Plasmodium falciparum-free merozoites and infected RBCs distinctly affect soluble CD40 ligand-mediated maturation of immature monocyte-derived dendritic cells

Free plasmodium merozoites released from the parasitized hepatocytes and erythrocytes represent a transitory, extracellular stage in its mammalian host. In this study, we compared the effect of Plasmodium falciparum-free merozoites with infected RBCs (iRBCs) on the maturation of human monocyte-derived dendritic cells (DCs) in vitro. Phagocytosed-free merozoites prevented soluble CD40 ligand (sCD40L)-induced, phenotypic maturation of DCs and secretion of IL-12p70 but enhanced IL-10 production and primed, naive CD4+ cells to produce a high level of IL-10 compared with IFN-gamma. Free merozoites augmented sCD40L-induced ERK1/2 activation, and inhibition of ERK1/2 with its inhibitor PD98059 markedly abrogated IL-10 production and rescued IL-12 production. Therefore, the molecular mechanisms by which free merozoites antagonized sCD40L-induced DC maturation appeared to involve the activation of the ERK pathway. In contrast, phagocytosed iRBCs by itself induced DCs to semi-maturation, responded to CD40 signaling by maturing and secreting increased levels of TNF-alpha, IL-6, and also IL-12p70, and led to a pronounced, proinflammatory response by the allogenic CD4+ T cells. iRBCs regulate CD40-induced p38MAPK. Studies using inhibitors selective for p38MAPK (SB203580) showed that p38MAPK played an essential role in the maturation and function of DCs. Our results reveal the ability of free merozoites and iRBCs to distinctly alter the sCD40L-induced DC functioning by regulating the activation of the MAPK pathway that can inactivate or exacerbate immune responses to promote their survival and the development of parasite-specific pathologies.     

HN protein of Newcastle disease virus causes apoptosis in chicken embryo fibroblast cells

Newcastle disease virus (NDV), an avian paramyxovirus, induces apoptosis in chicken embryo fibroblast (CEF) cells. In the present investigation, the ability of haemagglutinin-neuraminidase (HN) protein of NDV to cause apoptosis in CEF cells was examined. The results revealed that cells expressing the HN protein demonstrated decreased DNA content, phosphatidylserine exposure and increased cytoplasmic vacuolation. Up-regulation of caspase-1, -9, -8, -3, loss of mitochondrial transmembrane potential and an increase in oxidative stress were also observed in cells expressing the HN protein. Based on the above results it can be concluded that HN protein of NDV causes apoptosis in CEF cells.     

Gemcitabine concurrent with radiation therapy for locally advanced head and neck carcinomas

Background

Management of advanced head and neck carcinoma is a challenging proposition. Presently concomitant chemo-irradiation has become the standard of care in such patients. Many chemotherapeutic drugs have shown radio-sensitising effects when used concomitantly along with radiation. The present study was carried out with the objective of assessing the feasibility and efficacy of low dose gemcitabine as radiosensitizer when used during radical radiotherapeutic management of patients with locally advanced head and neck carcinomas.

Patients and methods

From November 2000 to March 2003, Eighty histopathologically proven cases of squamous cell head and neck carcinoma were included in this trial, 40 patients were randomly assigned to receive radiotherapy alone and 40 patients to receive gemcitabine along with radiotherapy.

Results

All patients were assessable for toxicity and response. Severe mucositis (WHO level 5 reactions were observed in 67% patients in the CT/RT group vs 16% patients in the RT only group. No severe hematological toxicity was seen. The rates of complete and partial responses were 42.5% & 57.5% respectively for RT only and 62.5% &37.5%, respectively for CT/RT group. There was no significantdifference in the response rates at the end of treatment but disease free survival at three years was better in the CT/RT group (63.3% vs 20%). Nine of the 17 patients with complete response in the radiation only group developed relapse while no relapses were seen in CT/RT group.

Conclusion

In the present study the combination of gemcitabine and radiotherapy has not shown any statistical difference in locoregional control but survival advantage was seen as compared to radiotherapy alone. At the same time more mucosal and skin toxicity was encountered when Gemcitabine is given concurrently with radiation.     

Increase in endothelin B receptor expression in optic nerve astrocytes in endothelin-1 induced chronic experimental optic neuropathy

The purpose of this study was to determine whether endothelin B (ETB) receptor levels in the optic nerve are related to retinal ganglion cell (RGC) loss in a model of chronic endothelin-1 (ET-1) induced optic neuropathy. RGCs of adult Brown Norway rats were first retrogradely labeled with fluorochrome from the superior colliculi. An osmotic minipump was surgically implanted 7 days later to deliver 10⁻¹¹ M (n = 9), 10⁻⁹ M (n = 12) or 10⁻⁷ M (n = 9) ET-1 to the retrobulbar optic nerve for 28 days. RGC survival was expressed as the ratio of RGC counts in experimental versus control eyes in wholemounted retinas. Optic nerves were used for either ETB western blot analysis (n = 24) or immunohistochemistry (n = 6) for ETB and glial fibrillary acidic protein (GFAP) to localize astrocytes. ETB expression was higher in the experimental nerve compared to the fellow untreated control nerve in 19 (79%) of the 24 animals with a mean increase of 16.7 ± 4.5% in densitometric analyses of the immunoblots. Experimental nerves showed stronger labeling for both ETB and GFAP compared to control nerves. ETB-positive cells almost completely co-localized with GFAP-positive cells in both experimental and untreated control nerves, however, ETB expression was stronger in the astrocyte soma and proximal processes, while GFAP was expressed more strongly in the distal processes. There was a weak relationship between RGC loss and increase in ETB expression (r = −0.417, p = 0.076). There is an upregulation of ETB expression in optic nerve astrocytes in ET-1 induced chronic optic neuropathy causing RGC loss.     

