Salam Al Kindi

Cytokines in Sickle Cell Disease

Abstract Sickle red cells express adhesion molecules including integrin 4β1, CD36, band 3 protein, sulfated glycolipid, Lutheran protein, phosphatidylserine and integrin-associated protein. The proadhesive sickle cells may bind to endothelial cell P-selectin, E-selectin, intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), CD36 and integrins leading to its activation. Monocytes also activate endothelium by releasing proinflammatory cytokines like tumor necrosis factor alpha (TNF-) and interleukin 1β (IL-1β). Sickle monocytes also express increased surface CD11b and cytoplasmic cytokines TNF and IL-1β indicating activated state. Polymorphonuclear leukocytes (PMNs) are also activated with reduced L-selectin expression, enhanced CD64 expression and elevated levels of sL-selectin, sCD16 and elastase resulting in increased adhesiveness to the endothelium. Platelets are also activated and secrete thrombospondin (TSP) and cytokine IL-1. They also form platelet- monocytes aggregates causing endothelial cell P-selectin expression. Endothelial cell activation by these multiple mechanisms leads to a loss of vascular integrity, expression of leukocyte adhesion molecules, change in the surface phenotype from antithrombotic to prothrombotic, excessive cytokine production and upregulation of HLA molecules. Furthermore, contraction of these activated endothelial cells leads to exposure of extracellular matrix proteins, such as TSP, laminin, and fibronectin and their participation in adhesive interactions with bridging molecules from the plasma such as von Willebrand factor (vWf) released from endothelial cells, ultimately culminating in vasoocclusion and local tissue ischemia, the pathognomonic basis of vasoocclusive crisis.

Familial lymphoma in an Omani kindred with identical class II HLA type

We report familial Hodgkin lymphoma (FHL) in three brothers of an Omani family with 13 children. Two brothers were diagnosed to have a nodular sclerosing Hodgkin lymphoma (NSHL), and a nodular lymphocyte predominant Hodgkin lymphoma (nLPHL)/ T-cell rich B cell lymphoma (TCRBCL) within 6 months of each other, while the third brother (a halfbrother) had been diagnosed to have nLPHL, 8 years prior to the two other brothers. All three are currently in complete remission. Familial clustering of lymphoma is well documented, however, the magnitude of risk and the mechanisms of oncogenesis remain unclear [1]. Chang et al. [2] using a population-based case– control study, demonstrated an almost 2-fold increased risk of NHL in families of patients with a hematopoietic malignancy amongst Swedish subjects. Goldin et al. [3] using a similar design reported an absolute life-time risk of 3.6% in the first-degree relatives, compared with 2.1% in the general population. Chaterjee et al. [1] also reported a higher incidence of lymphoproliferative disorders in families of patients with lymphoma in a US-based case– control study. Besides familial aggregation of NHL and HL, FHL has also been reported [4]. Two types of FHL have been reported. First, clustering of different histological sub-types of FHL, ascribed to either genetic factors such as, HLA-identical haplotypes, or environmental factors, such as, a prior EBV infection [5,6]. Second, familial aggregation of nLPHL, does not seem to be associated with either the HLA-type or EBV infection [7]. A 37-year-old Omani gentleman presented with an enlarged inguinal lymph node measuring 56363 cm. There was no history of fever, weight loss or of night sweats. Excision biopsy revealed NSHL. Staging investigations including CT scan of the chest, abdomen and pelvis and a bone marrow biopsy did not reveal evidence of disease. The patient was diagnosed to have stage IA NSHL, which had been completely excised. The patient was treated with involved field radiotherapy (IFRT) to a dose of 45 Gy. He is under regular follow-up and continues to be in complete remission 7 years after the diagnosis. The 27-year-old brother of the patient presented 6 months after the diagnosis of lymphoma of the elder brother, with an enlarged axillary lymph node. There were no other symptoms. Staging investigations, including CT scan of the chest and abdomen revealed lymph nodes in the cervical, axillary, mediastinal and retroperitoneal area. Excision biopsy of the axillary node revealed effacement of architecture of the lymph node with an infiltrate consisting of atypical large cells (positive for CD20, weakly positive in a few cells for CD30, and negative for CD10, CD15, bcl-2 and epithelial membrane antigen). These large atypical cells were interspersed within a background of small lymphocytes (positive for CD3 and CD5), some of which were seem to be arranged in a rosette fashion around the CD20 positive large atypical lymphocytes. A diagnosis of nLPHL/TCRBCL was made. Review of slides at a different institution concurred with this diagnosis of

Aetiological profile of women presenting with premature ovarian failure to a single tertiary care center in Oman

