respiratory distress syndrome have been described in the literature. Recognition is important since these manifestations may signal previously unsuspected underlying pulmonary disease. Treatment requires appropriate antimicrobial therapy and close surveillance to prevent recurrence or complications.

Publication Types:

• Review
• Review, tutorial

PMID: 10399702, UI: 99327901

Am J Hematol 1999 Jul;61(3):194-202

Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD).

Prasad AS, Beck FW, Kaplan J, Chandrasekar PH, Ortega J, Fitzgerald JT, Swerdlow P

Department of Medicine, Division of Hematology-Oncology and the Barbara Ann Karmanos Cancer Institute, Wayne State University, School of Medicine, Detroit, Michigan, USA.

Zinc deficiency is a common nutritional problem in adult sickle-cell disease (SCD) patients. Hyperzincuria and increased requirement of zinc due to continued hemolysis in SCD are probable bases for zinc deficiency in these patients. Zinc deficiency affects adversely T-helper1 (TH1) functions and cell mediated immunity and interleukin (IL)-2 production is decreased in zinc deficient subjects. We hypothesized that zinc supplementation will improve T-helper1 function and decrease incidence of infections in patients with SCD. We tested this hypothesis in 32 SCD subjects who were divided in three groups (Grs A, B, and C). Grs A (n = 11) and B (n = 10) were zinc deficient based on cellular zinc criteria and Gr C (n = 11) were zinc sufficient. Gr A subjects were observed for 1 year (baseline), following which they received zinc acetate (50 to 75 mg of elemental zinc orally daily) for 3 years. Gr B subjects were observed for 1 year (baseline), following which they received placebo for 1 year and then switched to zinc supplementation (50 to 75 mg of elemental zinc orally daily) for 2 years. Gr C subjects did not receive any intervention inasmuch as they were zinc sufficient. Prolonged zinc supplementation resulted in an increase in lymphocyte and granulocyte zinc (P = 0.0001), and an increase in interleukin-2 production (P = 0.0001), decreased incidence of documented bacteriologically positive infections (P = 0.0026), decreased number of hospitalizations and decreased number of vaso-occlusive pain crisis (P = 0.0001). The predominant pathogens isolated were staphylococci and streptococci involving the respiratory tract and aerobic gram-negative bacteria, particularly Escherichia coli, involving the urinary tract. Further confirmation of our observations will require prospective studies of zinc supplementation in a larger number of SCD patients. Copyright 1999 Wiley-Liss, Inc.

Publication Types:

• Clinical trial
• Controlled clinical trial

PMID: 10398312, UI: 99327136

J Dev Behav Pediatr 1999 Jun;20(3):157-63

Psychosocial adjustment of children with chronic illness: an evaluation of three models.

Gartstein MA, Short AD, Vannatta K, Noll RB

Division of Hematology/Oncology, Children's Hospital Medical Center, Cincinnati, Ohio 45229-3039, USA.

This study was designed to assess social, emotional, and behavioral functioning of children with chronic illness and to evaluate three models addressing the impact of chronic illness on psychosocial functioning: discrete disease, noncategorical, and mixed. Families of children with cancer, sickle cell disease, hemophilia, and juvenile rheumatoid arthritis participated, along with families of classroom comparison peers without a chronic illness who had the closest date of birth and were of the same race and gender (COMPs). Mothers, fathers, and children provided information regarding current functioning of the child with chronic illness or the COMP child. Child Behavior Checklist and Children's Depression Inventory scores were examined. Results provided support for the noncategorical model. Thus, the mixed model evaluated in this study requires modifications before its effectiveness as a classification system can be demonstrated.

PMID: 10393072, UI: 99320243

Am Fam Physician 1999 Jun;59(11):3153-4

Chronic non-healing ulcers.

Shekarappa RJ, Ruiz-Montero J

Department of Internal Medicine, Cook County Hospital, Chicago, IL 60612, USA.

PMID: 10392596, UI: 99319767

Pediatr Emerg Care 1999 Jun;15(3):179-82

Effect of ketorolac in pediatric sickle cell vaso-occlusive pain crisis.

Hardwick WE Jr, Givens TG, Monroe KW, King WD, Lawley D

University of Alabama School of Medicine, Birmingham, USA.

BACKGROUND: Ketorolac is a parenteral, nonsteroidal analgesic that does not have a narcotic's risks of respiratory depression, hypotension, or dependence. Its usefulness in providing pain relief in pediatric patients with acute vaso-occlusive crisis of sickle cell disease has not been studied to date. METHODS: Twenty-nine patients with sickle cell disease between the ages of 5 and 18 years who presented to The Children's Hospital of Alabama emergency department (ED) with 41 distinct episodes of acute vaso-occlusive pain crisis were enrolled prospectively and randomized to receive either 0.9 mg/kg intravenous (IV) ketorolac or placebo in a double-blind fashion. All patients also received IV fluids and an initial 0.1 mg/kg of IV morphine. Subsequent standardized doses of morphine were given every 2 hours over a 6-hour observation period based upon severity of pain as scored by a 10-cm linear visual analog scale (VAS). Vital signs and pain severity were recorded initially and assessed hourly. Disposition was made at the end of the observation period. RESULTS: Patients receiving ketorolac and those receiving placebo were of similar age, weight, gender, number of prior ED visits, number of prior hospital admissions, duration of pain prior to presentation, and initial pain score. The total dose of morphine received, reduction in severity of pain as measured by VAS, rate of hospital admission, and rate of return to the ED for discharged patients did not differ significantly between the two groups. CONCLUSION: We were unable to demonstrate a synergistic analgesic effect for ketorolac in the treatment of pain from acute vaso-occlusive crisis in pediatric sickle cell disease. Further investigations involving larger samples of sickle cell patients may be needed to further define a role for ketorolac in the acute management of sickle cell vaso-occlusive pain.

Publication Types:

• Clinical trial
• Randomized controlled trial

PMID: 10389953, UI: 99316815

Blood Cells Mol Dis 1999 Apr;25(2):110-9

Anti-beta s-ribozyme reduces beta s mRNA levels in transgenic mice: potential application to the gene therapy of sickle cell anemia.

Alami R, Gilman JG, Feng YQ, Marmorato A, Rochlin I, Suzuka SM, Fabry ME, Nagel RL, Bouhassira EE

Department of Medicine, Albert Einstein College of Medicine, Bronx, New York 10461, USA.

Our current strategy for gene therapy of sickle cell anemia involves retroviral vectors capable of transducing "designer" globin genes that code for novel anti-sickling globins (while resisting digestion by a ribozyme), coupled with the expression of a hammerhead ribozyme that can selectively cleave the human beta s mRNA. In this report, we have tested in vivo an anti-beta s hammerhead ribozyme embedded within a cDNA coding for the luciferase reporter gene driven by the human beta-globin promoter and hyper-sensitive sites 3 and 4 of the locus control region. We have created mice transgenic for this luciferase-ribozyme construct and bred the ribozyme transgene into mice that were already transgenic for the human beta s gene. We then measured expression of the beta s transgene at the protein and RNA levels by HPLC and primer extension. The presence of the ribozyme was associated with a statistically significant reduction in the level of beta s mRNA in spleen stress reticulocytes (from 60.5 +/- 4.1% to 52.9 +/- 4.2%) and in the percentage of beta s globin chains in very young mice (from 44.5 +/- 0.6% to 40.8 +/- 0.7%). These results demonstrate that it is possible to decrease the concentration of beta s chains and mRNA with the help of a hammerhead ribozyme. While the enormous amount of globin mRNA in reticulocytes is a challenge for ribozyme technology, the exquisite dependence of the delay time for formation of Hb S nuclei on the concentration of Hb S in red blood cells suggests that even a modest reduction in Hb S concentration would have therapeutic value.

PMID: 10389593, UI: 99317824

Curr Opin Ophthalmol 1998 Dec;9(6):111-5

Ocular manifestations of pediatric disease.

Kelly CJ, Calhoun JH

Pediatric Ophthalmology Service, Wills Eye Hospital, Philadelphia, PA 19107, USA.

A review of the ocular manifestations of pediatric disease is in some ways a review of pediatrics itself. A paper this size cannot hope to be comprehensive in scope or encyclopedic in detail. Instead, we have chosen to touch on recent developments in pediatrics that we feel may be of particular interest to the ophthalmologist, as well as certain areas of pediatric ophthalmology that make it clear that a child's ocular disease takes place in the larger context of the growing child.

Publication Types:

• Review
• Review, tutorial

PMID: 10387330, UI: 99260079

Am Heart J 1999 Jul;138(1 Pt 2):S1-5

Potential non-glycoprotein IIb/IIIa effects of abciximab.

Coller BS

Samuel Bronfman Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.

The antithrombotic effect of abciximab is believed to be primarily due to its blockade of platelet glycoprotein IIb/IIIa receptors, leading to the inhibition of platelet aggregation. Studies have, however, identified that antibody 7E3, the parent molecule of abciximab, and/or abciximab itself, binds to both "activated" alphaMbeta2 receptors and alphaVbeta3 receptors. Because alphaMbeta2 receptors are present on granulocytes and monocytes, cells that have been implicated in contributing to atherosclerosis, intimal hyperplasia after vascular injury, reperfusion injury, and thrombin generation, it is possible that some of abciximab's effects relate to this reactivity. Similarly, because alphaVbeta3 has been implicated in platelet adhesion to osteopontin, intimal hyperplasia after vascular injury, and platelet-mediated thrombin generation, it is possible that some of abciximab's beneficial effects relate to this reactivity. Blockade of alphaVbeta3 receptors may also be beneficial in other disease states because, in animal models, such blockade inhibits tumor angiogenesis and sickle cell adhesion to blood vessel endothelium. Despite these intriguing observations, there are no direct data to support any beneficial roles or any unwanted side effects related to the reactivities of abciximab with "activated" alphaMbeta2 or alphaVbeta3 receptors.

Publication Types:

• Review
• Review, tutorial

PMID: 10385784, UI: 99315112

J Lab Clin Med 1999 Jan;133(1):15-22

Benign ethnic neutropenia: what is a normal absolute neutrophil count?

Haddy TB, Rana SR, Castro O

Department of Pediatrics and Child Health and the Sickle Cell Center, Howard University College of Medicine, Washington, District of Columbia, USA.

Approximately 25% to 50% of persons of African descent and some ethnic groups in the Middle East have benign ethnic neutropenia, with low leukocyte and neutrophil counts. It is important to recognize the existence of this condition, the most common form of neutropenia throughout the world, and thus avoid both under-and overevaluation. Although there is no scientific basis for an absolute neutrophil count of 1.5x10(9)/L to be considered minimal, counts below this level are empirically regarded as inadequate in persons of all ethnic groups who are above the age of 1 year. Many individuals, however, maintain consistently low absolute neutrophil counts without evidence of increased susceptibility to infection or any other adverse effect. The important determination is not how many neutrophils are present in the peripheral blood, but whether the bone marrow is able to produce enough normally functioning cells when needed. A description of benign ethnic neutropenia, as set forth in this review, suggests that the lower limit now considered acceptable for the absolute neutrophil count should be readjusted downward for all ethnic groups.

Publication Types:

• Review
• Review, academic

PMID: 10385477, UI: 99312203

Ann Emerg Med 1999 Jul;34(1):64-9

Clinician assessment for acute chest syndrome in febrile patients with sickle cell disease: is it accurate enough?

Morris C, Vichinsky E, Styles L

Departments of Emergency Medicine and Hematology/Oncology, Children's Hospital Oakland, Oakland, CA, USA. lstyles@lanminds.com

STUDY OBJECTIVE: To determine whether the use of empiric chest radiography (CXR) is of significant value in detecting clinically unsuspected acute chest syndrome (ACS) in febrile patients with sickle cell disease (SCD). METHODS: Patients with SCD presenting to the emergency department and hematology clinic with temperature greater than or equal to 38 degrees C were prospectively evaluated using a physician-completed questionnaire. The questionnaire included inquiries into the patient's physical signs and symptoms and the physician's clinical impression for the presence of ACS. The questionnaire was completed before obtaining CXR results in all patients. RESULTS: Seventy-three patients with SCD with 96 febrile events were evaluated over a 1-year period. Twenty-four percent (23/96) of the patients had CXR evidence of ACS. On the basis of the questionnaire data, 61% (14/23) of ACS cases were not clinically suspected by the evaluating physician before obtaining CXR. Comparing the patients with and without ACS revealed that, with the exception of splinting (4/23 [17%] versus 0/73 [0%]), no symptom or physical examination finding helped to identify which patients had ACS. Fifty-seven percent of patients with ACS had completely normal findings on physical examination. The presentation of patients with clinically detected versus clinically unsuspected ACS also did not differ significantly. Length of hospitalization, oxygen use, and need for transfusion were the same in both the unsuspected and detected ACS groups. Overall physician sensitivity for predicting ACS was only 39%, and diagnostic accuracy did not improve significantly with increasing levels of pediatric training. CONCLUSION: ACS is common in patients with SCD who present with fever and was grossly underestimated by evaluating physicians. History and physical examination appear to be of little value in defining which febrile patients require CXR. In view of the mortality and morbidity associated with ACS, empiric CXR should be considered when evaluating a febrile patient with SCD.

PMID: 10381996, UI: 99315127

Br J Ophthalmol 1999 Jul;83(7):838-846

Angiogenic factors in human proliferative sickle cell retinopathy.

Cao J, Mathews MK, McLeod DS, Merges C, Hjelmeland LM, Lutty GA

Wilmer Ophthalmological Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

BACKGROUND/AIMS: Preretinal neovascular formations called sea fans develop at the border of non-perfused peripheral retina in sickle cell retinopathy. Angiogenic factors which could contribute to their development, however, have not been examined previously. The objective of this study was to determine immunohistochemically if vascular endothelial growth factor (VEGF) or basic fibroblast growth factor (bFGF) were associated with sea fan formations. METHODS: Immunohistochemistry on cryosections was used to localise bFGF, VEGF, heparan sulphate proteoglycan, human serum albumin, collagens IV and II, and von Willebrand factor in tissue from five sickle cell and one control subject. RESULTS: The greatest immunoreactivity for VEGF and bFGF was in the feeder and preretinal vessels of sea fans (p<0.01). The most prominent reaction product was localised to vascular endothelial cells. In retinal vessels, VEGF and bFGF immunoreactivities were greater in sickle cell subjects (both proliferative and non-proliferative) than in the control subject (p<0.01 and p<0.02 respectively). In the sickle cell retina, no angiogenic factor immunoreactivity was detected in non-perfused periphery and there was no significant difference in bFGF or VEGF immunoreactivity between perfused retina and the border of perfused and non-perfused areas. CONCLUSION: Our results demonstrate for the first time that VEGF and bFGF are associated with sea fan formations in sickle cell retinopathy. Both factors may function in an autocrine manner because immunoreactivity for these factors was greater within the neovascularisation than in adjacent retina.

PMID: 10381672

Blood 1999 Jul 1;94(1):302-9

The carboxy-terminal cell-binding domain of thrombospondin is essential for sickle red blood cell adhesion.

Hillery CA, Scott JP, Du MC

Department of Pediatrics, Medical College of Wisconsin, Milwaukee, USA. chillery@bcsew.edu

Sickle red blood cells (SS-RBCs) have enhanced adhesion to the plasma and subendothelial matrix protein thrombospondin-1 (TSP) under conditions of flow in vitro. TSP has at least four domains that mediate cell adhesion. The goal of this study was to map the site(s) on TSP that binds SS-RBCs. Purified TSP proteolytic fragments containing either the N-terminal heparin-binding domain, or the type 1, 2, or 3 repeats, failed to sustain SS-RBC adhesion (<10% adhesion). However, a 140-kD thermolysin TSP fragment, containing the carboxy-terminal cell-binding domain in addition to the type 1, 2, and 3 repeats fully supported the adhesion of SS-RBCs (126% +/- 25% adhesion). Two cell-binding domain adhesive peptides, 4N1K (KRFYVVMWKK) and 7N3 (FIRVVMYEGKK), failed to either inhibit or support SS-RBC adhesion to TSP. In addition, monoclonal antibody C6. 7, which blocks platelet and melanoma cell adhesion to the cell-binding domain, did not inhibit SS-RBC adhesion to TSP. These data suggest that a novel adhesive site within the cell binding domain of TSP promotes the adhesion of sickle RBCs to TSP. Furthermore, soluble TSP did not bind SS-RBCs as detected by flow cytometry, nor inhibit SS-RBC adhesion to immobilized TSP under conditions of flow, indicating that the adhesive site on TSP that recognizes SS-RBCs is exposed only after TSP binds to a matrix. We conclude that the intact carboxy-terminal cell-binding domain of TSP is essential for the adhesion of sickle RBCs under flow conditions. This study also provides evidence for a unique adhesive site within the cell-binding domain that is exposed after TSP binds to a matrix.

PMID: 10381526, UI: 99310652

Hum Biol 1999 Jun;71(3):333-40

Some atypical and rare sickle cell gene haplotypes in populations of Andhra Pradesh, India.

Niranjan Y, Chandak GR, Veerraju P, Singh L

Department of Human Genetics, Andhra University, Visakhapatnam, India.

We have investigated the clinical, hematological, and molecular genetic characteristics of sickle cell anemia patients from 6 populations of Andhra Pradesh, South India. Of 72 sickle cell chromosomes (HBB*S) 60 belong to characteristic Arab-Indian haplotypes, 6 to variant Arab-Indian haplotypes, 1 to a Bantu haplotype, 2 to a Cameroon haplotype, and 3 to rare haplotypes. This is the first report of a Bantu haplotype in an Indian population. Some information on haplotype characteristics of normal chromosomes (HBB*A) is also presented. The average hemoglobin level was 7.3 g% and mean fetal hemoglobin (HbF) level was 12.6%. The higher HbF levels corroborate earlier observations in sickle cell homozygotes from India. Clinical investigations have revealed splenomegaly and painful crises as the most common features in these patients.

PMID: 10380370, UI: 99309468

Cas Lek Cesk 1999 Mar 1;138(5):131-5

[Priapism].

Hora M, Ouda Z

Urologicka klinika FN, Plzen.

Priapism is prolonged, and usually painful, erection not associated with sexual desire. It is a relatively rare acute urological disease where treatment must be started within 6 hours after its development, as after a longer time interval due to ischaemia irreversible fibrotic changes of the cavernous tissue of the penis develop which lead to permanent erectile dysfunction. There may be either low flow priapism (inadequate outflow of blood from the cavernous tissue) or more rarely high flow priapism (excessive inflow of blood). Priapism is classified with regard to its aetiology into primary (cause unknown) or secondary. The causes of secondary priapism are most frequently overdosage of vasodilatating agents during intracavernous injection treatment of erectile dysfunction (specially papaverine), tumours (obstruction of the efferent veins or direct infiltration of the corpora cavernosa)--in particular carcinoma of the urinary bladder, prostate and rectum. Priapism is frequently due to injuries of the prostate and straddle injuries. 5% men with sickle-cell anaemia suffer from an attack of priapism. Treatment of priapism differs, depending on the type, and should be entrusted to an experienced urologist in an in-patient department.

Publication Types:

• Review
• Review, tutorial

PMID: 10376395, UI: 99304683

J Behav Med 1999 Apr;22(2):115-26

Depression, disease severity, and sickle cell disease.

Wison Schaeffer JJ, Gil KM, Burchinal M, Kramer KD, Nash KB, Orringer E, Strayhorn D

Department of Psychology, University of North Carolina at Chapel Hill 27599-3270, USA.

The present study examined depressive symptomatology in 440 adults with sickle cell disease (SCD). Participants completed the Center for Epidemiologic Studies--Depression scale (CES-D) as part of their yearly routine visits to the Duke University--University of North Carolina Comprehensive Sickle Cell Center. They also completed questions regarding demographics, disease severity, pain, and health care use. Data analyses revealed that the percentage of patients with SCD exhibiting significant depressive symptomatology dropped from 43 to 18% when a more stringent cutoff was used on the CES-D, suggesting that future studies should determine the most valid cutoff score for identifying depression in patients with SCD. Gender and family income were positively and significantly associated with depressive symptomatology. Also, patients who reported more frequent painful episodes were more likely to report depressive symptoms. Implications for assessment and treatment of depression in adults with SCD are discussed.

PMID: 10374138, UI: 99302368

J Wound Ostomy Continence Nurs 1999 Mar;26(2):98-104

Treatment of painful lower extremity ulcers in a patient with sickle cell disease.

Hyperbaric Oxygen, Inc., San Antonio, Texas, USA.

PMID: 10373866, UI: 99302096

Nucleic Acids Res 1999 Jul 1;27(13):2806-2813

Peptide nucleic acid (PNA) binding-mediated induction of human [gamma]-globin gene expression.

Wang G, Xu X, Pace B, Dean DA, Glazer PM, Chan P, Goodman SR, Shokolenko I

Department of Structural and Cellular Biology and

Peptide nucleic acids (PNAs) can bind to homopurine/homopyrimidine sequences of double-stranded DNA targets in a sequence-specific manner and form [PNA]2/DNA triplexes with single-stranded DNA D-loop structures at the PNA binding sites. These D-loop structures have been found to have a capacity to initiate transcription in vitro. If this strategy can be used to induce transcription of endogenous genes, it may provide a novel approach for gene therapy of many human diseases. Human [beta] globin disorders such as sickle cell anemia and [beta]-thalassemia are very common genetic diseases that are caused by mutations in the [beta]-globin gene. When [gamma]-globin genes are highly expressed in sickle cell patients, the presence of high levels of fetal hemoglobin (HbF, [alpha]2[gamma]2) can compensate for the defective [beta]-globin gene product and such patients have much improved symptoms or are free of disease. However, the [gamma]-globin genes are developmentally regulated and normally expressed at very low levels (>1%) in adult blood cells. We have investigated the possibility of inducing [gamma]-globin gene expression with PNAs. Using PNAs designed to bind to the 5[prime] flanking region of the [gamma]-globin gene, induction of expression of a reporter gene construct was demonstrated both in vitro and in vivo. More importantly, PNA-mediated induction of endogenous [gamma]-globin gene expression was also demonstrated in K562 human erythroleukemia cells. This result suggests that induction of [gamma]-globin gene expression with PNAs might provide a new approach for the treatment of sickle cell disease. PNA-induced gene expression strategy also may have implications in gene therapy of other diseases such as genetic diseases, cancer and infectious diseases.

PMID: 10373600

Arch Pediatr 1999;6 Suppl 2:345s-347s

[Hematopoietic stem cell transplantation in sickle cell anemia].

Cornu G, Vermylen C, Ferster A, Brichard B, Ninane J, Ferrant A, Zenebergh A, Maes P, Dhooge C, Benoit Y, Beguin Y, Dresse MF, Sariban E

Cliniques universitaires Saint-Luc, UCL, Belgique.

Publication Types:

• Clinical trial
• Multicenter study

PMID: 10370531, UI: 99298669

Arch Pediatr 1999;6 Suppl 2:343s-344s

[Early detection and medical management of sickle cell anemia: five years of experience in Cotonou].

Rahimy MC

Faculte des sciences de la sante de Cotonou, Universite nationale du Benin.

PMID: 10370530, UI: 99298668

Rev Pneumol Clin 1999 Mar;55(1):31-3

[Acute respiratory distress in a patient with sickle-cell anemia].

Wislez M, Mangiapan G, Saidi F, Parrot A

Unite de reanimation respiratoire, Hopital Tenon, Paris.

The acute chest syndrome is a frequent complications of sickle-cell disease characterized by chest pain, fever, and new infiltrate on chest x-ray image. Pathophysiologic factors appear to be multifactorial and better known. We report the case of a 28-year-old woman with homozygous sickle cell anemia who developed acute chest syndrome probably secondary to fat embolism.

PMID: 10367313, UI: 99295389

Philos Trans R Soc Lond B Biol Sci 1999 Apr 29;354(1384):777-85

The epidemiology of pneumococcal infection in children in the developing world.

Greenwood B

Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, UK.

Pneumonia causes about three million deaths a year in young children, nearly all of which are in developing countries. Streptococcus pneumoniae (the pneumococcus) is the most important bacterial cause of pneumonia in young children and so is likely to be responsible for a high proportion of these deaths. The pneumococcus is also responsible for a substantial proportion of the 100,000-500,000 deaths that occur from meningitis in children each year. The incidence of invasive pneumococcal disease in children in the developing world is several times higher than in industrialized countries. This discrepancy may, in part, be due to socio-economic differences but genetic factors may also play a role. Children with sickle cell disease have a substantially increased risk of invasive pneumococcal infection and a search is being made for other possible genetic risk factors. Infection with human immunodeficiency virus (HIV) also predisposes to invasive pneumococcal disease and so the incidence of this disease in young children is expected to rise as increasing numbers of African and Asian children are born with a perinatally acquired HIV infection. Until recently, pneumococcal infections could be treated effectively with penicillin, a cheap and safe antibiotic. However, pneumococci that are resistant to penicillin are becoming prevalent in many countries, necessitating a change to more costly antibiotics which may be beyond the reach of the health services of poor, developing countries. The spread of antibiotic resistance has provided an added stimulus to the development of vaccines that might be able to prevent pneumococcal disease in infants. Recently developed polysaccharide-protein conjugate vaccines show promise and are now undergoing field trials. How deployment of these vaccines will influence the balance between invasive pneumococcal infections and asymptomatic nasopharyngeal carriage of pneumococci is uncertain.

Publication Types:

• Review
• Review, tutorial

PMID: 10365403, UI: 99293737

Indian J Physiol Pharmacol 1999 Apr;43(2):267-9

Osmotic fragility of normal and sickle haemoglobin containing red blood cells.

Dash BP, Mittra A, Kar BC

Publication Types:

• Letter

PMID: 10365325, UI: 99293659

Ann R Coll Surg Engl 1999 May;81(3):175-8

Pre-operative blood tests in children undergoing plastic surgery.

Ansermino JM, Than M, Swallow PD

St Andrew's Centre for Plastic Surgery and Burns, Broomfield Hospital, Chelmsford, Essex, UK.

In a retrospective review of 1177 children presenting for plastic surgical procedures, investigations were performed in 487 and abnormal results were found in 138 as defined by variation from the local laboratory reference range. Most of the abnormalities were of no clinical significance. Twenty one children had abnormal haemoglobin results (the lowest was 9 g/dl) and 101 children had clinically insignificant platelet or white cell abnormalities. One child, with a family history of sickle cell trait, was confirmed as sickle-cell trait. No case was postponed as a result of these investigations. The non-selective ordering of pre-operative blood tests leads to unnecessary patient discomfort, the potential for additional superfluous investigations and higher costs.

PMID: 10364949, UI: 99293283

BMJ 1999 Jun 12;318(7198):C

Hospital experiences affect pain management in sickle cell disease.

PMID: 10364148

BMJ 1999 Jun 12;318(7198):1585-90

Experiences of hospital care and treatment seeking for pain from sickle cell disease: qualitative study.

Maxwell K, Streetly A, Bevan D

Department of Public Health Sciences, Guy's, King's, and St Thomas's Schools of Medicine, Dentistry, and Biomedical Sciences, King's College London, London SE1 3QD.

OBJECTIVE: To investigate how sociocultural factors influence management of pain from sickle cell disease by comparing the experiences of those who usually manage their pain at home with those who are more frequently admitted to hospital for management of their pain. DESIGN: Qualitative analysis of semistructured individual interviews and focus group discussions. PARTICIPANTS: 57 participants with genotype SS or S/beta-thal (44 subjects) or SC (9) (4 were unknown). 40 participants took part in focus groups, six took part in both focus groups and interviews, and nine were interviewed only. Participants were allocated to focus groups according to number of hospital admissions for painful crisis management during the previous year, ethnic origin, and sex. RESULTS: The relation between patients with sickle cell disease and hospital services is one of several major non-clinical dimensions shaping experiences of pain management and behaviour for seeking health care. Experiences of hospital care show a range of interrelated themes, which are common to most participants across variables of sex, ethnicity, and hospital attended: mistrust of patients with sickle cell disease; stigmatisation; excessive control (including both over- and undertreatment of pain); and neglect. Individuals respond to the challenge of negotiating care with various strategies. Patients with sickle cell disease who are frequently admitted to hospital may try to develop long term relationships with their carers, may become passive or aggressive in their interactions with health professionals, or may regularly attend different hospitals. Those individuals who usually manage their pain at home express a strong sense of self responsibility for their management of pain and advocate self education, assertiveness, and resistance as strategies towards hospital services. CONCLUSIONS: The current organisation and delivery of management of pain for sickle cell crisis discourage self reliance and encourage hospital dependence. Models of care should recognise the chronic nature of sickle cell disorders and prioritise patients' involvement in their care.

PMID: 10364116, UI: 99292634

J Pediatr Hematol Oncol 1999 May-Jun;21(3):219-23

Plasma homocysteine levels and folate status in children with sickle cell anemia.

Rodriguez-Cortes HM, Griener JC, Hyland K, Bottiglieri T, Bennett MJ, Kamen BA, Buchanan GR

Department of Pediatrics, The University of Texas Southwestern Medical Center at Dallas Center for Cancer and Blood Disorders, 75235-9063, USA.