Ocular morbidity prevalence among school children in Shimla, Himachal, North India

Background

Data on eye diseases among school children is not readily available. Considering the fact that one-third of India''s blind lose their eyesight before the age of 20 years and many of them are under five when they become blind, early detection and treatment of ocular morbidity among children is important.

Aim

To estimate the prevalence of ocular morbidity among school children of age 6-16 years.

Settings

Government and private coeducational schools in urban area of Shimla.

Design

Cross-sectional

Materials and Methods

Government and private coeducational schools selected by stratified random sampling. About 1561 school children, studying in elementary through secondary class in these schools were examined from August 2001 to January 2002 in Shimla. A doctor did visual acuity and detailed ophthalmic examination.

Statistical analysis

The Chi-square test was used to test differences in proportions. Differences were considered to be statistically significant at the 5% level.

Results

Prevalence of ocular morbidity was 31.6% (CI=29.9-32.1%), refractive errors 22% (CI=21.1-22.8%), squint 2.5% (CI=2.4-2.6%), color blindness 2.3% (CI=2.2-2.4%), vitamin A deficiency 1.8 % (CI=1.7-1.9%), conjunctivitis 0.8% (CI=0.79-0.81%). Overall prevalence of ocular morbidity in government and private schools did not show any statistical significant difference. Prevalence of conjunctivitis was significantly (P<0.5) more in government schools.

Conclusion

A high prevalence of ocular morbidity among high-school children was observed. Refractive errors were the most common ocular disorders.     

First Successful Separation of Craniopagus Twins in India—Plastic Surgical Considerations

Separation of total vertical craniopagus with shared venous sinuses poses multiple challenges. Provision of soft-tissue cover to the exposed brains at the time of total separation is one of them, due to the large size of the defect and paucity of local tissues. Staged separation of twins is advised with partial venous and parenchymal disconnection in the first stage and total separation in the second stage. Tissue expanders are inserted in the first stage, and second stage planned to coincide with the period of adequate expansion. In the child being reported, emergency second stage was done due to the deteriorating general condition of the children. Left with inadequate expanded skin, the critical defect in a twin was managed with bilateral trapezius myocutaneous flaps. High ionotropic support of the postoperative period resulted in superficial necrosis of the flap, which was managed by debridement, allograft application and autograft later. Both twins had well-healed wounds by 3 months.     

Beta blockers normalize QT hysteresis in long QT syndrome

Objectives This study was performed to evaluate the impact of beta blockers on QT adaptation to heart rate during the exercise and recovery phases of exercise testing in long QT syndrome. Background Long QT syndrome is characterized by familial syncope and sudden death in the context of sudden heart rate changes. QT hysteresis has been proposed as a phenotypic marker of long QT syndrome, suggesting altered QT adaptation to changes in heart rate. Methods Fourteen patients with long QT syndrome (aged 26 ± 16 years, 6 male) and 10 healthy volunteers (aged 37 ± 11 years, 9 male) underwent graded exercise testing with continuous lead II electrocardiographic monitoring. Long QT patients underwent repeat assessment after 1 month of beta blockade. QT intervals at matching heart rates were compared during exercise and recovery to determine the effect of beta blockade on QT hysteresis, defined as the recovery QT peak interval subtracted from the exercise QT peak interval. Results In the 14 long QT syndrome patients, beta blockers slowed the resting heart rate without affecting the corrected QT interval (502 ± 52 ms baseline vs 481 ± 40 ms beta blocker, P = .17). The increase in heart rate with exercise was similar in the 3 groups (P = .73). Exaggerated hysteresis of the QT interval was seen in the patients with long QT syndrome at baseline compared with controls (46 ± 19 ms vs 19 ± 11 ms 1 minute into recovery, P = .006). Beta blockers had minimal effect on the QT interval but markedly reduced hysteresis with minimal separation of the exercise and recovery QT/RR curves (25 ± 35 ms 1 minute into recovery, P = .027). The combined curve separation at all 6 time points analyzed was 165 ± 95 ms in patients with long QT syndrome at baseline, 40 ± 131 ms after beta blockade, and 29 ± 30 ms in control subjects (P = .002). Comparison of the beta blocker effect on hysteresis in the 2 genotypes suggested a greater reduction in hysteresis in the 3 patients with long QT syndrome 1 compared with the 11 patients with long QT syndrome 2. Conclusions Beta blockers reduce QT hysteresis in patients with long QT syndrome to values seen in normal patients. This improved QT adaptation to changes in heart rate may explain the clinical benefit of beta blockers in long QT syndrome. (Am Heart J 2002;143:528-34.)     

Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin‐10

The functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft‐attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host’s alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell–mediated and inflammatory cytokine–induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well‐established models of corneal transplantation (low‐risk and high‐risk models), we show that Tregs derived from low‐risk graft recipients have a superior capacity in protecting CEnCs against effector T cell–mediated and interferon‐γ and tumor necrosis factor‐α‐induced cell death compared to Tregs derived from high‐risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low‐risk hosts occurs independently of direct cell‐cell contact and is mediated by the immunoregulatory cytokine IL‐10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL‐10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation.