Thesis (M Med (Haematology))--University of Limpopo, 2010. / Background. Infection with human immunodeficiency virus (HIV) is associated with a range of haematological abnormalities including: ineffective haematopoiesis, infiltrative disease of the bone marrow, nutritional deficiency and peripheral destruction of blood cells secondary to splenomegaly and immune deregulation. Aim. To review and describe bone marrow abnormalities and associated peripheral haematological abnormalities, in HIV/AIDS patients. Methodology. This is a retrospective study. Data was extracted from DISA, the National Laboratory Health Service Laboratory Information System database at the DGMH Tertiary Laboratory from 2003 to 2007. Medical and laboratory records of 80 HIV positive patients who underwent bone marrow examination for investigation of fever and/or cytopenia were reviewed. All statistical analyses were performed on SAS® Release 9.1.3. Results. Twenty-five patients out of a total of 80 (31.25%), had pancytopaenia. Of the 25, eight (32%) were males and 17 (68%) were females. In this study, pancytopaenia was described as a haemoglobin concentration, granulocyte count and platelet count below normal ranges for age and gender. Among male patients in this study, five (17%) patients had TB out of 30. Among female patients, five (10%) out of 50 patients had TB. The majority of patients with malignancies were males six out of nine (67%). Three of the five patients with non-Hodgkin’s lymphoma (NHL) and all of the patients with multiple myeloma (MM) were males. Conclusions. Haematological abnormalities were present in all patients. Bone marrow involvement by TB was found in 12.5% in the study population. Malignancies were more frequent in males; three patients with NHL, two with MM and one with Kaposi sarcoma (KS). The difference in distribution was not statistically significant (p=0.391002). Recommendations. It is recommended that health education and health promotion focus on the control of biological carcinogenic agents such as EBV, HPV and HHV-8 by routinely testing for these agents and by promotion of positive reproductive behaviour among people living with HIV/AIDS. The use of non-invasive tests will be helpful in our setting where there is high TB prevalence.

L’érythropoïèse adulte est un processus complexe qui a lieu dans la moelle osseuse, il aboutit à la formation de globules rouges (GR) à partir des cellules souches hématopoïétiques. L’AMPK (AMP-activated protein kinase) est un complexe hétérotrimérique (αβγ) connu pour son rôle de régulateur du métabolisme énergétique cellulaire. L'implication de l’AMPK dans le maintien de la survie et de l’intégrité des globules rouges murins a été démontrée. En effet, les souris invalidées pour Ampk α1, β1 ou γ1 présentent une anémie hémolytique due à une anomalie de la déformabilité des globules rouges. Nous avons émis l’hypothèse que les altérations observées dans les érythrocytes déficients en AMPK pourraient se mettre en place au cours du processus de différenciation des érythroblastes. L’objectif de ce travail est donc d’étudier le rôle de l'AMPK au cours de l’érythropoïèse murine et humaine adulte. Chez la souris, nos résultats démontrent que l’absence de l’AMPK n’affecte ni la prolifération ni la survie ni la différenciation des érythroblastes Ampkα1-/-. De la même façon, l’activation de l’AMPK n’a pas d’effet sur les érythroblastes murins. Chez l’homme, nous avons montré par une approche shRNA que l’inhibition de l’expression de la sous-unité α1 de l’AMPK induit un ralentissement de la prolifération cellulaire et une anomalie de l’érythropoïèse révélée par une modification de l’expression des protéines membranaires à la surface des érythroblastes au cours de la différenciation. Nous avons également montré que l’AMPK est fortement activée dans les érythroblastes immatures (Pro-E –Baso-E) et que cette activation diminue dans les érythroblastes matures (Poly-E – Retic). Une activation de l’AMPK par des activateurs directs (GSK621 et 991) dans les érythroblastes immatures n’a pas d’effet. Par contre, le maintien de son activation par les activateurs directs dans les érythroblastes matures induit, un arrêt du cycle cellulaire en phase S, une induction de l’autophagie, une apoptose caspase dépendante conduisant à un arrêt de la différenciation au stade Baso-E. Ces résultats montrent l’importance de la diminution de l’activation de l’AMPK pour la survie et la différenciation des érythroblastes matures. L’AMPK est donc importante pour la différenciation des cellules érythroïdes humaines alors que chez la souris, elle est impliquée dans le fonctionnement du globule rouge. Notre travail illustre donc un nouveau point de divergence entre l’érythropoïèse murine et l’érythropoïèse humaine. / AMPK (AMP-activated protein kinase) is a heterotrimeric complex containing α, β, and γ subunits, known for its role in the maintenance of cellular energy homeostasis. It has been shown that Ampk is involved in maintaining integrity of murine RBCs as well as their survival. Indeed, Ampk α1-/- and Ampk γ1-/- mice present a hemolytic anemia, and their RBCs show elasticity defects in their plasma membrane. We hypothesized that the alterations observed in AMPK-deficient erythroblasts were the results of a lack of Ampk earlier during erythroid differentiation. Therefore, we aim to study the role of AMPK during human and murine erythropoiesis. We showed that the absence or activation of Ampk in mice does not affect either the survival, proliferation, or the differentiation of KO erythroblasts compared to WT ones. In human, our data show that the knockdown of the α1 subunit expression by shRNA induces a slowing down of cell proliferation and a dyserythropoiesis, indicated by the shift in pattern of cell surface markers expression during differentiation. In addition, we showed that phosphorylation of AMPK (Thr172) and its target ACC (Ser 79) are elevated in immature (Pro-E –Baso-E) erythroblasts, and then decreased conjointly with the erythroid differentiation. AMPK activation in immature erythroblasts has no effect. Conversely, in mature (Poly-E – Retic) erythroblasts, the persistence of AMPK expression induces a cell cycle arrest in S phase, followed by the induction of autophagy, and of caspase-dependent apoptosis with a differentiation arrest at basophilic erythroblast stage. Our results demonstrate the importance of finely-tuned regulation of AMPK during adult human erythropoiesis. AMPK is needed for efficient erythropoiesis in human, whereas it is involved solely in RBCs function in mice, showcasing yet another contrasting point between human and mouse erythropoiesis.