Background Premature ovarian failure is estimated to affect at least 1%–3% of adult women. There are several aetio-pathogenic factors that may cause premature ovarian failure including iatrogenic causes, genetic, autoimmune, infectious and idiopathic. The aim of this study was to identify the aetiological profile of women with premature ovarian failure presenting to Sultan Qaboos University hospital. Method A retrospective medical record review was conducted from June 2006 to October 2012. All women diagnosed with symptoms and/or laboratory evidence of premature ovarian failure (follicle stimulating hormone ≥40 UI/L and less than 40 years of age) were enrolled in this study. Possible causes of premature ovarian failure were obtained and classified into main aetiological factors. Results There were 90 patients during the study period, of which, 39 (43%) were following chemotherapy and bone marrow transplant. The second most common reason was idiopathic (n = 29; 31%) followed by autoimmune diseases (n = 8; 9%) and genetic disorders (n = 7; 8%). Most chemotherapy cases (69%) were among the young age group, while in the older age group idiopathic was the commonest (48%). Conclusion Compared to the world literature, the most common cause of premature ovarian failure in this study was chemotherapy induced, especially in young girls undergoing bone marrow transplantation. This is due to high prevalence of transplantable hereditary haematological disorders like thalassemia and sickle-cell disease in this part of the world. Current standard of care recommends cryopreservation of ovarian tissue to preserve ovarian function in young girls undergoing bone marrow transplantation for such disorders.

Idiopathic thrombocytopenic purpura and hypokalaemic dRTA with compensated haemolysis and striking acanthocytosis in a band 3 (SLC4A1/AE1) A858D homozygote

Dear Editor, The pleiotropic effects of mutations of the band 3 (SCL41/ AE1) gene which result in familial distal renal tubular acidosis (dRTA) and red cell abnormalities are now wellestablished [1]. The occurrence of dRTA and haemolytic anaemia in A858D homozygotes was first reported recently in children from India [2] and Oman [3]. This letter describes certain unusual features in an Omani adolescent A858D homozygote. A 17-year-old Omani Arab youth, son of a consanguineous marriage presented with complaints of bleeding gums and easy bruising for a few weeks. Also, he reported experiencing progressively severe muscle weakness which, after several weeks, culminated in his inability to rise out of bed. He was of normal stature and weight with mild scleral icterus, generalised skin purpura, buccal mucosal petechiae and mild splenomegaly; hypotonia, hyporeflexia and quadriparesis were additional findings. Investigations showed a normal haemoglobin (Hb— 131 g/L), haematocrit (0.39) and white blood cell count, but an increased reticulocyte count (373.5×10/L) and a very low platelet count (6.0×10/L). Freshly drawn blood films revealed polychromasia, a striking predominance of acanthocytes (70–85 %), a moderate number of ovalocytes and a few other poikilocytes (Fig. 1). Ahaptoglobinaemia, unconjugated hyperbilirubinaemia, normal serum immunoglobulins and a negative antiglobulin test provided supportive evidence for a non-immune-compensated haemolysis. The bleeding problem was diagnosed as autoimmune idiopathic thrombocytopenic purpura (ITP) despite negative results of platelet and other relevant autoantibody tests [4]. Associated autoimmune diseases such as SLE and Sjogrens syndrome [5] were ruled out. Quadriparesis was due to hypokalaemia (serum K, 2.5 mmol/L) secondary to complete dRTA characterised essentially by hyperchloraemic acidosis (Cl, 117 mmol/ L), reduced serum HCO3 − (18 mmol/L) concentration and normal values of serum anion gap, blood urea, serum creatinine, arterial blood pH and blood gases, coupled with a positive urine anion gap and a persistent urine pH >6.0; the patient refused a urine acidification test. DNA analysis revealed a homozygous A858D (alanine → aspartic acid) mutation of the SLC41/AE1 gene. Following a 3-week course of oral prednisolone, bleeding symptoms ceased, platelet count was normalised (317×10/ L) and muscle weakness improved considerably on oral potassium chloride, sodium bicarbonate and spironolactone. During the ensuing years, because of poor drug compliance, he was hospitalised several times with hypokalaemic limb pareses (serum K levels varying between 2.0 and 3.1 mmol/L), but his blood counts have remained normal throughout. Ultrasonography later revealed bilateral J. U. Rehman : S. Al Zadjali :N. A. Fawaz : S. Al Kindi Department of Haematology, College of Medicine & Health Sciences, Sultan Qaboos University, PO Box 35, Muscat 123, Sultanate of Oman

Isochromosome 9q as a sole anomaly in an Omani boy with acute lymphoblastic leukaemia.

This report describes a case of acute lymphoblastic leukaemia in which isochromosome 9q (i(9q)) was the sole acquired cytogenetic abnormality. The Immunophenotype showed positivity for CD3, CD4, CD5, CD7, CD8, CD10, CD71, CD117 and TdT, consistent with T cell acute lymphoblastic leukaemia (ALL). The chromosomal analysis of bone marrow showed 46,XY,i(9)(q10) in all the metaphases analysed. The bone marrow morphology was ALL-L2 as per the French–American–British criteria. Isochromosomes are rare chromosomal abnormalities in childhood ALL and the effect of i(9q) is not well established. The patient’s good response to therapy with normal cytogenetics within a month of induction, and disease-free survival after bone marrow transplant are indicative of a good prognosis in such cases.