Immunogenicity and safety study of Indirab: A Vero cell based chromatographically purified human rabies vaccine

A chromatographically purified Vero cell rabies vaccine, Indirab manufactured by Bharat Biotech International Limited, Hyderabad, India was subjected to safety and immunogenicity studies by both intramuscular and intradermal routes of administration in parallel with a reference vaccine, Verorab. A Pre-exposure study was undertaken in 239 subjects by intramuscular (IM) route (Study I), Post-exposure study in 188 patients by intramuscular route (Study II) and Simulated post-exposure study in 134 subjects by intradermal (ID) route (Study III). All subjects in these studies were administered with either the test or the reference vaccine as per WHO approved intramuscular and intradermal regimens. The blood samples were collected on days 0, 14 and 35 in case of Study 1, and days 0, 14, 28 and 90 in case of studies II and III. In all studies both vaccine groups had adequate antibody titers (>0.5 IU/mL) on all days tested post-vaccination and there was no significant difference in the titers observed (p > 0.05). Some side effects like pain, induration, itching and fever were noted in both vaccine groups in all studies. Both vaccines were well tolerated. Hence it can be concluded that Indirab is as safe and immunogenic as Verorab when administered by both intramuscular and intradermal routes.     

Vitamin D in esophageal cancer: Is there a role for chemoprevention?

Vitamin D has emerged as a promising anti-cancer agent due to its diverse biological effects on tumor differentiation, apoptosis and suppression of cellular proliferation. Current evidence suggests a protective role of vitamin D in colon cancer. The effect of vitamin D on esophageal cancer remains controversial. Multiple studies investigated the association between vitamin D and esophageal cancer, employing different modes of assessment of vitamin D status such as serum 25-hydroxyvitamin D levels, vitamin D dietary intake or exposure to ultraviolet B (UVB) radiation. Genetic variations of the vitamin D receptor (VDR) gene and VDR expression in esophageal specimens have also been investigated. Ecological studies evaluating exposure to UVB radiation yielded an inverse correlation with esophageal cancer. When vitamin D dietary intake was assessed, direct association with esophageal cancer was observed. However, circulating 25-hydroxyvitamin D concentrations showed inconsistent results. In this review article, we present a detailed summary of the current data on the effects of vitamin D on various histological subtypes of esophageal cancer and their precursor lesions. Well-powered prospective studies with accurate measurement of vitamin D status are needed before chemoprevention with vitamin D is recommended, as current evidence does not support a chemopreventive role of vitamin D against esophageal cancer. Future studies looking at the incidence of esophageal cancer in patients with pre-cancerous lesions (Barrett's esophagus and squamous cell dysplasia) receiving vitamin D supplementation are needed.     

Open globe injury in Hospital Universiti Sains Malaysia - A 10-year review

AIM: To identify the aetiology of open globe injuries at Hospital Universiti Sains Malaysia over a period of 10y and the prognostic factors for visual outcome.METHODS:Retrospective review of medical records of open globe injury cases that presented from January 2000 to December 2009. Classification of open globe injury was based on the Birmingham Eye Trauma Terminology (BETT). Records were obtained with hospital permission via the in-house electronic patient management system, and the case notes of all patients with a diagnosis of open globe injury were scrutinised. Patients with prior ocular trauma, pre-existing ocular conditions affecting the visual acuity, contrast sensitivity, central vision or corneal thickness, as well as those with a history of previous intraocular or refractive surgery were excluded. Analysis of data was with SPSS version 20.0. Ordinal logistic regression analysis was used to examine the association between prognostic factors and visual outcome.RESULTS: This study involved 220 patients (n=222 eyes). The most common place of injury was the home (51.8%), followed by the workplace (23.4%). Among children aged less than 16y of age, domestic-related injury was the predominant cause (54.6%), while in those aged 16y and above, occupational injuries were the most common cause (40.0%). Most eyes (76.5%) had an initial visual acuity worse than 3/60, and in half of these, the visual acuity improved. The visual outcome was found to be significantly associated with the initial visual acuity (P<0.005), posterior extent of wound (P<0.001), length of wound (P<0.001), presence of hyphaema (P<0.001) and presence of vitreous prolapse ((P<0.005).CONCLUSION:The most common causes of open globe injury are domestic accidents and occupational injuries. Significant prognostic factors for final visual outcome in patients with open globe injury are initial visual acuity, posterior extent and length of wound, presence of hyphaema and presence of vitreous prolapse. Awareness of the factors predicting a poor visual outcome may be helpful during counselling of patients with open globe injuries.     

