Human leukocyte antigen (HLA) diversity and clinical applications in South Africa.

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa.

Heterogeneity of cell therapy products.

Cellular therapy has become a billion-dollar industry and is set to become one of the therapeutic pillars of healthcare in the 21st century. Adult stem cells, which include haematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal/stem cells (MSCs), is one of the major cell types currently under investigation for use in cell therapy. This review focuses on HSPCs and MSCs and discusses their heterogeneous nature and the problems faced in expanding these cells to therapeutic numbers for use in clinical applications.

HIV and haematopoiesis.

Human immunodeficiency virus (HIV) infection not only leads to a compromised immune system, but also disrupts normal haematopoiesis, resulting in the frequent manifestation of cytopenias (anaemia, thrombocytopenia and neutropenia). Although there is a definite association between the severity of cytopenia and HIV disease stage, this relationship is not always linear. For example, cytopenias such as thrombocytopenia may occur during early stages of infection. The aetiology of these haematological abnormalities is complex and multifactorial, including drug-induced impaired haematopoiesis, bone marrow suppression due to infiltration of infectious agents or malignant cells, HIV-induced impaired haematopoiesis, and several other factors. In this review, we describe the frequencies of anaemia, thrombocytopenia and neutropenia reported for HIV-infected, treatment-naïve cohorts studied in eastern and southern sub-Saharan African countries. We present a rational approach for the use of diagnostic tests during the workup of HIV-infected patients presenting with cytopenia, and discuss how HIV impacts on haematopoietic stem/progenitor cells (HSPCs) resulting in impaired haematopoiesis. Finally, we describe the direct and indirect effects of HIV on HSPCs which result in defective haematopoiesis leading to cytopenias.

Heterogeneity of cell therapy products

Cellular therapy has become a billion-dollar industry and is set to become one of the therapeutic pillars of healthcare in the 21st century. Adult stem cells, which include haematopoietic stem and progenitor cells (HSPCs) and mesenchymal stromal/stem cells (MSCs), is one of the major cell types currently under investigation for use in cell therapy. This review focuses on HSPCs and MSCs and discusses their heterogeneous nature and the problems faced in expanding these cells to therapeutic numbers for use in clinical applications

Human leukocyte antigen (HLA) diversity and clinical applications in South Africa

The major histocompatibility complex, known as the human leukocyte antigen (HLA) complex in humans, forms an integral component of adaptive T cell immunity by presenting self and non-self peptides to the T cell receptor, thereby allowing clonal expansion of responding peptide-specific CD4+ and CD8+ T cells. HLA likewise forms an integral part of the innate immune response through the binding of killer-cell immunoglobulin-like receptor (KIR) molecules, which regulate the response of natural killer (NK) cells. The HLA complex is found on the short arm of chromosome 6 and is the most polymorphic region in the human genome. Africans are genetically more diverse than other populations; however, information on HLA diversity among southern Africans, including South African populations, is limited. Paucity of African HLA data limits our understanding of disease associations, the ability to identify donor-recipient matches for transplantation and the development of disease-specific vaccines. This review discusses the importance of HLA in the clinical setting in South Africans and highlights how tools such as HLA imputation might augment standard HLA typing methods to increase our understanding of HLA diversity in our populations, which will better inform disease association studies, donor recruitment strategies into bone marrow registries and our understanding of human genetic diversity in South Africa

HIV and haematopoiesis

Human immunodeficiency virus (HIV) infection not only leads to a compromised immune system, but also disrupts normal haematopoiesis, resulting in the frequent manifestation of cytopenias (anaemia, thrombocytopenia and neutropenia). Although there is a definite association between the severity of cytopenia and HIV disease stage, this relationship is not always linear. For example, cytopenias such as thrombocytopenia may occur during early stages of infection. The aetiology of these haematological abnormalities is complex and multifactorial, including drug-induced impaired haematopoiesis, bone marrow suppression due to infiltration of infectious agents or malignant cells, HIV-induced impaired haematopoiesis, and several other factors. In this review, we describe the frequencies of anaemia, thrombocytopenia and neutropenia reported for HIV-infected, treatment-naïve cohorts studied in eastern and southern sub-Saharan African countries. We present a rational approach for the use of diagnostic tests during the workup of HIV-infected patients presenting with cytopenia, and discuss how HIV impacts on haematopoietic stem/progenitor cells (HSPCs) resulting in impaired haematopoiesis. Finally, we describe the direct and indirect effects of HIV on HSPCs which result in defective haematopoiesis leading to cytopenias

[Gallstone disease in the elderly]. / Galsteensiekte in bejaardes.

The clinical manifestations, management and outcome of gallstone disease in 100 elderly patients are described. A total of 65 patients presented with a complication, acute cholecystitis (43), gallstone pancreatitis (8) and obstructive jaundice (6) being the commonest manifestations. The clinical picture was often misleadingly mild. Associated disease occurred in 70 patients but precluded surgery in only 3. Emergency surgery was indicated in 18 patients. Surgery was performed on 96 patients (cholecystostomy 2, cholecystectomy 94); 35 explorations of the common bile duct were done, with stones present in 33. Four patients died, 1 following an endoscopic retrograde cholangiopancreatography (ERCP) and 3 postoperatively (2 patients with gallstone pancreatitis); no death occurred following an elective operation. Alternative modalities of treatment of gallstone are expected to play a minor role in the management of gallstone disease in the elderly.

Penetration of a gastric ulcer into the right ventricle. A complication of para-oesophageal hiatus hernia.

A 74-year-old woman presented with massive upper gastro-intestinal tract bleeding that necessitated an emergency laparotomy. At operation a para-oesophageal hiatal hernia with an ulcer in the herniated fundus of the stomach penetrating the right ventricle was discovered to be the source of the bleeding. Although various complications of para-oesophageal hiatal hernias have been reported, including bleeding, this is the first reported case of ulcer penetration into the ventricle.

[Congenital defects of the aortic system]. / Artériopathies congénitales du système aortique.

The authors give a basic embriological classification of congenital arterial defects. Congenital abnormalities of the arterial system (arising in an embryo of 12 to 30 mm) affect the primary segments, and comprise excessive involution of the antibrachial trunk, of the popliteal artery, of the tibio-peroneal trunk and peroneal artery, abnormal or persistence of the interosseus artery, of the artery of sciatic nerve, and of the peroneal artery, a high axillary origin of the radial or antecubital artery, renal polar arteries arising directly from the aorta, and agenesis of the palmar or plantar arches. In the second generation arteries, they comprise agenesis or hypogenesis of the radial, antecubital or tibial arteries, and gross hypogenesis of the trunk of the renal artery with an immature kidney. Arrested or mal-development in the foetus can give rise to coarctation and stenosis of the thoracic aorta and large vessels, to segmental agenesis with huge collaterals, to imperforate osita, especially in the mesenteric arteries, to sudden variations in diameter of the renal arteries, and to parietal dyplasia and aneurysms in vessels in the residual undifferentiated mesenchymatous tissue, and diffuse dilatation or stenosis. The authors give their experience for a cardiological clinic, adding arterial hypertension and arterioparenchymatous dysplasia of the kidneys, Raynaud's, Takayasbu's and Burger's disease, and intermittent claudication of the lower limbs; they indicate the areas which they are currently studying.

[Analysis of the electrophysiological effects of amiodarone using simultaneous recordings of monophasic and bundle-of-his action potentials]. / Analyse des effets électrophysiologiques de l'amiodarone par l'enregistrement simultané des potentiels d'action monophasiques et du faisceau de His

The effects of amiodarone given by rapid intravenous injection at a dosage of 10 mg/kg have been studied in the dog. The peak activity is found between the fifth and the tenth minute. The rate of discharge of the sinus is lowered by 36%. At the atrial level, the duration of the monophasic action potential (MAP) is increased by 9% and its dv/dt is lowered slightly, the total refractory period is increased by 22%, the effective refractory period is increased by 27%, the functional refractory period is increased by 19%, the ratio of the length of the effective period/duration of the MAP becomes slightly greater than unity, conduction facilitation disappears, and the period of slow conduction increases. In the A/V node the AH interval increases by 44% under normal rhythm, while atrial stimulation at 200/min. results in conversion to total AV block in more than half of the cases. The potential of the bundle of His and the HV interval are not altered. At ventricular level the duration of the monophasic action potential increases by 25%, its dv/dt decreases slightly, the total refractory period is increased by 8%, and the effective refractory period is increased by 14%.

[Atrioventricular block and localized reentry into the trunk of the bundle of His]. / Bloc auriculo-Ventriculaire et ré-entrée localisés au tronc du faisceau de His

In a patient with an AV block and a resulting variable rhythm, the coupled ventricular complexes with dissociated P waves on the standard tracing suggested a reentry into the atrioventricular area. Intracavitary investigation revealed: 1) a complete bidirectional AV block in the upper portion of the bundle of His (there being a proximal His potential with a fixed relationship with the dissociated atrial activity shown on the ventriculogram); 2) escape of the bundle of His low down, or of the beginnings of the branches, preceded by a distal Hispotential; 3) re-entry echos preceded by a third variety of potential in the bundle of His.

[Study of monophasic action potentials of the myocardium by endocavitary approach. Methodology]. / Etude des potentiels daction monophasiques du myocarde par voie endocavitaire. Méthodologie

The suction electrode makes it possible to record the monophasic action potentials (MAP) of the heart in situ. The technical characteristics of the tripolar electrode which we use are described. The O phase of the MAP is more prolonged than that of the intracellular action potential, but makes it possible to demonstrate the time of arrival of the activation wave in front of the exploring electrode. The phase 1-2 and the phase 3 have their characteristic contour in the right atrium and ventricle. The duration of repolarization makes it possible to assess the refractory period of different parts of the atrial and ventricular myocardium. The relatively simple and harmless method of recording of the monophasic action potentials by the endocardial route, both in the animal and in man, widens our investigation field of electrophysiology applied to the study of arrhythmias, of the repolarization disturbances and of the drug influences on the cell activity.