PURPOSE: A sensitive inverse relationship between plasma homocysteine concentration and folate status has been demonstrated. Although children with sickle cell anemia (SCA) are at potential risk for folate deficiency, plasma homocysteine levels have not been reported in such patients. Therefore, a study was designed to assess plasma homocysteine levels as a marker of folate status. DESIGN: Plasma homocysteine concentrations were measured in 120 children with SCA (102 in steady state and 18 during an acute complication) who had never received supplemental folic acid. Folate status was directly assessed in 34 of these patients. RESULTS: Plasma homocysteine levels in the patients with SCA and control subjects were similar. The mean value +/- 1 SD was 5.8+/-2.5 micromol/L (range, 1.6 to 14.1 micromol/L) in the patients with SCA and 6.1+/-2.7 micromol/L (range, 1.7 to 15.3 micromol/L) in 73 pediatric control subjects. In a subpopulation of the study group (34 children), simultaneous serum folate, red cell folate, and total homocysteine concentrations were also measured. Their serum folate and red cell folate concentrations were normal: 12.4+/-10.0 nmol/L (range, 1 to 42 nmol/L) and 604+/-374.7 nmol/L (range, 205 to 1741 nmol/L), respectively. There was no correlation of plasma homocysteine concentration with various clinical or laboratory measures or with red cell folate concentration. CONCLUSION: Folate stores in children with SCA not receiving folic acid supplements are adequate despite an underlying hemolytic anemia.

Comments:

• Comment in: J Pediatr Hematol Oncol 1999 May-Jun;21(3):176-8

PMID: 10363855, UI: 99290523

J Pediatr Hematol Oncol 1999 May-Jun;21(3):176-8

Role of nutritional supplement in sickle cell disease.

Wang WC

Department of Hematology/Oncology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.

Publication Types:

• Comment

Comments:

• Comment on: J Pediatr Hematol Oncol 1999 May-Jun;21(3):219-23

PMID: 10363848, UI: 99290516

Clin Nucl Med 1999 Jun;24(6):445

Symmetric avascular necrosis of the shoulders and hips in sickle cell disease.

Sinha P, Kim A, Freeman LM

Department of Nuclear Medicine, Montefiore Medical Center, University Hostpital of the Albert Einstein College of Medicine, Bronx, New York 10467, USA.

PMID: 10361944, UI: 99288790

J Lab Clin Med 1999 Jun;133(6):605-12

Low-density lipoprotein susceptibility to oxidation and cytotoxicity to endothelium in sickle cell anemia.

Belcher JD, Marker PH, Geiger P, Girotti AW, Steinberg MH, Hebbel RP, Vercellotti GM

Department of Medicine, University of Minnesota, Minneapolis 55455, USA.

Patients with sickle-cell anemia exhibit pro-oxidative metabolic perturbations. We hypothesize that because of chronic oxidative stress, plasma low-density lipoprotein (LDL) from patients with sickle-cell anemia is more susceptible to oxidation. To test this hypothesis, LDL susceptibility to copper-mediated oxidation was measured in 24 patients with sickle-cell anemia and 48 control subjects. Sickle-cell LDL was more susceptible to oxidation than control LDL, measured by a 22% shorter mean lag time between LDL exposure to CuSO4 and conjugated diene formation (97 vs 124 minutes; P = .023). LDL vitamin E, iron, heme, and cholesterol ester hydroperoxide (CEOOH) levels were also measured. LDL vitamin E levels were significantly lower in patients with sickle-cell anemia compared with control subjects (1.8 vs 2.9 mol/mol LDL; P = .025), but there was no correlation with lag time. Pro-oxidant heme and iron levels were the same in sickle-cell and control LDL. LDL CEOOHs were not significantly different in sickle and control LDL (3.1 vs 1.2 mmol/mol of LDL unesterified cholesterol, P = .15), but LDL CEOOH levels were inversely correlated with lag times in patients with sickle-cell anemia (r2 = 0.38; P = .018). The cytotoxicity of partially oxidized LDL to porcine aortic endothelial cells was inversely correlated with lag times (r2 = 0.48; P = .001). These preliminary data suggest that increased LDL susceptibility to oxidation could be a marker of oxidant stress and vasculopathy in patients with sickle-cell anemia.

PMID: 10360636, UI: 99287381

Adolesc Med 1994 Jun;5(2):271-292

Advances in the Treatment of Adolescents with Sickle Hemoglobinopathies.

Radel E

Department of Pediatrics, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467, USA.

This detailed review of sickle hemoglobinopathies covers their incidence and epidemiology, pathophysiology, diagnosis, clinical manifestations, complications, and organ changes. Issues such as pregnancy and birth control in patients with sickle cell disease, surgery and anesthesia, and medical management are also discussed.

PMID: 10358277

Pediatr Nephrol 1999 Apr;13(3):267-8

Clinical quiz. Cortical infarction secondary to intravascular sickling in the renal cortex.

al Ani O, Baqi N

Division of Pediatric Nephrology, State University of New York at Brooklyn, 11203, USA.

PMID: 10353420, UI: 99279860

Anaesthesist 1999 Apr;48(4):231-5

[Perioperative monitoring of hemoglobin fractions in homozygous sickle cell disease].

Frietsch T, Segiet W, Schutz P, Haux P, Lorentz A

Institut fur Anasthesiologie und Operative Intensivmedizin, Fakultat fur klinische Medizin Mannheim der Ruprecht-Karls-Universitat Heidelberg.

This case report presents the perioperative management of double-sided hip arthroplasty in a patient (female, 25 years old) homozygous for sickle cell anemia (SS). The fraction of sickle hemoglobin (Hb S) to total hemoglobin was monitored with an automated cation exchange microcolumn chromatography. The main purpose of ion exchange chromatography is to measure glycated hemoglobin A (HbA1c) in diabetic patients. Furthermore, as a by-product, this test enables the quantitative assessment of aberrant hemoglobin molecules such as sickle cell hemoglobin Hb S with sufficient precision and selectivity. The standard method, hemoglobin-electrophoresis is more complicated and not generally available. For the perioperative estimation of the risk for sickle cell related complications and as a guide for transfusion therapy, knowledge of preoperative Hb S level is essential. In this case report, the clinical use of a rapid laboratory test at low costs with common equipment in a patient with known homozygous sickle cell anemia is demonstrated.

PMID: 10352787, UI: 99281053

Pediatr Rev 1999 Jun;20(6):204-8

Hemolytic anemia: Part 2.

Sackey K

Division of Hematology/Oncology, The University of Texas Medical Branch, Galveston, TX, USA.

Publication Types:

• Review
• Review, tutorial

PMID: 10352043, UI: 99280614

AJR Am J Roentgenol 1999 Jun;172(6):1639-41

Idiopathic pulmonary vein thrombosis: detection by CT and MR imaging.

Selvidge SD, Gavant ML

Department of Radiology, College of Medicine, Health Science Center, University of Tennessee, Memphis 38163, USA.

Publication Types:

• Review
• Review of reported cases

PMID: 10350306, UI: 99277809

Clin Pediatr (Phila) 1999 May;38(5):293-6

Correlation of serum cholylglycine level with hepatic dysfunction in children with sickle cell anemia.

Sayad AE, Farah RA, Rogers ZR, Heubi JE, Buchanan GR, Squires RH Jr

Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas 75235-9063, USA.

Hepatic dysfunction occurs commonly in children with sickle cell disease (SCD). Although the etiology is multifactorial, cholestasis is a prominent feature. Serum cholylglycine (CG) has been found to be a very sensitive indicator of cholestasis. Our objective was to determine whether CG levels are elevated in children with SCD and whether they are predictive of hepatic dysfunction. Blood samples were obtained from 97 children with SCD. Liver function tests were done and serum CG concentrations were measured. Patients were followed up for 2 years. Thirty-eight percent of the patients had an elevated CG level. During the 2 years of follow-up, 16% of the children with a previously elevated CG level developed abnormal liver function test results or required a cholecystectomy as compared with 13% with a previously normal CG level (p = 0.92). We conclude that although CG level was elevated in 38% of the patients with SCD, it did not appear to predict liver dysfunction during the ensuring 2 years.

PMID: 10349527, UI: 99279144

Medicina (B Aires) 1999;59(1):95-104

[Heparin cofactor II, a thrombin inhibitor with a still not clarified physiologic role].

Rossi EB, Duboscq CL, Kordich LC

Departamento de Quimica Biologica, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina. lht@qb.fcen.UBA.ar

Heparin Cofactor II (HCII) is a glycoprotein in human plasma which inactivates thrombin rapidly in the presence of dermatan sulfate. Inhibition occurs by formation of a stable equimolar complex between HCII and thrombin. HCII association with thrombotic events has not always been observed, thus decreased HCII does not appear to be a strong risk factor for thromboembolic events. Reduced HCII levels have been detected in different clinical conditions, such as hepatic failure, disseminated intravascular coagulation, thalasemina, sickle cell anemia. Increased physiological levels have been found in pregnant women and oral contraception. In our laboratory, we measured HCII plasmatic levels in the normal Buenos Aires city population and in patients under different clinical conditions, such as sepsis, diabetis, burns, oral anticoagulation and in patients treated with heparin, hyperhomcysteinemia in whom septic and diabetic patients showed decreased values. HCII thrombin inhibition possibly takes place in extravascular sites where dermatan sulfate is present. HCII activity would be important in the regulation of wound healing, inflammation, or neuronal development.

Publication Types:

• Review
• Review, tutorial

PMID: 10349131, UI: 99278748

J Chromatogr B Biomed Sci Appl 1999 Apr 16;726(1-2):303-7

High-performance liquid chromatographic method for determination of vanillin and vanillic acid in human plasma, red blood cells and urine.

Farthing D, Sica D, Abernathy C, Fakhry I, Roberts JD, Abraham DJ, Swerdlow P

Division of Clinical Pharmacology and Hypertension, Medical College of Virginia, Virginia Commonwealth University, Richmond 23298-0160, USA.

A simple high-performance liquid chromatographic method was developed for the determination of vanillin and its vanillic acid metabolite in human plasma, red blood cells and urine. The mobile phase consisted of aqueous acetic acid (1%, v/v)-acetonitrile (85:15, v/v), pH 2.9 and was used with an octadecylsilane analytical column and ultraviolet absorbance detection. The plasma method demonstrated linearity from 2 to 100 microg/ml and the urine method was linear from 2 to 40 microg/ml. The method had a detection limit of 1 microg/ml for vanillin and vanillic acid using 5 microl of prepared plasma, red blood cells or urine. The method was utilized in a study evaluating the pharmacokinetic and pharmacodynamic effects of vanillin in patients undergoing treatment for sickle cell anemia.

PMID: 10348200, UI: 99275956

Lancet 1999 May 22;353(9166):1760

A midlife crisis.

Wrenn K, Wright SW, Kent LP

Vanderbilt University School of Medicine, Nashville, TN 37232-4700, USA.

PMID: 10347990, UI: 99275746

Mol Pharmacol 1999 Jun;55(6):1006-10

Detection of nitrosyl hemoglobin in venous blood in the treatment of sickle cell anemia with hydroxyurea.

Glover RE, Ivy ED, Orringer EP, Maeda H, Mason RP

Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, North Carolina, USA. glover1@niehs.nih.gov

The clinical efficacy of hydroxyurea (HU) in the treatment of sickle cell anemia has mainly been attributed to increased levels of fetal hemoglobin (HbF), which reduces the tendency for sickle hemoglobin to polymerize, thereby reducing the frequency of the vaso-occlusive phenomena associated with the disease. However, benefits from HU treatment in patients have been reported in advance of increased HbF levels. Thus, it has been suggested that other hydroxyurea-dependent mechanisms may, in part, account for its clinical efficacy. We have previously demonstrated that HU is metabolized in rats to release nitric oxide and, therefore, postulated the same to occur in humans. However, to our knowledge, evidence of nitric oxide production from HU metabolism in humans has yet to be demonstrated. Here we report that oral administration of HU for the treatment of sickle cell anemia produced detectable nitrosyl hemoglobin. The nitrosyl hemoglobin complex could be detected as early as 30 min after administration and persisted up to 4 h. Our observations support the hypothesis that the ability of HU to ease the vaso-occlusive phenomena may, in part, be attributed to vasodilation and/or decreased platelet activation induced by HU-derived nitric oxide well in advance of increased HbF levels.

PMID: 10347241, UI: 99278506

Am J Prev Med 1999 Feb;16(2):116-21

Preventing morbidity and mortality from sickle cell disease. A public health perspective.

Olney RS

Birth Defects and Genetic Diseases Branch, Centers for Disease Control and Prevention (CDC), Atlanta, Georgia, USA.

CONTEXT: Sickle cell disease is a group of conditions characterized by production of abnormal hemoglobin, with clinical manifestations that vary by genotype and age. OBJECTIVE: To discuss current public health issues associated with sickle cell disease, and approaches to preventing complications from these conditions in the United States. DESIGN: Literature review. RESULTS: Most clinical interventions for people with sickle cell disease discussed in the medical literature can be classified as tertiary prevention: for example, therapy to ameliorate anemia, reduce the frequency of pain crises, or prevent stroke recurrences. A form of secondary prevention, newborn screening, has emerged as an important public health approach to identifying affected children before they develop complications. Newborn screening is the starting point for simple public health strategies such as parental education, immunization, and penicillin prophylaxis. Identification of affected families by newborn or community screening programs has also been an entry point for genetic counseling, although utilization of prenatal testing has varied by factors such as geographic location. Public health agencies have had significant involvement with funding, policy making, and formulation of laboratory and clinical guidelines for sickle cell disease. Since the introduction of penicillin prophylaxis policies, newborn screening, new immunizations, and comprehensive medical care centers, the survival of young children with sickle cell disease has improved. CONCLUSIONS: Although the efforts of preventive medicine providers in public health programs are not solely responsible for the improved survival of children with sickle cell disease, such programs remain an important component in preventing sickle cell complications.

Publication Types:

• Review
• Review, tutorial

PMID: 10343888, UI: 99275356

Clin Lab Haematol 1999 Apr;21(2):99-102

Red cell exchange in sickle cell disease.

Lawson SE, Oakley S, Smith NA, Bareford D

Department of Haematology, Birmingham Children's Hospital NHS Trust, UK.

Red cell exchange transfusion is frequently of use in the management of patients with sickle cell disease either electively or therapeutically. Modern cell separators allow this procedure to be performed rapidly, effectively and safely. These machines have a number of advantages over manual exchange procedures. The patient remains isovolaemic, there is little loss of plasma or platelets, the procedure is relatively short and in elective circumstances can be performed on an outpatient basis. In this series 66 exchanges were performed on 21 patients with an overall increase in HbA of 70%. The COBE Spectra gave a mean increase in HbA of 77%, with the majority of patients achieving an HbA of > 90% post exchange. Automated redcell exchange was well tolerated by most patients, and adverse effects were limited to symptoms of hypocalcaemia which were easily treated, and to transfusion reactions. Cell separators can therefore be recommended for exchange transfusion in patients with sickle cell disease, who require an increase in HbA levels either prophylactically or therapeutically. They are safe, effective, easy and quick to use.

PMID: 10342068, UI: 99273614

Br J Radiol 1999 Jan;72(853):9-17

Sonographic detection and characterization of musculoskeletal and subcutaneous tissue abnormalities in sickle cell disease.

