Abnormal function of the bone marrow microenvironment in chronic myelogenous leukemia: role of malignant stromal macrophages

The bone marrow microenvironment supports and regulates the proliferation and differentiation of hematopoietic cells. Dysregulated hematopoiesis in chronic myelogenous leukemia (CML) is caused, at least in part, by abnormalities in CML hematopoietic progenitors leading to altered interactions with the marrow microenvironment. The role of the microenvironment itself in CML has not been well characterized. We examined the capacity of CML stroma to support the growth of long-term culture-initiating cells (LTC-IC) obtained from normal and CML marrow. The growth of normal LTC-IC on CML stroma was significantly reduced compared with normal stroma. This did not appear to be related to abnormal production of soluble factors by CML stroma because normal LTC- IC grew equally well in Transwells above CML stroma as in Transwells above normal stroma. In addition, CML and normal stromal supernatants contained similar quantities of both growth-stimulatory (granulocyte colony-stimulating factor (CSF), interleukin-6, stem cell factor, granulocyte-macrophage CSF, and interleukin-1 beta) and growth- inhibitory cytokines (transforming growth factor-beta, macrophage inflammatory protein-1 alpha, and tumor necrosis factor-alpha). The relative proportion of different cell types in CML and normal stroma was similar. However, polymerase chain reaction and fluorescence in situ hybridization studies showed the presence of bcr-abl-positivo cells in CML stroma, which were CD14+ stromal macrophages. To assess the effect of these malignant macrophages on stromal function, CML and normal stromal cells were separated by fluorescence-activated cell sorting into stromal mesenchymal cell (CD14-) and macrophage (CD14+) populations. CML and normal CD14- cells supported the growth of normal LTC-IC equally well. However, the addition of CML macrophages to normal or CML CD14- mesenchymal cells resulted in impaired progenitor support. This finding indicates that the abnormal function of CML bone marrow stroma is related to the presence of malignant macrophages. In contrast to normal LTC-IC, the growth of CML LTC-IC on allogeneic CML stromal layers was not impaired and was significantly better than that of normal LTC-IC cocultured with the same CML stromal layers. These studies demonstrate that, in addition to abnormalities in CML progenitors themselves, abnormalities in the CML marrow microenvironment related to the presence of malignant stromal macrophages may contribute to the selective expansion of leukemic progenitors and suppression of normal hematopoiesis in CML.     

Essential Medicines: An Indian Perspective

The concept of defining essential medicines and establishing a list of them was aimed to improve the availability of affordable medicines for the world''s poor. Access to essential medicines is a major determinant of health outcomes. Several countries have made substantial progress towards increasing access to essential medicines, but access to essential medicines in developing countries like India is not adequate. In this review we have tried to present the Indian scenario in respect to availability and accessibility of essential medicines over last one decade. To enhance the credibility of Indian healthcare system, procurement and delivery systems of essential medicines have to be strengthened through government commitment, careful selection, adequate public sector financing, efficient distribution systems, control on taxes and duties, and inculcating a culture of rational use of medicines in current and future prescribers.     

Quantification of Antioxidant Contents in Sweet Pepper as Influenced by Planting Time and Fruit Picking Stage

The present study reports the quantification of changes in the contents of plant pigments and ascorbic acid as influenced by the planting time and fruit picking stages in sweet pepper. The crop was planted on five different dates at 10 days interval in randomized block design under open field conditions in temperate area to quantify the changes which took place in the contents of plant pigments and ascorbic acid in green and red fruits. The results showed that the planting time and fruit picking stage had significant (p ≤ 0.05) influence on plant pigments and ascorbic acid contents in sweet pepper. The last week of May was observed as the optimal planting time when fruits exhibited higher contents of lycopene, β-carotene and ascorbic acid. The red fruit picking stage had significantly higher concentration of these phytonutrients than the green picking stage. In order to pick-up fruits at right stage and time with high plant pigments and ascorbic acid contents, these results would help meet out the increasing demand of sweet pepper quality fruits.     

Can visceral leishmaniasis be eliminated from Asia?

Data on the burden of visceral leishmaniasis (VL) in Indian sub-continent are vital for elimination programme planners for estimating resource requirements, effective implementation and monitoring of elimination programme. In Indian sub-continent, about 200 million population is at risk of VL. Nearly 25,000-40,000 cases and 200-300 deaths are reported every year, but these are grossly underestimates. Recent well-designed multicentric studies identified VL burden of 21 cases/10,000 among sampled population in Indian sub-continent (Bangladesh, India and Nepal). This estimates 4,20,000 cases per 200 million risk population clearly indicating that the disease is highly under-reported. Chemical and environmental vector control studies show that the indoor residual spraying (IRS) and long-lasting insecticidal nets (LLINs) are effective and significantly reduce sandfly densities. The findings documented from different sources revealed that some gaps and weakness in existing policies for introducing VL vector control interventions. Our studies emphasize the need of integrated vector management with both IRS and LLIN vector control interventions. Active case detection with rK39 strip test as diagnostic tool is the key element for detection of VL cases. The use of oral drug miltefosine for the treatment after assessing feasibility at community level is important. Kala-azar elimination in Indian sub-continent is possible if elimination programmes ensure access to health care and prevention of kala-azar for people at risk with particular attention to the poorest and marginalized groups. The evidence-based policy should be designed that motivates to implement the programmes, which will be cost-effective. Maintaining the acceptable level of incidence requires public awareness, vector control, appropriate diagnosis and treatment. The five pillars of VL elimination strategies identified are: early diagnosis and complete treatment; integrated vector management and vector surveillance; effective disease surveillance through passive and active case detection; social mobilization and building partnerships; and clinical and operational research which need to be re-enforced to effective implementation.     

Detection of HBsAg in newborns

Cord blood samples collected from 150 newborns were tested for HBsAg using micro ELISA technique. Only 8 (5.3 per cent) out of 150 samples were found to be positive for HBsAg in variable titres. It is important to identify these HBsAg positive newborns so that appropriate measures could be adopted at the earliest to prevent the complications of HBsAg carriage.     

The study of fecal-Escherichia coli peritonitis-induced septic shock in a neonatal pig model

Peritonitis-induced septic shock in the neonate is associated with a high mortality. Because there exists no clinically relevant model to study resuscitation of these patients, a model using the neonatal pig was developed. After arterial and central venous cannulation, and placement of a left pulmonary-artery thermodilution catheter, 12 anesthetized neonatal pigs were "resuscitated" with fluids (5% albumin in lactated Ringer's solution at 15 ml/kg/hr), antibiotics, and correction of acidemia. The pigs were divided into two groups: a control group (n = 5), which was not subjected to peritonitis and which was killed after 6 hours of monitoring, and a septic group (n = 7), which was inoculated with an intraperitoneal injection of sterile pig feces and Escherichia coli and was monitored until death (mean survival time (S.D.) 546(159) minutes). Serial measurements of hemodynamic and laboratory data were obtained. While pigs in the control group showed no significant changes in these data as measured against time, the pigs in the experimental group showed an early transient rise in cardiac index which was significant (p less than .05) and which was followed by a steady decline in cardiac index until death. These changes in cardiac index were accompanied by a continuous decline in mean arterial pressure, central venous pressure, pulmonary artery pressure, and systemic vascular resistance index, while pulmonary vascular resistance index showed a gradual continuous rise. The observed changes in hemodynamic and laboratory data mimic those anticipated in the human neonate with peritonitis-induced septic shock. This model proves reliable and reproducible, and shows promise as a tool to study the resuscitation of neonates with septic shock.     

SDF-1 enhances the expansion and maintenance of highly purified human hematopoietic progenitors

The stromal-derived factor-1 (SDF-1) chemokine and its putative receptor, CXCR4, have been implicated in hematopoiesis. Here we aim to characterize the effects of cytokine-induced CXCR4 expression and SDF-1 treatment on primitive human umbilical cord blood (CB) cells in vitro. Highly purified CD34+CD38-Lin-CXCR4- blood cells were capable of forming CD34+CXCR4+ cells during short-term liquid culture, but maintained distinct erythroid and myeloid progenitor composition, similar to the parent population prior to culture. In vitro, SDF-1 enhanced the expansion and differentiation of primitive CB cells in a manner that was dependent upon both the concentration of SDF-1 and the presence of specific cytokines. In the absence of cytokine addition, cultures seeded with CD34+CD38-Lin- cells demonstrated substantial cell death; however, the addition of SDF-1 alone preferentially increased progenitor cell frequency. Our study demonstrates that induction of CXCR4 expression does not alter the differentiative potential of human blood progenitors and suggests a role for SDF-1 as a growth factor required for human hematopoiesis.     

Atrial fibrillation: epidemiology, mechanisms and management

The incidence of AF, the most common sustained arrhythmia in clinical practice, increases with age and coronary artery disease, hypertension and valvular heart disease are common underlying substrates; however, occasionally, AF may occur without any underlying heart disease. The most widely accepted theory of its mechanism is Moe's multiple wavelet hypothesis, although recent studies are helping to shed light on other mechanisms, including the focal origin of AF in some patients. Most patients experience palpitations, but fatigue, dyspnoea, and dizziness may also occur. Therapy includes prevention of thromboembolism, control of rate, and restoration and maintenance of sinus rhythm. The risks and benefits of each treatment modality need to be assessed according to each patient's circumstances. Unlike other arrhythmias, there is still no highly successful therapy for treating AF. However, significant advances are being made using non-pharmacological approaches to either prevent or cure this troublesome arrhythmia.