Thesis (MMedVet. (Companion Animal Medicine, Veterinary Science))--University of Pretoria, 2001. / Also available in print format.

Tesis-Universitas Indonesia. / Summary in English. Includes bibliographical references (p. 225-240).

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Indiana University-Purdue University Indianapolis (IUPUI) / Studies performed by our lab have investigated the potential radioprotective effect of rDEK protein. Although roles played by DEK in cell differentiation, DNA repair, DNA binding, chromatin regulating and different malignancies have been investigated previously in different cell types, the prospect of DEK being used as a potential radioprotective agent for HSCs has not yet been explored. In this study, using primary cells isolated from bone marrow of C57BL/6 mice in vitro, our data indicated that rDEK has the ability to act as potential radioprotector of HSC. Moreover, a significant decrease in percentages of caspase-3 and caspase-9 protease enzymes was observed after irradiation in presence of rDEK. Taken, together the data suggests that DEK imparts its effect as a potential radioprotective agent, via inhibiting the caspase-dependent intrinsic apoptosis pathway. We found no evidence that DEK could act as a radiomitigator but this was not tested in primary cells as well as in animals.

No description available.

No description available.

Systemic mastocytosis refers to a heterogeneous group of clinical disorders characterized by excessive mast cell accumulation in one or multiple organs. Mastocytosis is now considered as a separate disease category in the 2016 WHO classification of myeloid neoplasm and acute leukemia. It is no longer considered as a subgroup of meyloproliferate neoplasms. The clinical presentation of mastocytosis is heterogeneous ranging from skin-limited disease (cutaneous mastocytosis) to a more aggressive form with extra cutaneous presentation (systemic mastocytosis) with or without skin involvement. We are presenting a case of systemic mastocytosis that aroused in a patient who carried diagnosis of CMML for almost 2 years. The worsening B symptoms along with worsening splenomegaly were the driving factor for further investigations including Bone Marrow biopsy which revealed the diagnosis. A 74 year old Caucasian male with past oncology history of Chronic myelomoncytic leukemia diagnosed after persistant monocytosis on complete blood count . Patient presented with gradual onset of low grade fever , weight loss and night sweating , CT abdomen showed hepatosplenomegaly. core biopsy of the liver showed portal and lobular infiltrate consistent with involvement by mastocytes and extra medullary hematopoiesis. The infiltrate was positive for CD117, CD33, CD68, myeloperoxidase and CD163. Patient had bone marrow biopsy which showed increased CD117 positive cells consistent with involvement by systemic mastocytosis. The core biopsy showed multifocal nodules of spindle cells with fibrosis which was morphologically consistent with abnormal mast cells. Immunohistochemistry for CD117 was strongly positive in the spindle cell nodules and scattered polygonal cell nodules. KIT D816V mutation was detected. Patient met criteria for diagnosis of systemic mastocytosis with presence of previous diagnosis of CMML and classified as Systemic mastocytosis with an associated hematologic neoplasm (SM-AHN). Due to patient multiple comorbiditeis , he was not a candidate for Allo HCT. In an attempt to control his disease , patient was started on dose reduced Dacogen, but his functional status continued to delined and eventually dacogen was discontinued and patient was placed on best supportive car Conclusion Systemic mastocytosis is a rare entity with heterogeneous clinical presentation, highly variable disease course and consequently survival rates.Though recent advances in understanding genetic and molecular basis of disease, bone marrow transplantation remains the only treatment with possible curative potential in patients with advanced form of mastocytosis though carrying substantial mortality risk .Further understanding of Kit mutation might be able to offer a highly effective medication with durable response in a fashion similar to the success story of gleevac with CML treatment .

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