Sidhu PS, Rich PM

Department of Diagnostic Radiology, Kings College Hospital, Denmark Hill, London, UK.

Pain due to bone marrow infarction is common in homozygous sickle cell disease (SS disease). Musculoskeletal pathology may be responsible for persistent atypical symptoms. We have assessed the frequency and ultrasound appearances of soft tissue and joint abnormalities in SS disease. SS disease patients with atypical musculoskeletal symptoms were examined with ultrasound over a 2 year period. Ultrasound findings were correlated with those at surgery or percutaneous drainage. 31 episodes in 23 patients were referred for ultrasound. There were 36 abnormalities in 18 patients: abscess (n = 15), effusions (n = 5), soft tissue induration (n = 12), fat necrosis (n = 2), haematoma (n = 1) and reactive lymph node (n = 1). Five examinations were normal. Soft tissue abnormalities in patients over the age of 14 years were associated with intramuscular injections: fat necrosis (n = 1), haematoma (n = 1), indurated soft tissue (n = 1) and abscess (n = 7). Soft tissue abnormalities with no underlying cause were seen in seven patients: abscess (n = 4), indurated soft tissue (n = 2) and fat necrosis (n = 1). Ultrasound is the imaging modality of choice for delineating these abnormalities and allows percutaneous drainage.

Publication Types:

• Clinical trial

PMID: 10341683, UI: 99273229

Blood 1999 Jun 1;93(11):3824-30

Sickle cell anemia as a possible state of enhanced anti-apoptotic tone: survival effect of vascular endothelial growth factor on circulating and unanchored endothelial cells.

Solovey A, Gui L, Ramakrishnan S, Steinberg MH, Hebbel RP

Departments of Medicine and Pharmacology, University of Minnesota, Minneapolis, MN, USA.

The biologic processes of apoptosis and angiogenesis are linked in endothelial biology because some endothelial cell growth factors also exert anti-apoptotic effects. We studied whether apoptosis is occurring in circulating endothelial cells (CEC) that have lost the survival signals derived from anchorage to extracellular matrix. Consistent with this expectation, 64% +/- 16% of CEC from normal donors showed evidence of apoptosis (by morphology and TdT-mediated dUTP nick end labeling [TUNEL] assay). However, only 30% +/- 15% (P <.001 v normal) of CEC from donors with sickle cell anemia were apoptotic. Vascular endothelial growth factor (VEGF) levels were significantly (P =.001) higher in plasma of sickle donors (120.1 +/- 81.4 pg/mL) than that of normal donors (37.6 +/- 34.6 pg/mL), and there was an inverse correlation between VEGF and CEC apoptosis (r =. 612, P =.001). Consistent with stimulation by VEGF, CEC from sickle donors exhibited increased expression of alphavbeta3. In vitro experiments showed that VEGF inhibits apoptosis for cultured endothelial cells that are kept unanchored and not allowed to re-establish attachment to extracellular matrix, thus demonstrating that VEGF provides survival signals independent of its ability to promote matrix reattachment. These data suggest the hypothesis that sickle cell anemia is a state of enhanced anti-apoptotic tone for endothelial cells. If true, this has implications for disease pathobiology, particularly the development of neovascularizing retinopathy.

PMID: 10339489, UI: 99272425

Pediatr Med Chir 1998 Nov-Dec;20(6):415-6

[A case report of drepanocytic anemia with "belt syndrome"].

Ughi M, Trevenzoli G, Rubin R, Lanzone B

Divisione Pediatrica, Ospedale Civile di Legnago, VR.

Following article describes the case of a child with painful abdominal symptomatology showing characteristics of an acute abdomen. Following the laboratory tests abdominal crises have been classified as vessel occlusion crises with sickle cell anemia.

PMID: 10335543, UI: 99268024

Biochem Biophys Res Commun 1999 May 27;259(1):172-7

Interleukin-17 induces rapid tyrosine phosphorylation and activation of raf-1 kinase in human monocytic progenitor cell line U937.

Subramaniam SV, Pearson LL, Adunyah SE

Department of Biochemistry and Comprehensive Sickle Cell Center, Meharry Medical College, Nashville, Tennessee, 37208, USA.

Interleukin-17 is a T cell derived pro-inflammatory cytokine exhibiting multiple biological activities in a variety of cells and believed to fine tune all general phases of hematopoietic response. However, the signaling mechanism of this novel cytokine remains unknown. The purpose of this study was to determine whether Interleukin-17 induces tyrosine phosphorylation of proteins and to find out whether the raf-1 kinase signaling pathway is involved in mediating its signaling. Using immunoblotting and immunocomplex kinase assays, we report that the early signaling events triggered by rhIL-17 involves rapid tyrosine phosphorylation of several cellular proteins including raf-1 within 0.5 to 30 min. Optimal stimulation of tyrosine phosphorylation was observed with 0.5 to 1.0 ng/ml of Interleukin-17. Further, Interleukin-17 stimulates rapid activation of raf-1 kinase. These findings provide the first evidence that the mechanism of IL-17 signaling involves rapid tyrosine phosphorylation and activation of raf-1 serine/threonine kinase. Copyright 1999 Academic Press.

PMID: 10334935, UI: 99268817

Nephrol Dial Transplant 1999;14 Suppl 2:37-45

Should anaemia in subtypes of CRF patients be managed differently?

van Ypersele de Strihou C

Cliniques Universitaires St. Luc, Brussels, Belgium.

In patients with cardiovascular disease, partial correction of anaemia with epoetin improves quality of life and exercise capacity, and reduces left ventricular hypertrophy. The currently recommended haemoglobin in these patients is 11-12 g/dl. The optimal haemoglobin in patients with diabetes mellitus does not differ from that in non-diabetic patients; however, haemoglobin should be increased slowly. There is no difference in the recommended haemoglobin between children and adults. However, epoetin sensitivity is lower in children who, therefore, typically need the same absolute dose of epoetin as adults. Epoetin treatment may delay the progression of chronic renal failure (CRF) in paediatric patients. Elderly patients obtain similar benefits from epoetin as younger adults; moreover, there are no differences in the doses of epoetin required or the optimal haemoglobin. There are very few data available on the effects of epoetin in patients with CRF and chronic obstructive pulmonary disease. At present, a haemoglobin of 11 g/dl seems appropriate. In sickle-cell anaemia patients with CRF, a high haemoglobin could precipitate painful crises; consequently, the recommended haemoglobin is the pre-CRF concentration of 6-9 g/dl. There is no convincing evidence of any effect of previous epoetin treatment on the long-term outcome of renal transplantation. In patients with a failing or failed transplant, the required dose of epoetin may be higher than in pre-transplantation patients. In such cases, transplant nephrectomy might be considered.

Publication Types:

• Review
• Review, tutorial

PMID: 10334666, UI: 99265835

Chest 1999 May;115(5):1316-20

Determination of hemoglobin saturation in patients with acute sickle chest syndrome: a comparison of arterial blood gases and pulse oximetry.

Kress JP, Pohlman AS, Hall JB

Department of Medicine, University of Chicago, IL 60637, USA.

STUDY OBJECTIVES: To evaluate three different methods of measuring oxygen saturation in patients suffering from acute sickle chest syndrome. DESIGN: A prospective, descriptive study of 9 months' duration. SETTING: A tertiary care university hospital. PATIENTS: Adult patients with acute sickle chest syndrome scheduled to undergo RBC exchange transfusion. INTERVENTIONS: None. MEASUREMENTS: Baseline hemoglobin oxygen saturation was determined simultaneously by (1) calculation based on PaO2 and an oxyhemoglobin dissociation curve algorithm, (2) co-oximetry, and (3) pulse oximetry. These same measures were repeated after exchange transfusion. Baseline and postexchange hemoglobin electrophoresis was performed in all patients. RESULTS: Baseline calculated saturation overestimated true saturation (determined by co-oximetry) with a baseline mean bias (co-oximetry minus calculated saturation) of -6.78 +/- 2.63% (95% confidence interval for bias: -8.37% to -5.19%). Pulse oximetry was not different than co-oximetry at baseline with a baseline bias of +1.86 +/- 3.25% (95% confidence interval: -0.1% to 3.82%). After exchange transfusion, there was no bias between either co-oximetry and calculated saturation (mean difference: -0.17 +/- 1.31% [95% confidence interval: -0.95% to 0.61%]), or co-oximetry and pulse oximetry (mean difference: +0.3 +/- 1.53% [95% confidence interval: -0.62% to 1.22%]). CONCLUSIONS: Calculated saturation overestimates true saturation during acute sickle chest syndrome. This discrepancy abates after exchange transfusion. Pulse oximetry more closely follows co-oximetry than does calculated saturation during acute sickle chest syndrome.

PMID: 10334146, UI: 99265315

Am J Nurs 1999 May;99(5):36-7

Sickle cell anemia.

Mitchell R

Idaho State University, Pocatello, USA.

PMID: 10333798, UI: 99266340

Tunis Med 1999 Feb;77(2):105-7

[Leg ulcer associated with sickle cell disease].

Kharfi M, Chtourou O, Mokhtar I, Fazaa B, Zeglaoui F, Kamoun MR

Service de Dermatologie, Hopital Charles Nicolle, Tunis.

PMID: 10333708, UI: 99266250

Arch Dis Child 1999 Jun;80(6):537-541

Recurrent infections in homozygous sickle cell disease.

Magnus SA, Hambleton IR, Moosdeen F, Serjeant GR

The Medical Research Council Laboratories, University of the West Indies, Kingston 7, Jamaica.

The characteristics of 214 episodes of invasive bacterial infection among 176 patients with homozygous sickle cell (SS) disease were examined. Streptococcus pneumoniae occurred in 81 episodes, Salmonella spp in 70, Haemophilus influenzae type b in 30, Escherichia coli in 24, and Klebsiella spp in nine. The cumulative incidence showed that S pneumoniae and H influenzae occurred predominantly before 5 years of age and were uncommon thereafter, Salmonella spp increased almost linearly with age, and Klebsiella spp and E coli predominated in patients over 10 years of age. Escherichia coli had a different epidemiology-it was found in older children, almost entirely girls. Excluding this organism from an analysis of recurrent bacterial infections, the standardised incidence rates for second and third infections were 4.8 and 15.8 times greater, respectively, than the SS population average. This implies that the susceptibility to infection is characteristic of a subgroup of patients with SS disease and that sick patients with previous bacteraemia should be investigated early and aggressively for further infection.

PMID: 10332003

Am J Hematol 1999 May;61(1):40-5

Spontaneous erythroid colony formation in Brazilian patients with sickle cell disease.

Perlingeiro RC, Costa FF, Saad ST, Arruda VR, Queiroz ML

Department of Physiology, State University of Campinas-UNICAMP, Brazil.

The ability of circulating progenitor cells to develop erythroid colonies was studied in vitro in the presence or absence of growth factors (5637-CM and erythropoietin) in 63 patients with sickle cell disease (SCD) (36 homozygotes for hemoglobin [Hb] S, 13 double heterozygotes for Hb S and beta thalassemia, and 14 SC patients) in Southeast Brazil. In the presence of growth factors, SCD patients (all genotypes) presented significantly higher numbers of circulating burst-forming unit-erythroid (BFU-E/5 x 10(5) MNC), when compared with control subjects. However, when the progenitor cells were cultured in the absence of added stimulus, high numbers of BFU-E were observed only in the genotypes SS and S/beta thalassemia. SC patients presented a similar response to the control subjects. Moreover, there was an inverse correlation between spontaneous (without stimulus) BFU-E and Hb levels in SCD patients. These results suggest that the formation of spontaneous BFU-E observed in SCD may be due to an expanded erythropoiesis secondary to hemolysis.

PMID: 10331510, UI: 99260353

JAMA 1999 May 12;281(18):1768

JAMA Patient Page: sickle cell anemia.

PMID: 10328078, UI: 99258630

JAMA 1999 May 12;281(18):1701-6

First unaffected pregnancy using preimplantation genetic diagnosis for sickle cell anemia.

Xu K, Shi ZM, Veeck LL, Hughes MR, Rosenwaks Z

The Center for Reproductive Medicine and Infertility and the Department of Obstetrics and Gynecology, Weill Medical College of Cornell University, New York, NY 10021, USA. zrosenw@mail.med.cornell.edu

CONTEXT: Sickle cell anemia is a common autosomal recessive disorder. However, preimplantation genetic diagnosis (PGD) for this severe genetic disorder previously has not been successful. OBJECTIVE: To achieve pregnancy with an unaffected embryo using in vitro fertilization (IVF) and PGD. DESIGN: Laboratory analysis of DNA from single cells obtained by biopsy from embryos in 2 IVF attempts, 1 in 1996 and 1 in 1997, to determine the genetic status of each embryo before intrauterine transfer. SETTING: University hospital in a large metropolitan area. PATIENTS: A couple, both carriers of the recessive mutation for sickle cell disease. INTERVENTIONS: Standard IVF treatment, intracytoplasmic sperm injection, embryo biopsy, single-cell polymerase chain reaction and DNA analyses, embryo transfer to uterus, pregnancy confirmation, and prenatal diagnosis by amniocentesis at 16.5 weeks' gestation. MAIN OUTCOME MEASURE: DNA analysis of single blastomeres indicating whether embryos carried the sickle cell mutation, allowing only unaffected or carrier embryos to be transferred. RESULTS: The first IVF attempt failed to produce a pregnancy. Of the 7 embryos analyzed in the second attempt, PGD indicated that 4 were normal and 2 were carriers; diagnosis was not possible in 1. Three embryos were transferred to the uterus on the fourth day after oocyte retrieval. A twin pregnancy was confirmed by ultrasonography, and subsequent amniocentesis revealed that both fetuses were unaffected and were not carriers of the sickle cell mutation. The patient delivered healthy twins at 39 weeks' gestation. CONCLUSION: This first unaffected pregnancy resulting from PGD for sickle cell anemia demonstrates that the technique can be a powerful diagnostic tool for carrier couples who desire a healthy child but wish to avoid the difficult decision of whether to abort an affected fetus.

PMID: 10328069, UI: 99258621

Prenat Diagn 1999 Apr;19(4):299-304

Initiation of prenatal diagnosis of sickle-cell disorders in Africa.

Akinyanju OO, Disu RF, Akinde JA, Adewole TA, Otaigbe AI, Emuveyan EE

Department of Medicine, Lagos University Teaching Hospital, Nigeria. oluphysic@cyberspace.net

We introduced prenatal diagnosis of SCD in Nigeria in order to meet a rising demand. Our approach and experience are documented as a guide to others in countries with similar problems. A cost-recovery fee charged only to sustain the service predictably limited access to it. Ultrasound-guided transcervical (TC) or transabdominal (TA) sampling of 124 chorionic villi was done from nine weeks' gestation. All couples carried the sickle trait (AS) and 52 (51 per cent) women had previously had children with sickle-cell anaemia. 72 samples were obtained by the TA and 52 by the TC route. 7.2 per cent miscarried after CVS but the miscarriage rate was significantly higher (p=0.023) after TC CVS (13.5 per cent) than after TA CVS (2.8 per cent) and also higher in the first 62 (11.3 per cent) than after the last 62 CVS (3.2 per cent). DNA analysis of CVS indicated Hb AA in 29 (23.4 per cent), AS in 67 (54 per cent) and SS in 23 (18.5 per cent). No result was obtainable in five subjects for technical reasons. 96 per cent of the women with SS fetuses terminated the pregnancies. The need for a standby source of electricity where supply is unreliable and for providing an equitable service to all couples at risk are highlighted.

PMID: 10327132, UI: 99257064

Pubbl Stn Zool Napoli II 1998;20(2):189-214

Molecular diseases and diseased molecules: ontological and epistemological dimensions.

Strasser BJ, Fantini B

Institute Louis-Jeantet for the History of Medicine, University of Geneva, Switzerland.

In 1949, Linus Pauling and collaborators published in Science a paper provocatively titled: 'Sickle cell anemia, a molecular disease'. What was actually meant by 'molecular disease'? We interpret the concept of molecular disease in the frame of the traditional positions about the nature of diseases, the ontological and the physiological positions. We conclude that the physiological does not give an adequate account of what molecular diseases are. The ontological position, when correctly reinterpreted, leads to an understanding of molecular diseases where the macromolecule is seen as a symptom or as a part of a mechanism leading to the symptoms of the disease. We then show that the concept of molecular disease leads to a particular view of therapy, emphasizing eugenics as a way of eliminating disease. On the individual level, this concept leads to an increased power of diagnosis, and especially predictive diagnosis, but has little therapeutic consequence. Lastly, we examine how this concept of disease unifies two contemporary classifications of diseases, one based on the location of the diseases, the other on the cause of the diseases.

PMID: 10326332, UI: 99258191

Pediatr Hematol Oncol 1999 May-Jun;16(3):221-32

Effect of hydroxyurea in sickle cell anemia: a clinical trial in children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia.

Koren A, Segal-Kupershmit D, Zalman L, Levin C, Abu Hana M, Palmor H, Luder A, Attias D

Pediatric Hematology Unit, Haemek Central Hospital, Afula, Israel.

This study evaluated the efficacy of hydroxyurea treatment in the prevention of vaso-occlusive crises among children and teenagers with severe sickle cell anemia and sickle cell beta-thalassemia. Nineteen children and young adults with severe sickle cell disease were enrolled to the hydroxyurea treatment trial. The incidence of vaso-occlusive crises, acute chest syndrome, hemolytic crises, splenic sequestration episodes, blood transfusions, and hospital days in the 2 years before hydroxyurea (HU) treatment were compared with the same parameters in the first 2 years of treatment. The patients received a mean dose of 21.3 mg/kg/day daily and were treated during a mean period of 40.3 +/- 14 months (range 20 to 68 months). Significant increases were observed after 1 month in the Hgb, MCV, MCH, and MCHC levels and were more notable after 3 months. The increase in the Hgb F level became important after 3 months of HU therapy and was highly significant (p < .001) beyond 6 months. No differences were observed in the RDW, reticulocyte count, Hgb S, and Hgb A2. Severe neutropenia was observed in one case. A decrease in the frequency of vaso-occlusive crises, acute chest syndrome, hemolytic crises, blood transfusions, and days spent in the hospital was demonstrated during the HU treatment period compared to the same period before. The clinical and laboratory response to HU was dramatic in severely affected sickle cell anemia (SCA) patients. The response to HU in children and teenagers with severe sickle cell anemia is similar to the response in adults, and no severe adverse effects were observed.

Publication Types:

• Clinical trial

PMID: 10326220, UI: 99258070

Epidemiological features and diagnostic evaluation of intracranial aneurysms.

Carrizo AG

Department of Neurosurgery, Hospital Santa Lucia, Buenos Aires, Argentina

Female gender and cigarette smoking appear to be risk factors for the development of multiple intracranial aneurysms. An acquired nature is likely in this form. The mechanism of aneurysm formation in patients with sickle cell anemia is apparently different. These patients also present multiple aneurysms that show propensity for vertebrobasilar territory and appear at a younger age. Familial cerebral aneurysms are diagnosed once heritable connective tissue disorders have been excluded. The age of patients tends to be lower and the size of aneurysm to be smaller at the time of rupture in the familial form. These aneurysms are less frequently found in the anterior communicating artery than the sporadic aneurysms. A high incidence of asymptomatic familial aneurysms was detected in people with family histories of intracranial aneurysms studied by means of magnetic resonance angiography. Furthermore, familial aneurysms are more likely to rupture in families having members with aneurysmal subarachnoid hemorrhage (SAH) than in those without. The results of an interesting study using color "power" transcranial Doppler ultrasound in patients with aneurysmal SAH suggest that as the intracranial pressure diminished, the size of the aneurysm increased, and there was relatively little change between maximum and minimum dimensions during the cardiac cycle, i.e., the pulsatility is reduced. The use of postoperative angiography after clipping is a matter of debate. The indication more widely accepted is in large aneurysms with a wide neck, in which incomplete clipping can be suspected. Taking into account the current low risk of angiography in centers of excellence, its routine use may be recommended. Aneurysm remnants, vessel occlusion, vasospasm, and newly identified aneurysms are the main findings that were reported.

PMID: 10087098

J Med Screen 1999;6(1):11-5

Newborn screening for haemoglobinopathies: the Brussels experience.

Gulbis B, Tshilolo L, Cotton F, Lin C, Vertongen F

Department of Clinical Chemistry, Hopital Erasme, Universite Libre de Bruxelles, Brussels, Belgium.

OBJECTIVES: To determine the prevalence of haemoglobinopathies and the need for neonatal screening for haemoglobinopathies in Brussels. METHODS: Between December 1994 and June 1998 23,136 cord blood samples obtained in eight hospital nurseries of Brussels were systematically screened for haemoglobinopathies by isoelectric focusing. RESULTS: 45% of the newborns were from regions at risk for haemoglobinopathies. Sickle cell disease was diagnosed for 11 neonates (0.048%) and beta thalassaemia major for one neonate. Three hundred and fifty neonates (1.5%) were carriers for a haemoglobin variant, and Hb Bart's was found in 672 cases (2.9%). These prevalences are similar to those reported elsewhere in northern Europe. CONCLUSIONS: These results confirm the value of universal screening for haemoglobinopathies in Brussels.

PMID: 10321364, UI: 99254667

J Med Screen 1999;6(1):3-10

Outcomes of universal antenatal screening for haemoglobinopathies.

Greengross P, Hickman M, Gill M, Dugan B, Davies SC

Directorate of Public Health and Health Policy, Brent & Harrow Health Authority, London, UK.

OBJECTIVE: To evaluate universal antenatal screening for haemoglobinopathies. SETTING: District general hospital serving a London borough with 45% ethnic minorities. METHODS: Retrospective cohort study of 1444 women referred in 1688 pregnancies and 95 tertiary referrals during 101 pregnancies. RESULTS: Unselected women at risk for sickle cell disease booked 2.7 weeks (95% confidence interval (CI) 0.14 to 5.1) later in gestation than those at risk for beta thalassaemia were less likely to attend counselling (83% v 93%, relative risk (RR) 0.89; 95% CI 0.85 to 0.94), their partners were less likely to be tested (77% v 95%, RR 0.81; 0.77 to 0.83), and they were less likely to accept prenatal diagnosis (22% v 90%, RR 0.37; 0.24 to 0.57). Over 99% of tertiary referrals attended counselling and had their partners tested. There were no significant differences in acceptance of prenatal diagnosis between those at risk of sickle cell disease and beta thalassaemia (55% v 67%). Unselected women at risk of sickle cell disease were significantly less likely to have their partner tested or to accept prenatal diagnosis than tertiary referrals, but not those at risk of beta thalassaemia. 80% of beta thalassaemia and 16% of SS births were prevented. CONCLUSIONS: Uptake of prenatal diagnosis among unselected women at risk of beta thalassaemia is similar to that reported by tertiary centres. It is considerably lower for sickle cell disease but could increase considerably if screening occurred earlier in gestation. Acceptance of counselling is universally high, suggesting that informed choices are made, and indicating a need to measure these outcomes for cost effectiveness studies.

PMID: 10321363, UI: 99254666

Indian J Gastroenterol 1999 Apr-Jun;18(2):84-6

Hepatic sickling crisis mimicking recurrent cholangitis.

Mehta S, Nagral A, Sucheta VK, Nagral S, Gopal S, Joshi AS, Krishnamurthy S

Division of Digestive Diseases and Clinical Nutrition, Tata Memorial Hospital, Mumbai.

A 22-year-old man with homozygous sickle cell disease presented with recurrent fever, right upper quadrant pain and jaundice. Liver biopsy confirmed the diagnosis of hepatic sickling crisis; the symptoms responded to hydroxyurea therapy. Hepatic vasocclusive crisis can diagnosed on liver biopsy, and need not be a diagnosis of exclusion.

PMID: 10319541, UI: 99253099

Clin Exp Dermatol 1999 Jan;24(1):2-6

Use of hydroxyurea in psoriasis.

Smith CH

Skin Therapy Research Unit, St John's Institute of Dermatology, London, UK. kjackson@umds.ac.uk

Hydroxyurea is an effective treatment in chronic plaque psoriasis that is relatively simple to prescribe. Dose-related bone marrow toxicity is the principal side-effect of therapy although clinically significant complications are few, provided that blood counts are monitored carefully. In contrast with many other second-line agents, renal and liver disease do not necessarily preclude treatment, and there are few drug interactions likely to be of clinical relevance in dermatology. Recent studies on the use of hydroxyurea for sickle cell disease may provide more information on predicting the maximal tolerated dose and potential hazards of long-term therapy in nonmalignant disease and perhaps revive interest in the drug's use in dermatology.

Publication Types:

• Review
• Review, tutorial

PMID: 10233638, UI: 99330586

Br J Haematol 1999 May;105(2):491-6

Erythropoietic activity in patients with sickle cell anaemia before and after treatment with hydroxyurea.

Ballas SK, Marcolina MJ, Dover GJ, Barton FB

Cardeza Foundation for Hematologic Research, Department of Medicine, Jefferson Medical College, Philadelphia, Pennsylvania, USA.

In this project we have prospectively studied the erythropoietic activity in patients with sickle cell anaemia (SS) before and after treatment with hydroxyurea (HU). Some of the patients were enrolled in a double-blind placebo controlled trial of HU in patients with SS and others were enrolled in an open label study. Determinants of erythropoietic activity included the reticulocyte count, red blood cell (RBC) survival by the 51Cr method, plasma 59Fe clearance, plasma iron turnover (PIT), erythron transferrin uptake (ETU), RBC production/destruction rate, and RBC Fe utilization. Therapy with HU increased the mean corpuscular volume (MCV), haemoglobin (Hb)F, RBC survival and t1/2 59Fe clearance; it decreased the reticulocyte count, the white blood cell (WBC) count, ETU, and the PIT. Most of the changes in parameters of erythropoiesis could be explained by the increase in 51Cr RBC survival after therapy with HU. Together the data showed that in selected patients the net effect of HU on Hb level was a function of the difference between the suppressive effect of HU (decreased RBC production) and the increase in RBC survival. In the majority of patients who responded to HU, there was a preferential effect on RBC survival.

Publication Types:

• Clinical trial
• Randomized controlled trial

PMID: 10233426, UI: 99268881

J Am Soc Nephrol 1999 May;10(5):1014-9

Evidence that microdeletions in the alpha globin gene protect against the development of sickle cell glomerulopathy in humans.

Guasch A, Zayas CF, Eckman JR, Muralidharan K, Zhang W, Elsas LJ

Department of Medicine, Emory University School of Medicine, Atlanta, Georgia 30322, USA. aguasch@emory.edu

There is a large variability in the severity of the clinical manifestations of sickle cell anemia (SSA), including renal involvement. Haplotypes in the beta-globin gene cluster associated with the geographical origin of the sickle mutation, as well as microdeletions in the alpha-globin genes, could provide an epigenetic influence on the heterogeneous outcome in SSA. It has been determined that the cause of progressive renal insufficiency in SSA is a glomerulopathy, clinically detected by the presence of macroalbuminuria (albumin excretion rate >300 mg/g creatinine). To investigate the role of the alpha-globin gene microdeletion and beta-globin gene cluster haplotypes on the degree of glomerular involvement, 76 adult SSA patients (hemoglobin SS) were studied to determine the relationship between these genetic markers and the development of sickle cell glomerulopathy. Macroalbuminuria was present in 22 (29%) of 76 adult SSA patients. The coinheritance of microdeletions in one or two of the four alpha-globin genes (alpha-thalassemia) was associated with a lower prevalence of macroalbuminuria (13%) versus patients with intact alpha-globin genes (40%, P = 0.01). By contrast, there was no association between albuminuria and beta-globin gene haplotypes (Central African Republic [CAR] versus non-CAR haplotypes). Patients with alpha-globin gene microdeletions had lower mean corpuscular volumes and mean corpuscular hemoglobin concentration than patients with all four alpha genes (86+/-2 versus 99+/-3 fl, and 33.9+/-0.2 versus 34.9+/-0.2%, respectively, P<0.05). There were no such hematologic differences between CAR and non-CAR beta-globin haplotypes. There were no differences in duration of disease (age), hemoglobin levels, reticulocyte index, and lactate dehydrogenase levels between those with and without glomerulopathy, but the mean arterial pressure was higher (87+/-1 mm Hg) in patients with intact alpha gene locus versus those with microdeletions (80+/-2 mm Hg, P<0.05). It is concluded that the coinheritance of microdeletions in the alpha-globin gene locus in SSA patients confers "renoprotection" by mechanisms not related to the degree of anemia or the severity of hemolysis, but could be related to a reduced mean corpuscular volume or to a lower erythrocyte hemoglobin concentration.

PMID: 10232687, UI: 99247647

Lancet 1999 May 1;353(9163):1504

Addressing the crisis of care for sickle-cell disease.

Morris K

Publication Types:

• News

PMID: 10232329, UI: 99247289

Planta Med 1999 Apr;65(3):209-12

In vitro antisickling activity of a rearranged limonoid isolated from Khaya senegalensis.

Fall AB, Vanhaelen-Fastre R, Vanhaelen M, Lo I, Toppet M, Ferster A, Fondu P

Laboratoire de Pharmacognosie et Bromatologie, l'Universite Libre de Bruxelles, U.L.B., Belgium.

We previously observed that aqueous extracts of the stem bark and leaves of Khaya senegalensis exhibited a strong antisickling activity. These results prompted us to find out the constituent(s) responsible for these properties using an in vitro bio-guided fractionation. The bioassay was based on sickle cells countings, before and after deoxygenation, in blood samples taken from patients with severe sickle cell anemia and pre-incubated with the drugs to be tested. The main active constituent was identified as a rearranged limonoid whose structure was recently elucidated. In comparison with pentoxifylline used as standard, the in vitro antisickling activity of this limonoid was much higher at any concentrations and incubation conditions. In addition, it did not alter significantly the corpuscular indices.

PMID: 10232063, UI: 99248845

Magn Reson Imaging 1999 May;17(4):503-15

Diffuse T1 reduction in gray matter of sickle cell disease patients: evidence of selective vulnerability to damage?

Steen RG, Langston JW, Ogg RJ, Xiong X, Ye Z, Wang WC

Department of Diagnostic Imaging, St. Jude Children's Research Hospital, University of Tennessee School of Medicine, Memphis 38105-2794, USA. Grant.Steen@StJude.org

The objective of our study was to test the hypothesis that subtle brain abnormality can be present in pediatric sickle cell disease (SCD) patients normal by conventional MR imaging (cMRI). We examined 50 SCD patients to identify those patients who were normal by cMRI. Quantitative MR imaging (qMRI) was then used to map spin-lattice relaxation time (T1) in a single slice in brain tissue of all 50 patients and in 52 healthy age-similar controls. We also used a radiofrequency (RF) pulse to saturate blood spins flowing into the T1 map slice, to characterize the effect of blood flow on brain T1. Abnormalities were noted by cMRI in 42% (21/50) of patients, with lacunae in 32%, and encephalo malacia in 20%. Brain T1 in patients normal by cMRI was significantly lower than controls, in caudate, thalamus, and cortex (p < or =0.007), and regression showed that gray matter T1 abnormality was present in caudate and cortex by age 4 (p < or =0.002). In patients abnormal by cMRI, T1 reductions in gray matter were larger and more significant. White matter T1 was not significantly increased except in patients abnormal by cMRI. RF saturation in a slab below the T1 map produced no significant change in T1, compared to RF saturation in a slab above the T1 map, suggesting that inflow of untipped spins in blood does not cause an artifactual shortening of T1. Gray matter T1 abnormality was present in patients normal by cMRI, while white matter T1 abnormality was present only in patients also abnormal by cMRI. These findings suggest that gray matter is selectively vulnerable to damage in pediatric SCD patients and that white matter damage occurs later in the disease process. Our inability to find an effect from saturation of inflowing blood implies that rapid perfusion cannot account for T1 reduction in gray matter.

PMID: 10231177, UI: 99246208

Epidemiology 1999 May;10(3):282-7

Predictors of urinary tract infection at the first prenatal visit.

Pastore LM, Savitz DA, Thorp JM Jr

Department of Epidemiology, School of Public Health, University of North Carolina at Chapel Hill, 27599-7400, USA.

We identified maternal demographic, behavioral, and medical history factors that predict bacteriuria (that is, symptomatic and asymptomatic urinary tract infection) at prenatal care initiation. We applied logistic regression modeling to data from all prenatal care recipients who delivered during 1990-1993 and resided in selected North Carolina counties (N = 8037), omitting those with diabetes mellitus, human immunodeficiency virus, or structural urologic abnormalities. The two strongest predictors of bacteriuria at prenatal care initiation were an antepartum urinary tract infection prior to prenatal care initiation (for whites, adjusted prevalence odds ratio (POR) = 2.5, 95% CI 0.6-9.8; for blacks, POR = 8.8, 95% CI 3.8-20.3) and a pre-pregnancy history of urinary tract infection (POR = 2.1, 95% CI 1.4-3.2). For white women only, education beyond high school and age > or =30 years were inversely associated (POR < or = 0.6). Sickle cell hemoglobin nearly doubled the prevalence odds for bacteriuria among African-Americans (POR = 1.9, 95% CI 1.0-3.5), whereas African-Americans with normal hemoglobin had reduced prevalence odds compared with whites (POR = 0.6, 95% CI 0.4-0.9). This study suggests predictors not considered before, including race controlling for sickle cell disease or trait and antepartum urinary tract infections prior to prenatal care.

PMID: 10230839, UI: 99245870

J R Coll Surg Edinb 1999 Apr;44(2):130-1

Sickle cell trait and acute intermittent porphyria leading to small bowel infarction.

Budhoo MR, Mitchell S, Roberts I, Eddlestone J, MacLennan I

Department of General and Colorectal Surgery, Manchester Royal Infirmary, U.K.

Sickle cell trait patients rarely have crises. A case of co-morbidity with acute intermittent porphyria is described in which trans-mural infarction of the distal ileum secondary to red cell sickling resulted in a fatal outcome.

PMID: 10230209, UI: 99246824

Rinsho Byori 1999 Mar;47(3):238-43

[The origin of molecular disease: functional abnormalities and consequent clinical symptoms caused by single amino acid substitutions].

Imai K

Division of Physiology and Biosignaling, Graduate School of Medicine A4, Osaka University, Suita.

The discovery of sickle cell hemoglobin in 1949 lead to the concept of "molecular disease". Since then, the total number of abnormal hemoglobins has been increasing, reaching 750 in April, 1998. Of these, 91% are variants with single amino acid substitutions. A "scratch" made in the protein moiety can cause alterations in physicochemical properties such as oxygen affinity, stability and autooxidation of 50% of all variants, further causing hematological or clinical disorders with significant frequencies. Generally, these alterations in properties and consequent hematological or clinical disorders are closely related to the mode and intramolecular location of the mutation. Conventional laboratory methods for mass screening of abnormal hemoglobins such as electrophoresis, isoelectric focusing and ion-exchange HPLC may overlook clinically important variants which possess amino acid substitutions without change in the charge. Oxygen affinity measurement may be a useful method to detect silent variants. Modern apparatuses can quickly and conveniently construct a continuous oxygen dissociation curve from one drop of whole blood. The dissociation curve becomes biphasic when the red cell contains abnormal hemoglobin with abnormal oxygen affinity. The continuous curve recording is advantageous because the proportion of the abnormal hemoglobin component can be estimated and the abnormal chain, either alpha or beta, can be predicted based on the inflection point of the biphasic curve.

Publication Types:

• Review
• Review, tutorial

PMID: 10228389, UI: 99245073

Gastrointest Endosc 1999 May;49(5):626

Impacted pigment gallstone.

Zagnoon A, Ehrinpreis MN

Wayne State University School of Medicine, Detroit, Michigan, USA.

PMID: 10228262, UI: 99246301

Am J Respir Crit Care Med 1999 May;159(5 Pt 1):1368-76

The acute chest syndrome in sickle cell disease. Possible role of nitric oxide in its pathophysiology and treatment.

Gladwin MT, Schechter AN, Shelhamer JH, Ognibene FP

The Critical Care Medicine Department of the Warren G. Magnuson Clinical Center and the Laboratory of Chemical Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, 20892-1662, USA.

Publication Types:

• Review
• Review, tutorial

PMID: 10228097, UI: 99246465

Liver Transpl Surg 1999 May;5(3):161-5

Living related liver transplantation for acute liver failure in children.

Emre S, Schwartz ME, Shneider B, Hojsak J, Kim-Schluger L, Fishbein TM, Guy SR, Sheiner PA, LeLeiko NS, Birnbaum A, Suchy FJ, Miller CM

Recanati/Miller Transplantation Institute, Mount Sinai Medical Center, New York, NY 10029, USA.

The mortality rate among children with acute liver failure (ALF) on the waiting list for liver transplantation is high. We present our experience with living related donor liver transplantation (LRD-LT) in children who required urgent transplantation for ALF. Between December 1995 and July 1997, 6 children underwent LRD-LT for ALF. Cause of liver failure, recipient and donor demographics, clinical and laboratory data, surgical details, complications, and 6-month and 2-year graft and patient survival were recorded. Five boys and 1 girl received left lateral segment grafts from their parents. The mean age was 4 +/- 2.8 years (range, 1 to 9 years). ALF was caused by Wilson's disease in 1 patient and sickle cell intrahepatic cholestasis syndrome in 1 patient; in 4 patients, the cause was unknown. All patients had mental status changes; 2 were on life support. Mean pretransplantation liver function test values were: alanine aminotransferase, 972 +/- 565 U/L (normal, 1 to 53 U/L), total bilirubin, 31.3 +/- 12.4 mg/dL (normal, 0.1 to 1.2 mg/dL), prothrombin time, 34.3 +/- 12.4 seconds (normal, 10.8 to 13.3 seconds), international normalized ratio, 8.46 +/- 5.4 (normal < 2), and fibrinogen, 109 +/- 23.9 mg/dL (normal, 175 to 400 mg/dL). The donors were 5 mothers and 1 father. The mean donor age was 32.5 +/- 7.6 years (range, 19 to 40 years). No donor required blood transfusion, and no donor had any early or late postoperative complications. The donors' mean hospital length of stay was 5 days. In five cases, grafts were blood group-compatible; 1 child received a blood group-incompatible graft. All grafts functioned immediately. No patient had hepatic artery or portal vein thrombosis or biliary complications. The child who received a mismatched graft died of infection of the brain caused by Aspergillus spp at 22 days posttransplantation with a functioning graft. The child with ALF caused by sickle cell intrahepatic cholestasis syndrome developed outflow obstruction 3 months posttransplantation and required retransplantation; he eventually died of vascular complications related to his primary disease. Four children are alive at a mean follow-up of 27 months (range, 14 to 36 months). LRD-LT for children with ALF facilitates timely transplantation without drawing on cadaveric donor resources. The established safety record of LRD-LT made this option appealing to both physicians and parental donors.

PMID: 10226105, UI: 99244811

Trop Med Int Health 1999 Mar;4(3):187-93

Malaria infection and morbidity in infants in relation to genetic polymorphisms in Tanzania.

Stirnadel HA, Stockle M, Felger I, Smith T, Tanner M, Beck HP

Swiss Tropical Institute, Basel. stirnadel@ubaclu.unibas.ch

To investigate the effects of host polymorphisms on malaria morbidity and infection, the frequency distributions of TNF alpha promotor gene and sickle cell trait were studied in infants in an area highly endemic for Plasmodium falciparum transmission in Tanzania. Differences in parasite prevalence, density, febrile episodes with and without parasitaemia, PCV levels and the frequencies of different MSP-2 parasite infections were assessed by genotype. The frequency of the TNF alpha promotor allele 2 was 0.09, and the trait was in Hardy-Weinberg equilibrium. There were no differences in malariametric indices between infants with the normal TNF alpha promoter gene and those who were heterozygous for this trait. Infants heterozygous for the TNF alpha promotor gene appeared to have fewer febrile episodes when they were free of parasites. The two infants homozygous for the TNF alpha promoter allele 2 had both a much higher incidence of fever, independently of parasitaemia, than the average for the other genotypes. The frequency of the sickle cell allele S was 0.06 and the trait was also in Hardy-Weinberg equilibrium. Infants heterozygous for the sickle cell trait had significantly lower parasite densities, but similar prevalence, and MSP-2 infections compared to infants with normal haemoglobin. PCV levels, and the incidence of febrile episodes both with and without parasitaemia were also similar. In contrast to the sickle cell trait, the TNF alpha promotor polymorphism appeared not to have any protective effect on malaria in this study, and its importance in other unspecified fever-causing diseases in this population needs further investigation.

PMID: 10223213, UI: 99237724

J Cardiovasc Surg (Torino) 1999 Feb;40(1):171-2

Absence of severe haemolysis in an adult patient with an aortic mechanical prosthesis and a rare form of sickle cell trait.

Agnino A, Schena S, Vitale N, de Luca Tupputi Schinosa L

Publication Types:

• Letter

PMID: 10221409, UI: 99236598

Telemed J 1998 Winter;4(4):353-61

Primary-care delivery for sickle cell patients in rural Georgia using telemedicine.

Woods K, Kutlar A, Grigsby RK, Adams L, Stachura ME

Medical College of Georgia Sickle Cell Center, Augusta, Georgia 30912, USA.

BACKGROUND: Advances in newborn screening and pediatric management of sickle cell disease have resulted in patients living well into adulthood. For adults, preventive care and medication monitoring are crucial for optimal health maintenance. The Medical College of Georgia (MCG) in Augusta provides consultative services and comprehensive medical care to about 1200 sickle cell patients residing in middle and southern Georgia. An increase in the demand for clinical services in this patient population has resulted in expansion of sickle cell outreach efforts throughout the state. OBJECTIVE: A telemedicine clinic for adult sickle cell patients was established in order to meet the growing clinical demands. METHODS: An on-site outreach clinic was introduced in the target area. After 10 months of operation, a monthly telemedicine clinic was offered to patients as an option for routine medical follow-up. A clinic model was used, with scheduled appointments and a public health nurse assisting at the remote site. Phlebotomy and laboratory services enhanced the telemedicine encounter. RESULTS: Over a 12-month period, 52 encounters for 28 patients from 17 medically underserved counties were completed. All patients were African-American, and 89. 3% had Medicaid or Medicare insurance coverage or both. The clinic encounter time was 24 +/- 7.9 minutes (mean +/- SD), comparable to that for all telemedicine clinic encounters during the same period. CONCLUSIONS: The adult sickle cell population in rural Georgia accepts innovative health care delivery using telemedicine. Thus, the telemedicine sickle cell clinic has increased access to care for rural patients in underserved areas. For providers, it has allowed greater clinical productivity and diminished travel time to outreach clinics.

PMID: 10220476, UI: 99238544

Rev Prat 1999 Mar 15;49(6):667-74

[Thalassemia, sickle cell disease. Physiopathology and diagnosis].

Girot R

Service d'hematologie, hopital Tenon, Paris.

PMID: 10218408, UI: 99235032

Int J Vitam Nutr Res 1999 Mar;69(2):67-82

High-dose vitamin C: a risk for persons with high iron stores?

Gerster H

Vitamin Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.

The contribution of vitamin C (ascorbic acid) to the prevention of iron deficiency anemia by promoting the absorption of dietary non-heme iron-especially in persons with low iron stores--is well established. But the question has been raised whether high-dose intakes of vitamin C might unduly enhance the absorption of dietary iron in persons with high iron stores or in patients with iron overload, possibly increasing the potential risk of iron toxicity. Extensive studies have shown that overall the uptake and storage of iron in humans is efficiently controlled by a network of regulatory mechanisms. Even high vitamin C intakes do not cause iron imbalance in healthy persons and probably in persons who are heterozygous for hemochromatosis. The uptake, renal tubular reabsorption and storage of vitamin C itself are also strictly limited after high-dose intake so that no excessive plasma and tissue concentrations of vitamin C are produced. The effect of high-dose vitamin C on iron absorption in patients with iron overload due to homozygous hemochromatosis has not been studied. Of special importance is the early identification of hemochromatosis patients, which is assisted by the newly developed PCR test for hereditary hemochromatosis. Specific treatment consists of regular phlebotomy and possibly iron-chelating therapy. These patients should moreover avoid any possibility of facilitated absorption of iron and need to limit their intake of iron. Patients with beta-thalassemia major and sickle cell anemia who suffer from iron overload due to regular blood transfusions or excessive destruction of red blood cells need specialized medical treatment with iron chelators and should also control their intake of iron. The serum of patients with pathological iron overload can contain non-transferrin-bound iron inducing lipid peroxidation with subsequent consumption of antioxidants such as vitamin E and vitamin C. The role of iron in coronary heart disease and cancer is controversial. Early suggestions that moderately elevated iron stores are associated with an increased risk of CHD have not been confirmed by later studies. In vitro, ascorbic acid can act as a prooxidant in the presence of transition metals such as iron or copper, but in the living organism its major functions are as an antioxidant. High intakes of vitamin C have thus not been found to increase oxidative damage in humans. Accordingly, the risk of CHD or cancer is not elevated. On the contrary, most studies have shown that diets rich in vitamin C are inversely related to the incidence of these diseases.

Publication Types:

• Review
• Review, academic

PMID: 10218143, UI: 99234766

Ann Otol Rhinol Laryngol Suppl 1999 Apr;177:31-4

Using the CLARION cochlear implant in cochlear ossification.

Bird PA, Balkany TJ, Hodges AV, Butts S, Gomez O, Lee D

Department of Otolaryngology, University of Miami Ear Institute, Florida 33101, USA.

This paper is a retrospective review of 5 patients with various degrees of cochlear ossification who were implanted with the CLARION Multi-Strategy Cochlear Implant. Preoperative computed tomography scans, intraoperative findings, surgical technique, and hearing outcomes are discussed in a case report format. Full implantation was achieved in all cases by a systematic approach that included drill-through of proximal obstruction (2 cases), scala vestibuli insertion (2 cases), and complete drill-out (1 case). The only complication was delayed wound healing in a patient with sickle cell disease, chronic active hepatitis, and steroid dependency on antimetabolite therapy. Early results show that the 4 patients with at least 3 months of experience have a mean open-set sentence recognition score of 55% and a mean open-set word recognition score of 24%. The conclusion is that implantation of the Clarion device in ossified cochleas can be successful in all degrees of ossification and can provide significant hearing benefit.

Publication Types:

• Clinical trial

PMID: 10214798, UI: 99229611

Rev Epidemiol Sante Publique 1999 Mar;47(1):29-36

[Prevalence of hemoglobin abnormalities in Kebili].

Mseddi S, Gargouri J, Labiadh Z, Kassis M, Elloumi M, Ghali L, Dammak J, Harrabi M, Souissi T, Frikha M

Service d'hematologie-C.H.U. Hedi Chaker, Sfax, Tunisie.

BACKGROUND: Hemoglobin abnormalities constitute a public health problem in many countries in the world. In Tunisia, these disorders were thought to affect only the North-western population. However, the existence of hemoglobinosis concentration in Kebily in south Tunisia has been suggested by previous work. In order to estimate their frequencies, we performed a screening of hemoglobin abnormalities in the North-Kebili region, to establish a prevention program of the homozygous forms. METHODS: This screening concerned all 1st and 2nd grade primary school pupils in North Kebily. After a questionnaire, a blood sample was drawn from every child. Hemogram, sickling test, and hemoglobin electrophoresis at alkaline pH were performed for all children. Hemoglobin electrophoresis at acid pH and a specific hemoglobin A2 titration were performed for some children. RESULTS: The study concerned 1,400 children, aged between 5 and 12 years, the mean age was 7 years and 7 months +/- 10 months. Consanguinity rate and coefficient were respectively 44% and 2249 x 10(5). Endogamy was very high. The global rate of hemoglobin abnormalities was 9.4%. Drepanocytosis with a rate of 4.9% was the most frequent, followed by beta thalassemia (3.1%) and C hemoglobinosis (1.6%). These abnormalities were unequally distributed; very frequent in some localities, they were quite absent in others. CONCLUSIONS: This study revealed a hemoglobinosis concentration in Tunisia, which can be classified second after that of Beja in North-western Tunisia. The heterogeneous distribution of the hemoglobin abnormalities in North-Kebili region and the high consanguinity and endogamy rates constitute factors that promote homozygous and double heterozygous forms to arise and justify the elaboration of a preventive strategy.

PMID: 10214674, UI: 99231289

Int J Artif Organs 1999 Feb;22(2):61-3

Kidney transplant in sickle cell nephropathy.

Ribot S

Publication Types:

• Editorial

PMID: 10212038, UI: 99227020

Postgrad Med J 1998 Sep;74(875):516-23

Hyponatraemia: biochemical and clinical perspectives.

Gill G, Leese G

University Clinical Department, Fazakerley Hospital, Liverpool, UK.

Hyponatraemia is a common bio-chemical abnormality, occurring in about 15% of hospital inpatients. It is often associated with severe illness and relatively poor outcome. Pathophysiologically, hyponatraemia may be spurious, dilutional, depletional or redistributional. Particularly difficult causes and concepts of hyponatraemia are the syndrome of inappropriate antidiuresis and the sick cell syndrome, which are discussed here in detail. Therapy should always be targeted at the underlying disease process. 'Hyponatraemic symptoms' are of doubtful importance, and may be more related to water overload and/or the causative disease, than to hyponatraemia per se. Artificial elevation of plasma sodium by saline infusion carries the risk of induction of osmotic demyelination (central pontine myelinolysis).

PMID: 10211323, UI: 99227769

N Z Med J 1999 Mar 12;112(1083):78

An unusual cause of haematuria.

Macdonald A

Renal Unit, Wellington Hospital.

A case of gross haematuria is described in a young woman. This was initially attributed to the use of analgesics. Subsequent history and investigation confirmed that the cause for the haematuria was sickle cell trait occurring in an individual in whom it was not initially suspected.

PMID: 10210309, UI: 99225034

Ann Fr Anesth Reanim 1999 Feb;18(2):233-6

[Autologous transfusion and hemoglobin SC disease].

Lecam B, Woimant G, Gautreau C, Cherruau B, Conseiller C

Departement d'anesthesie-reanimation chirurgicale, etablissement de transfusion sanguine de l'AP-HP, Paris, France.

Three autologous blood units were transfused during elective orthopaedic surgery in a patient with undiagnosed haemoglobin SC disease. The packed red blood cells had been stored at 4 degrees C on SAG-M under standard conditions for 10 to 31 days. There was no evidence of adverse clinical reactions during the perioperative period. Six months later, a blood unit was collected at the initial step of an exchange transfusion in the same patient. Haemolysis was moderate after a 12-day-storage period and more significant after 32 days. This observation, as some other case reports, suggest that autologous blood transfusion may be considered for haemorrhagic surgery in selected patients with sickle cell disease.

PMID: 10207597, UI: 99224004

J Pediatr Hematol Oncol 1999 Mar-Apr;21(2):165-9

Delayed methotrexate clearance in a patient with sickle cell anemia and osteosarcoma.

Mantadakis E, Rogers ZR, Smith AK, Quigley R, Ratliff AF, Kamen BA

Department of Pediatrics, UT Southwestern Medical Center at Dallas and Children's Medical Center of Dallas, Texas 75235-9063, USA.

A 15-year-old girl with homozygous sickle cell anemia (HbSS) and osteosarcoma is described. Delayed clearance of methotrexate (MTX) after the second course of high-dose MTX (HDMTX) led to the development of renal and hepatic toxicities. Rescue was accomplished with high-dose leucovorin, intravenous carboxypeptidase G2, and thymidine. Although the renal and hepatic abnormalities resolved, focal tonic-clonic seizures developed, accompanied by abnormal brain imaging. Four weeks after this episode, all clinical and biochemical abnormalities resolved. Preexistent end-organ damage associated with HbSS may compromise the ability to deliver high-dose chemotherapy with curative intent in patients with malignant disease.

PMID: 10206466, UI: 99221307

J Pediatr Hematol Oncol 1999 Mar-Apr;21(2):129-35

Tonsillectomy, adenoidectomy, and myringotomy in sickle cell disease: perioperative morbidity. Preoperative Transfusion in Sickle Cell Disease Study Group.

Waldron P, Pegelow C, Neumayr L, Haberkern C, Earles A, Wesman R, Vichinsky E

Department of Pediatrics, University of Virginia, Charlottesville, USA.

PURPOSE: To compare the rates of perioperative morbidity of patients with sickle cell anemia who were randomly assigned to 2 preoperative transfusion regimens and to identify predisposing factors for perioperative complications. PATIENTS AND METHODS: Investigators at 36 centers enrolled 118 patients who were scheduled to have elective surgery and agreed to randomization between 2 preoperative transfusion regimens. Forty-seven subjects were enrolled but not randomized, including 20 who were not transfused before surgery. Perioperative management was based on a prescribed care plan. RESULTS: Tonsillectomy and/or adenoidectomy (TA) were performed on 136 persons, and 29 had myringotomy as their primary procedure. There were no differences in the frequency of complications between the randomized groups. The serious, non-transfusion complication rates for randomized patients were 32% (34 of 107) for TA and 36% (4 of 11) for myringotomy. A history of pulmonary disease was a predictor of postoperative sickle cell-related events for patients undergoing TA surgery. CONCLUSIONS: The more intensive transfusion regimen did not result in fewer perioperative complications. The high frequency of complications emphasizes the need for anticipatory management of persons undergoing TA. A history of pulmonary disease identifies patients at increased risk for sickle cell-related events after TA surgery. Patients undergoing myringotomy have a low frequency of sickle cell-related events but a significant frequency of other serious perioperative complications.

Publication Types:

• Clinical trial
• Multicenter study
• Randomized controlled trial

PMID: 10206459, UI: 99221300

Int J Pediatr Otorhinolaryngol 1999 Jan 25;47(1):23-8

Otologic findings in a pediatric cohort with sickle cell disease.

MacDonald CB, Bauer PW, Cox LC, McMahon L

Department of Otolaryngology--Head and Neck Surgery, Boston Medical Center, MA 02118-2393, USA.

OBJECTIVE: Sensorineural hearing loss (SNHL) has been associated with sickle cell disease (SCD) in older children and adults. Few studies have investigated this association in younger children. DESIGN: In a cohort of pediatric patients followed at our sickle cell clinic, with a mean age of 7.8 years, 154 audiograms were completed on 84 patients. RESULTS: This produced 22 subjects with abnormal audiograms. Middle ear effusion was the etiology of 19 subjects' audiometric findings. Three children were found to have mild SNHL. None of the subjects had hearing loss of severity which would warrant amplification. The prevalence rate for SNHL in our cohort of pediatric patients was 3.5%. CONCLUSION: This differs from past reports, and may reflect an age dependent prevalence of SNHL in this disease.

PMID: 10206391, UI: 99221232

Keio J Med 1999 Mar;48(1):12-21

Molecular biology and reproduction.

McDonough PG

Department of Obstetrics and Gynecology-Reproductive Endocrinology-Infertility, Medical College of Georgia, Augusta 30912-3360, USA. obgyn.pmcdonou@mail.mcg.edu

Modern molecular biology has provided unique insights into the fundamental understanding of reproductive disorders and the detection of microorganisms. The remarkable advances in DNA diagnostics have been expedited by the development of polymerase chain reaction (PCR) and the ability to isolate DNA and RNA from many different sources such as blood, saliva, hair roots, microscopic slides, paraffin-embedded tissue sections, clinical swabs, and even cancellous bone. These technical advances have been bolstered by the development of an increasing number of effective screening techniques to scan genomic DNA for unknown point mutations. The continued development of technology will ultimately result in automated DNA (desoxyribonucleic acid) diagnosis for the practicing clinician. The continuing expansion of information concerning the human genome will place an increasing emphasis on bioinformatics and the use of computer software for analyzing DNA sequences. With the automation of DNA diagnosis and the use of small samples (500 nanograms), the direct examination of the DNA of a patient, fetus, or microorganism will emerge as a definitive means of establishing the presence of the specific genetic change that causes disease. A knowledge of the precise pathology at the molecular level has and will provide important insights into the biochemical basis for many human diseases. A firm knowledge of the DNA alterations in disease and expression patterns of specific genes will provide for more directed therapeutic strategies. The refinement of vector technology and nuclear transplantion techniques will provide the opportunity for directed gene therapy to the early human embryo. This presentation is designed to acquaint the reader with current techniques of testing at the DNA level, prototype mutations in the reproductive sciences, new concepts in the molecular mechanisms of disease that affect reproduction, and therapeutic opportunities for the future. It is hoped that future refinement of these techniques combined with the ability to maintain genetic modification of these cells with recombinant vector technology will provide a definitive therapy for many single gene disorders, such as sickle cell anemia and thalassaemia. It is truly the challenge of the next century to decipher how these legions of newly discovered genes work, and to create a molecular language that can extend across all organisms.

Publication Types:

• Review
• Review, tutorial

PMID: 10206014, UI: 99222746

J Bone Joint Surg Br 1999 Mar;81(2):349-55

Decrease in the mesenchymal stem-cell pool in the proximal femur in corticosteroid-induced osteonecrosis.

Hernigou P, Beaujean F, Lambotte JC

Department of Orthopaedics, Hopital Henri Mondor, Creteil, France.

We have evaluated bone-marrow activity in the proximal femur of patients with corticosteroid-induced osteonecrosis and compared it with that of patients with osteonecrosis related to sickle-cell disease and with a control group without osteonecrosis. Bone marrow was obtained by puncture of the femoral head outside the area of necrosis and in the intertrochanteric region. The activity of stromal cells was assessed by culturing fibroblast colony-forming units (FCFUs). We found a decrease in the number of FCFUs outside the area of osteonecrosis in the upper end of the femur of patients with corticosteroid-induced osteonecrosis compared with the other groups. We suggest that glucocorticosteroids may also have an adverse effect on bone by decreasing the number of progenitors. The possible relevance of this finding to osteonecrosis is discussed.

PMID: 10204950, UI: 99219685

Other Formats:

Am J Hematol 1999 Apr;60(4):279-84

Hemoglobin S/O(Arab): thirteen new cases and review of the literature.

