Role of Th1 and Th2 Cytokines in Immune Response to Uncomplicated Plasmodium falciparum Malaria

The relative balance between Th1 and Th2 cytokines appears crucial, since the role of cytokines has been evaluated in several studies by comparison of clinically heterogeneous groups of patients. The aim of this study is to determine the role of proinflammatory Th1 cytokines, interleukin-12 (IL-12) and gamma interferon (IFN-γ), and anti-inflammatory Th2 cytokines, IL-4 and IL-10, in a homogeneous group of patients with uncomplicated Plasmodium falciparum malaria. Levels of IL-12, IFN-γ, Il-4, and IL-10 in serum for 20 adult patients and 15 healthy control subjects were determined by an immunoenzymatic assay. Serum levels of Th1 cytokines, IL-12 (8.6 ± 2.8 pg/ml; controls, 3.2 ± 0.7 pg/ml) and IFN-γ (39.2 ± 67.6 pg/ml; controls, 8.4 ± 6.3 pg/ml), were significantly increased at admission; 3 days later, levels of IL-12 in serum remained significantly high (8.8 ± 2.6 pg/ml), whereas IFN-γ levels returned to control values. The anti-inflammatory response of Th2 cytokines (IL-10 and IL-4) was distinct. Levels of IL-10 in serum were not significantly increased at day 0 and day 3 (306.6 ± 200.4 pg/ml and 56.6 ± 38.4 pg/ml, respectively; controls, 17.4 ± 9.0 pg/ml). In contrast, levels of IL-4 in serum were not increased on admission (3.4 ± 1.2 pg/ml; controls, 2.4 ± 0.8 pg/ml), but at day 3 a moderate and significant increase of IL-4 levels was observed (4.5 ± 1.7 pg/ml). In conclusion, the increase of Th1 cytokine IL-12 and IFN-γ levels during the acute phase of uncomplicated P. falciparum malaria may reflect an early and effective immune response regulated by proinflammatory Th1 cytokines, and in particular IFN-γ may play a role in limiting progression from uncomplicated malaria to severe and life-threatening complications.     

Viral determinants and host immune responses in the pathogenesis of HBV infection

Hepatitis B virus (HBV) is a virus that infects about 350,000,000 people worldwide with a clinical spectrum of acute hepatitis, the healthy carrier state, cirrhosis and hepatocellular carcinoma (HCC). The outcome of HBV infection is the result of complicated viral-host interactions. As in other infections with non-cythopatic viruses, the immune response is thought to play a crucial role in disease pathogenesis but there is increasing evidence that a variety of viral mechanisms, some depending on the function of virally encoded proteins, have a profound impact on the infected hepatocytes, the liver microenvironment, and host anti-viral responses. Indeed, the virus has evolved multiple mechanisms to ensure its success in infecting a susceptible host. The essential aspects of the life cycle of HBV and the host immune response are reviewed and recent new developments in the molecular virology of HBV, including experimental animal models, in the role of accessory viral proteins in disease pathogenesis and HCC development and in the characterisation of the T cell response in the control of HBV infection, are highlighted.     

Loss of membranous E-cadherin expression in pancreatic cancer: Correlation with lymph node metastasis,high grade,and advanced stage

Epithelial cadherin (E-cadherin) is a Ca²⁺-dependent cell-cell adhesion molecule that connects cells via homotypic interactions. Its function is critical in the induction and maintenance of cell polarity and differentiation, and its loss of downregulation is associated with an invasive and poorly differentiated phenotype in colon and other tumours. We have used an avidin-biotin immunoperoxidase technique to localize E-cadherin in microwave-treated, paraffin-embedded sections from 36 patients with pancreatic adenocarcinomas. E-cadherin was expressed by normal ductal and acinar cells with typical membranous staining at the intercellular junctions. Loss of normal surface E-cadherin expression was found in 19/36 (53 per cent) tumours compared to the adjacent normal ductal cells. Abnormal E-cadherin expression was found more frequently in poorly differentiated (grade III) (6/7, 86 per cent) than in well-differentiated tumours (grade I) (4/14, 28 per cent) (P=0·012). Membranous E-cadherin expression was also lost more frequently in primary tumours with lymph node (stage III) (14/23, 61 per cent) and distant metastasis (stage IV) (2/2, 100 per cent) compared with 3/11 (27 per cent) lymph node-negative tumours (stage I) (P=0·043). In conclusions, our data indicate that loss of membranous E-cadherin expression is associated with high grade and advanced stage in pancreatic cancer.     

Effects of prolonged cycle ergometer exercise on maximal muscle power and oxygen uptake in humans

Summary The mechanical power (W_tot, W·kg^–1) developed during ten revolutions of all-out periods of cycle ergometer exercise (4–9 s) was measured every 5–6 min in six subjects from rest or from a baseline of constant aerobic exercise [50%–80% of maximal oxygen uptake (VO_2max)] of 20–40 min duration. The oxygen uptake [VO₂ (W·kg^–1, 1 ml O₂ = 20.9 J)] and venous blood lactate concentration ([la]_b, mM) were also measured every 15 s and 2 min, respectively. During the first all-out period, W_tot decreased linearly with the intensity of the priming exercise (W_tot = 11.9–0.25·VO₂). After the first all-out period (i greater than 5–6 min), and if the exercise intensity was less than 60% VO_2max, W_tot, VO₂ and [la]_b remained constant until the end of the exercise. For exercise intensities greater than 60% VO_2max, VO₂ and [la]_b showed continuous upward drifts and W_tot continued decreasing. Under these conditions, the rate of decrease of W_tot was linearly related to the rate of increase of V [(d W_tot/dt) (W·kg^–1·s^–1) = 5.0·10^–5 –0.20·(d VO₂/dt) (W·kg^–1·s^–1)] and this was linearly related to the rate of increase of [la]_b [(d VO₂/dt) (W·kg^–1·s^–1) = 2.310^–4 + 5.910^–5·(d [la]_b/dt) (mM·s^–1)]. These findings would suggest that the decrease of W_tot during the first all-out period was due to the decay of phosphocreatine concentration in the exercising muscles occurring at the onset of exercise and the slow drifts of VO₂ (upwards) and of W_tot (downwards) during intense exercise at constant W_tot could be attributed to the continuous accumulation of lactate in the blood (and in the working muscles).     

Smooth muscle cells of the media in the dilatative pathology of ascending thoracic aorta: morphology, immunoreactivity for osteopontin, matrix metalloproteinases, and their inhibitors

The etiopathogenesis of thoracic aortic aneurysms is currently an issue of debate. The present study investigated ultrastructural, morphometric, and immunohistochemical aspects of smooth muscle cells (SMCs) in chronic aneurysm of the thoracic aorta (aneurysm group), aortic dilatation associated with valvular disease (valvular group), and dissection of the thoracic aorta (dissection group). Fragments of the ascending aorta that had been taken from the patients during coronary bypass surgery were used as controls. No significant difference was observed in the density of SMCs between the 3 pathologic groups put together and the controls. Only separate analysis of SMC density in each of the pathologic groups showed that the valvular group samples had significantly smaller amounts of SMCs in the internal layer of the media than the dissection group samples and controls. Ultrastructural analysis, in situ end labeling, propidium iodide assay, and DNA laddering did not show apoptosis of SMCs in the samples investigated. Ultrastructure of SMCs characteristic of the synthetic phenotype, together with increased expression of osteopontin in the media of pathologic thoracic aortas indicated the transition of SMCs from the contractile to the synthetic phenotype. Immunohistochemical investigation showed that medial SMCs in the samples taken from aortas of all 3 pathologic groups expressed stronger immunoreactivity for matrix metalloproteinase 1, 2, and 9 and tissue inhibitor of metalloproteinase 1 and 2 than the controls. The present study shows that during the formation of aneurysms, dissection of the thoracic aorta, or aortic dilatation associated with valvular disease, loss of SMCs was not of great importance with respect to their transition from the contractile to the synthetic type in leading to increased production of matrix metalloproteinases.     

Recovery of the endogenous beta cell function in the NOD model of autoimmune diabetes

In light of accumulating evidence that the endocrine pancreas has regenerative properties and that hematopoietic chimerism can abrogate destruction of beta cells in autoimmune diabetes, we addressed the question of whether recovery of physiologically adequate endogenous insulin regulation could be achieved in the nonobese diabetic (NOD) mice rendered allogeneic chimerae. Allogeneic bone marrow (BM) was transplanted into NOD mice at the preclinical and overtly clinical stages of the disease using lethal and nonlethal doses of radiation for recipient conditioning. Islets of Langerhans, syngeneic to the BM donors, were transplanted under kidney capsules of the overtly diabetic animals to sustain euglycemia for the time span required for recovery of the endogenous pancreas. Nephrectomies of the graft-bearing organs were performed 14 weeks later to confirm the restoration of endogenous insulin regulation. Reparative processes in the pancreata were assessed histologically and immunohistochemically. The level of chimerism in NOD recipients was evaluated by flow cytometric analysis. We have shown that as low as 1% of initial allogeneic chimerism can reverse the diabetogenic processes in islets of Langerhans in prediabetic NOD mice, and that restoration of endogenous beta cell function to physiologically sufficient levels is achievable even if the allogeneic BM transplantation is performed after the clinical onset of diabetes. If the same pattern of islet regeneration were shown in humans, induction of an autoimmunity-free status by establishment of a low level of chimerism, or other alternative means, might become a new therapy for type 1 diabetes.