Multifocal epithelioid hemangioendothelioma presenting with hemoptysis

We present a case of multifocal epithelioid hemangioendothelioma occurring in an adolescent boy who presented with massive hemoptysis and showed a pulmonary perihilar mass with multiple lesions in the liver and two lytic lesions in the ribs on imaging. The diagnosis was confirmed by lung and liver biopsy. He was treated with oral steroids.     

Phosphoregulatory protein 14-3-3 facilitates SAC1 transport from the endoplasmic reticulum

Most secretory cargo proteins in eukaryotes are synthesized in the endoplasmic reticulum and actively exported in membrane-bound vesicles that are formed by the cytosolic coat protein complex II (COPII). COPII proteins are assisted by a variety of cargo-specific adaptor proteins required for the concentration and export of secretory proteins from the endoplasmic reticulum (ER). Adaptor proteins are key regulators of cargo export, and defects in their function may result in disease phenotypes in mammals. Here we report the role of 14-3-3 proteins as a cytosolic adaptor in mediating SAC1 transport in COPII-coated vesicles. Sac1 is a phosphatidyl inositol-4 phosphate (PI4P) lipid phosphatase that undergoes serum dependent translocation between the endoplasmic reticulum and Golgi complex and controls cellular PI4P lipid levels. We developed a cell-free COPII vesicle budding reaction to examine SAC1 exit from the ER that requires COPII and at least one additional cytosolic factor, the 14-3-3 protein. Recombinant 14-3-3 protein stimulates the packaging of SAC1 into COPII vesicles and the sorting subunit of COPII, Sec24, interacts with 14-3-3. We identified a minimal sorting motif of SAC1 that is important for 14-3-3 binding and which controls SAC1 export from the ER. This LS motif is part of a 7-aa stretch, RLSNTSP, which is similar to the consensus 14-3-3 binding sequence. Homology models, based on the SAC1 structure from yeast, predict this region to be in the exposed exterior of the protein. Our data suggest a model in which the 14-3-3 protein mediates SAC1 traffic from the ER through direct interaction with a sorting signal and COPII.Most of the transmembrane secretory cargo proteins from the endoplasmic reticulum (ER) are selectively exported in cytosolic coat protein complex II (COPII) vesicles via direct interaction of their export motif with the COPII coat. The COPII coat core machinery consists of five cytosolic proteins: Sar1, Sec23, Sec24, Sec13, and Sec31 (secretory pathway proteins) (1). Sec24 is considered to be the primary subunit responsible for binding to membrane cargo proteins at the ER and concentrating them into the forming vesicle (2). Some of these cargo proteins require the assistance of cytosolic or membrane-spanning accessory adaptor proteins for their incorporation into COPII vesicles. Several adaptor proteins have been identified to assist the COPII machinery in yeast (3–5); however, fewer have been characterized in higher eukaryotes. In metazoans, ERGIC-53 mediates the export of blood clotting factors, Cathepsin Z and C and α-1 antitrypsin (6), and SCAP [sterol-regulatory elementary binding protein (SREBP) cleavage activating protein] mediates the regulated transport of SREBP protein from the ER to the Golgi in cells that are sterol-deficient (7). Most COPII adaptor proteins are membrane-embedded, but at least one example of a cytosolic accessory protein, 14-3-3, has been proposed to control the anterograde trafficking of many of cell surface receptor proteins, possibly at the level of the ER (8). 14-3-3s are small (30 kDa), acidic, and ubiquitously expressed eukaryotic proteins that are conserved from yeast to mammals and modulate various cellular processes by interacting with a variety of target proteins (9, 10). These include cell cycle regulation, signaling by MAP kinases, apoptosis, and transfer of signaling molecules between the nucleus and cytosol (11–14). Yeast cell viability depends on the expression of at least one of the two 14-3-3 isoforms (Bmh1 and Bmh2) (15). There are seven different isoforms in mammals (β, γ, δ, ε, η, σ, θ), some of which show differential tissue localization (14). Because of their redundant roles in cellular processes, depleting cellular levels of 14-3-3 to study a particular process poses a challenge. It is thought that their role in trafficking is to interfere with the ER retention/retrieval motif of target membrane proteins, and thus promote the transport of these cargos to the cell surface (16). For some proteins (e.g., KCNK3 and MHC class II, GPR15) (17–19), recruitment of 14-3-3 requires phosphorylation of a residue involved in 14-3-3 binding, whereas in other proteins (e.g., Kir6.2) 14-3-3 recognizes the correct assembly of multimeric proteins (20, 21).In this paper we examine the role of 14-3-3 proteins as an adaptor for COPII vesicular transport of SAC1 (suppressor of actin mutations 1-like protein). SAC1 is a phosphatidyl inositol-4 (PI4) lipid phosphatase that belongs to a family of enzymes with a CX₅R(T/S) Sac catalytic domain, which is conserved from yeast to metazoans. Sac proteins control several cellular processes, including phosphoinositide homeostasis, membrane trafficking, and cytoskeleton organization. SAC1 is a 587-aa transmembrane protein with both N- and C-terminal domains exposed to the cytosol. Deletion of SAC1 in yeast and mammalian cells leads to changes in Golgi morphology and function and a SAC1 mouse knockout is embryonically lethal. Recently, SAC1 has been identified as Drosophila vesicle-associated protein binding partner and down-regulation of Drosophila vesicle-associated protein or SAC1 in Drosophila leads to the pathogenesis associated with amyotrophic lateral sclerosis (22).It has been reported previously that SAC1 is localized to the Golgi membranes only when cells are starved for nutrients or growth factors, but remains in the ER under normal growth conditions (23, 24). Given the role for PI(4)P in vesicle traffic from the trans Golgi network, starvation conditions that lodge SAC1 and thus deplete the local supply of PI(4)P in the Golgi may suppress anterograde traffic in cells that must cease net cell growth. The regulation of SAC1 traffic may be crucial to the control of cell growth and anterograde membrane traffic.The retrieval of mammalian SAC1 from the Golgi to the ER in the presence of growth factors or mitogens is controlled by COPI-mediated retrograde transport and requires the p38 MAPK pathway (23). Although the regulation of SAC1 retrieval from the Golgi has been reported, little is known about the control of SAC1 export from the ER under conditions of serum starvation. Recently, the N-terminal cytoplasmic domain of SAC1 was reported to contribute to Golgi localization in mammalian cells (25). We have established a cell-free reconstitution system that recapitulates the biogenesis and ER export of SAC1 and identified 14-3-3 proteins as an important factor in the packaging of SAC1 into COPII transport vesicles. Given the role of 14-3-3 proteins in various signaling pathways and the fact that SAC1 transport is affected by the p38 MAPK pathway, an understanding of the molecular role of 14-3-3 proteins in vesicular traffic could provide a mechanistic link between signaling and membrane assembly (23).     

Impact of socioeconomic factors on the prevalence of lymphatic filariasis in Andhra Pradesh,India

Aim

Lymphatic filariasis is an important public health problem that causes economic loss and poverty in many endemic regions of India. This study explores the influence of socioeconomic factors on filariasis prevalence in the Chittoor district of Andhra Pradesh.

Subjects and methods

To understand the influence of socioeconomic variables on lymphatic filariasis, a pilot-scale epidemiological and socioeconomic study was conducted in 30 villages of Chittoor district, Andhra Pradesh, India, from 2004 to 2007. Data were analyzed statistically by frequency distribution, multivariate logistic regression and principal component analysis (PCA).

Results

A total of 5133 blood samples were collected and screened for microfilaria; 77 were found to be positive (1.52 %). The multivariate analysis showed that variables such as age (OR?=?2.4, 95 % CI: 1.47–4.01), income [Indian rupees (INR): <1000: OR?=?4.2, 95 % CI: 1.48–11.76; INR: 1000–3000: OR?=?3.84, 95 % CI:1.92–7.68], drainage system (OR?=?3.5, 95 % CI: 1.62–7.5), mosquito avoidance (OR?=?1.41, 95 % CI: 0.69–2.87) and participation in mass drug administration (MDA) programs (OR?=?1.33, 95 % CI:0.74–2.38) were risk factors for filariasis. The socioeconomic index derived from the PCA was categorized into low (1.7 %), medium (1.7 %) and high (1.3 %) in relation to the percentage of parasite prevalence.

Conclusion

This study reveals that filariasis is largely associated with various socioeconomic factors. Hence, health officials should focus on improving the quality of life to minimize the filarial incidence in the endemic villages by considering the socioeconomic index as a marker for targeting low and medium socioeconomic level groups for disease control programs.