Zimmerman SA, O'Branski EE, Rosse WF, Ware RE

Department of Pediatrics, Duke University Medical Center, Durham, North Carolina 27710, USA. Zimme008@mc.duke.edu

Hemoglobin S/O(Arab) (Hb S/O(Arab)) is a rare compound heterozygous hemoglobinopathy characterized by the presence of two variant beta-globin chains: beta6Glu --> Val (Hb S) and beta121Glu --> Lys (Hb O(Arab)). The diagnosis of Hb S/O(Arab) requires electrophoresis on both cellulose acetate and citrate agar, since Hb O(Arab) co-migrates with Hb C at alkaline pH and close to Hb S at acidic pH. To date only case reports and small series of patients with Hb S/O(Arab) have been described. To better characterize the clinical and laboratory aspects of this unusual disorder, we reviewed the Duke University Medical Center experience. We identified 13 African-American children and adults with Hb S/O(Arab) ranging in age from 2.7 to 62.5 years. All patients had hemolytic anemia with a median Hb of 8.7 gm/dL (range 6.1-9.9 gm/dL), and a median reticulocyte count of 5.8% (range 1.2-10.3%). The peripheral blood smear typically showed sickled erythrocytes, target cells, polychromasia, and nucleated red blood cells. All 13 patients have had significant clinical sickling events including acute chest syndrome (11), recurrent vasoocclusive painful events (10), dactylitis (7), gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis (2), leg ulcers (2), cerebrovascular accident (CVA) (1), osteomyelitis (1), and retinopathy (1). Four patients have died, including two from pneumococcal sepsis/meningitis at ages 5 and 10 years, one of acute chest syndrome at age 14 years, and one of multiorgan failure at age 35 years. We conclude that Hb S/O(Arab) disease is a severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those of homozygous sickle cell anemia.

Publication Types:

• Review
• Review of reported cases

PMID: 10203101, UI: 99217751

Am J Hematol 1999 Apr;60(4):268-72

Role of positron emission tomography in determining the extent of CNS ischemia in patients with sickle cell disease.

Reed W, Jagust W, Al-Mateen M, Vichinsky E

Department of Hematology/Oncology, Children's Hospital Medical Center, Oakland, California 94609, USA.

Nearly 25% of patients with sickle cell disease (SCD) experience central nervous system morbidity involving both large and small vessel disease. Optimal imaging methods for determining the extent of ischemia are not known. Positron emission tomography (PET) has the unique ability to show tissue function as well as structure. Reports concerning patients with non-SCD neurodegenerative disorders suggest PET may be useful in determining prognosis. We compared magnetic resonance imaging, magnetic resonance angiography, and neuropsychological testing with PET prospectively. Six patients with SCD and a history of stroke, aged 10 to 28, were enrolled. PET studies were performed on an ECAT HR 47 scanner (Siemens/CTI, Knoxville, TN) using 18-F-fluorodeoxyglucose as a tracer. PET interpretations were conducted in blinded fashion. MRI studies found two patients with only small vessel disease and four with both large and small vessel disease. In two of four subjects with large vessel disease, PET showed a corresponding metabolic abnormality and also identified an area of hypometabolism extending beyond the anatomical lesion as shown by MRI. PET did not demonstrate an abnormality corresponding with small vessel disease. Detailed neuropsychological testing demonstrated cognitive dysfunction in all cases. For some patients, PET may add sensitivity in detecting impaired metabolism in the area surrounding a major vessel infarct. However, the technique does not appear to be generally useful in characterizing small watershed or deep white matter infarcts. Larger studies, to include control subjects and carefully selected untransfused SCD patients, are needed. A combination of conventional imaging and neuropsychological testing remains the preferred evaluation for most SCD patients with neurologic symptoms.

PMID: 10203099, UI: 99217749

Nat Struct Biol 1999 Apr;6(4):307

First molecular explanation of disease.

Smith T

Publication Types:

• Historical article

Comments:

• Comment in: Nat Struct Biol 1999 Apr;6(4):293-4

PMID: 10201392, UI: 99215575

J Investig Med 1999 Mar;47(3):121-7

Platelet-erythrocyte adhesion in sickle cell disease.

Wun T, Paglieroni T, Field CL, Welborn J, Cheung A, Walker NJ, Tablin F

Division of Hematology-Oncology, UC Davis, School of Medicine, Sacramento 95817, USA.

BACKGROUND: The abnormal adherence of sickle red blood cells (sRBC) to other cell types likely contributes to vaso-occlusion. Increased numbers of platelet-erythrocyte aggregates (PEA) and platelet activation have been described in sickle cell disease. The present study was undertaken to determine the contribution, if any, of the extracellular matrix protein thrombospondin to the adhesion of sRBC and platelets. METHODS: Platelet activation and PEA were measured using fluorescent-labeled monoclonal antibodies and flow cytometry. Platelet red-cell adhesion was measured by a gravity sedimentation assay. Erythrocyte-bound thrombospondin (TSP) was determined by enzyme-linked immunoabsorbant assay (ELISA). RESULTS: Our studies demonstrate significant platelet activation and adhesion of sRBC to platelets in sickle cell disease. Thrombospondin was detected on sRBC. There was variable inhibition of sRBC-platelet adhesion by antibodies to CD36 (thrombospondin receptor) and antibodies to thrombospondin. CONCLUSIONS: Thrombospondin on sRBC may mediate, at least in part, sRBC-platelet adhesion in sickle cell disease. The study of heterotypic cell-cell interactions is important in understanding the pathogenesis of vaso-occlusion in sickle cell disease.

PMID: 10198567, UI: 99214756

Arch Dis Child Fetal Neonatal Ed 1998 Nov;79(3):F161-7

Costing model for neonatal screening and diagnosis of haemoglobinopathies.

Cronin EK, Normand C, Henthorn JS, Hickman M, Davies SC

Department of Public Health Policy, London School of Hygiene and Tropical Medicine.

AIM: To compare the costs and cost effectiveness of universal and targeted screening for the haemoglobinopathies; to compare the cost of two laboratory methods; and to estimate the cost effectiveness of programmes at different levels of prevalence and mix of haemoglobinopathy traits. METHODS: A retrospective review of laboratory and follow up records to establish workload and costs, and estimation of costs in a range of circumstances was made in a haematology department and sickle cell and thalassaemia centre, providing antenatal and neonatal screening programmes in Inner London. The costs for 47,948 babies, screened during 1994, of whom 25 had clinically significant haemoglobinopathies and 704 had haemoglobinopathy traits, were retrospectively assessed. RESULTS: The average cost per baby tested (isoelectric focusing and high power liquid chromatography) was 3.51 Pounds /3.83 Pounds respectively; the cost per case of sickle cell disease identified (IEF/HPLC) was 6738 Pounds /7355 Pounds; the cost per trait identified (IEF/HPLC) was 234 Pounds /255 Pounds; the cost per extra case of SCD and trait identified by universal programme varied. CONCLUSIONS: IEF and HPLC are very similar in terms of average cost per test. At 16 traits/1000 and 0.5 SCD/1000 there was no significant identification cost difference between universal and targeted programmes. Below this prevalence, a targeted programme is cheaper but likely to miss cases of SCD. If targeted programmes were 90-99% effective, universal programmes would cease to be good value except at very high prevalence. Greater use of prenatal diagnosis, resulting in termination, and therefore fewer affected births, reduces the cost effectiveness of universal screening. Screening services should aim to cover a screened population which will generate a workload over 25,000 births a year, and preferably over 40,000.

PMID: 10194984, UI: 99210888

Anaesthesia 1998 Dec;53(12):1204-6

Major vascular surgery in a patient with sickle cell disease.

Vipond AJ, Caldicott LD

Department of Anaesthetics, St James's University Hospital, Leeds, UK.

We report a patient with homozygous sickle cell disease who underwent femoropopliteal bypass for claudication on walking 10m. Isotope studies showed a blood flow in his left femoral artery of only 0.808 ml. 100ml.min-1. The potential problems of sickle cell disease combined with peripheral vascular disease were probably reduced in this patient because he had an increased fetal haemoglobin level of 13%. Despite the femoral artery being clamped for 100 min, no sickling crisis occurred.

PMID: 10193226, UI: 99209306

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Blood Coagul Fibrinolysis 1999 Mar;10(2):111-2

Incidence of G20210A mutation in severe vaso-occlusive events complicating sickle cell anemia.

Favier R, Neonato MG, Maillet F, Feingold J, Cayre Y, Girot R

Publication Types:

• Letter

PMID: 10192661, UI: 99206879

Br J Haematol 1999 Mar;104(4):930

Overwhelming septicaemia in a patient with sickle cell/beta(0) thalassaemia and partial splenectomy.

Svarch E, Nordet I, Gonzalez A

Publication Types:

• Letter

PMID: 10192464, UI: 99206682

Br J Haematol 1999 Mar;104(4):868-70

Red cell deformability in oral contraceptive pill users with sickle cell anaemia.

Yoong WC, Tuck SM, Yardumian A

Department of Obstetrics and Gynaecology, Royal Free Hospital and School of Medicine, London.

The use of the combined oral contraceptive pill (COCP) in women with sickle cell anaemia (SCA) is controversial, as contraceptive steroids are thought to adversely affect erythrocyte deformability. This observational study was performed to investigate whether hormonal contraception influenced erythrocyte deformability in women with SCA. 30 women with SCA using various contraceptive modalities: COCP (n = 10); progestogen only (PO) contraception (n = 10) and non-hormonal contraception (n = 10) were recruited. Erythrocyte deformability was assessed using the clogging rate (CR) and red cell transit time (RCTT). There was no statistical difference in the mean CR and RCTT between the three groups of women (one-way ANOVA). Current contraceptive steroids do not appear to impair red cell deformability in women with SCA.

Publication Types:

• Multicenter study

PMID: 10192452, UI: 99206670

Br J Haematol 1999 Mar;104(4):860-7

Mapping the prevalence of sickle cell and beta thalassaemia in England: estimating and validating ethnic-specific rates.

Hickman M, Modell B, Greengross P, Chapman C, Layton M, Falconer S, Davies SC

Centre for Research on Drugs and Health Behaviour, ICSM, London.

A range of estimates for sickle cell and beta thalassaemia have been derived for the different ethnic groups living in the U.K., reflecting uncertainty over the true population value in certain countries and the heterogeneity within and between countries of origin comprising the same ethnic group. These were validated against six community screening programmes, with the estimated range correctly predicting the number of affected births observed by the programmes. In England approximately 3000 affected babies (0.47%) carry sickle cell trait and 2800 (0.44%) carry beta thalassaemia trait annually: with approximately 178 (0.28 per 1000 conceptions) affected by sickle cell disease (SCD) and 43 (0.07 per 1000) by beta thalassaemia major/intermedia. Allowing for termination, about 140-175 (0.22-0.28 per 1000) affected infants are born annually with SCD and from 10 to 25 (0.02-0.04 per 1000) with beta thalassaemia major/intermedia. These are the first evidence-based rates for sickle cell and beta thalassaemia for use in the U.K., and should underpin the future planning of services. The long-term solution to monitoring changes in the rates of trait and disease in the population is to introduce a standardized instrument for collecting ethnicity for all community screening programmes.

PMID: 10192451, UI: 99206669

J Trop Pediatr 1999 Feb;45(1):23-30

Growth and pubertal development in transfusion-dependent children and adolescents with thalassaemia major and sickle cell disease: a comparative study.

Soliman AT, elZalabany M, Amer M, Ansari BM

Department of Paediatrics, University of Alexandria Children's Hospital, Egypt.

Despite regular blood transfusion and desferrioxamine treatment, growth impairment and pubertal delay are commonly seen in children and adolescents with transfusion-dependent thalassaemia and sickle cell disease (SCD). We evaluated growth parameters and sexual maturation in a large cohort of children and adolescents with SCD (n = 110) and thalassaemia (n = 72) receiving nearly the same protocol of transfusion and chelation, and compared them with those for 200 normal age-matched children, 30 children with constitutional delay of growth (CSS), and 25 children with growth hormone deficiency (GHD). Before transfusion, haemoglobin concentration had not been less than 9 g/dl in the past 7 years; desferrioxamine was administered for 7-10 years, including by the intramuscular and subcutaneous routes, three times or more per week. The height standard deviation score (HtSDS), growth velocity (GV) (cm/yr), and growth velocity standard deviation score (GVDSD) of children and adolescents with thalassaemia and SCD were significantly decreased compared to normal children (p < 0.01). Forty-nine per cent of thalassaemic patients and 27 per cent of patients with SCD had HtSDS less than -2, and 83 per cent of thalassaemic patients and 67 per cent of SCD patients had HtSDS less than -1. Fifty-six per cent of thalassaemic children and 51 per cent of children with SCD had GVSDS less than -1. The GV of thalassaemic children was significantly slower than that for children with SCD. Children with thalassaemia and SCD had HtSDS and GVSDS comparable to those for children with CSS but higher than those for patients with GHD. Serum ferritin concentration was correlated significantly with the linear GV in all patients (r = 0.45, p < 0.001). The bone age delay did not differ among the three groups with thalassaemia, SCD and CSS, but the delay was significant in the group with GHD. The mid-arm circumference was significantly smaller in children with thalassaemia and SCD than in normal children. The triceps skin-fold thickness of patients with SCD was significantly decreased compared to thalassaemic and normal children. The upper/lower segment ratio was significantly lower in thalassaemic and SCD patients than in normal children. In thalassaemic patients between the ages of 13 and 21 years a complete lack of pubescent changes was present in 73 per cent of boys and 42 per cent of girls. Seventy-four per cent of the thalassaemic girls had primary amenorrhoea. Girls with SCD aged between 13 and 21 years had markedly delayed breast development and menarche. Twenty-five per cent of boys with SCD above the age of 14 years had absence of testicular development. Males with thalassaemia and SCD who had spontaneous testicular development had significantly smaller testicular volume than did normal controls. Short children with thalassaemia and SCD had significantly decreased serum insulin-like growth factor 1 (IGF-1) concentrations compared to children with CSS. Collectively, these data confirm the high prevalence of impaired growth and pubertal delay/failure in children and adolescents with thalassaemia and SCD. The aetiology of impaired growth includes the contributions of lack of pubertal growth spurt due to delayed/absent puberty, decreased synthesis of IGF-1 which might be secondary to a disturbed GH-IGF-1 axis and/or under nutrition, probably due to the hypermetabolic status of these children. It is suggested that newer protocols of treatment, in addition to optimization of transfusion and chelation requirements, should increase the caloric intake of these patients and properly manage their pubertal delay-failure in order to improve their adult height.

PMID: 10191589, UI: 99207313

Hum Genet 1999 Feb;104(2):117-25

Contribution of gene conversion in the evolution of the human beta-like globin gene family.

Papadakis MN, Patrinos GP

Center for Thalassemia, Unit of Prenatal Diagnosis, Athens, Greece.

Gene conversion is referred to as one of two types of mechanisms known to act on gene families, mainly to maintain their sequence homogeneity or, in certain cases, to produce sequence diversity. The concept of gene conversion was established 20 years ago by researchers working with fungi. A few years later, gene conversion was also observed in the human genome, i.e. the gamma-globin locus. The aim of this article is to emphasize the role of genetic recombination, particularly of gene conversion, in the evolution of the human beta-like globin genes and further to summarize its contribution to the convergent evolution of the fetal globin genes. Finally, this article attempts to re-examine the origin and spread of specific mutations of the beta-globin cluster, such as the sickle cell or beta-thalassemia mutations, on the basis of repeated gene conversion events.

Publication Types:

• Review
• Review, tutorial

PMID: 10190321, UI: 99204596