Search

BackgroundParkinson’s disease (PD) is caused by the progressive loss of dopaminergic cells in substantia nigra pars compacta (SNc). The root cause of this cell loss in PD is still not decisively elucidated. A recent line of thinking traces the cause of PD neurodegeneration to metabolic deficiency. Due to exceptionally high energy demand, SNc neurons exhibit a higher basal metabolic rate and higher oxygen consumption rate, which results in oxidative stress. Recently, we have suggested that the excitotoxic loss of SNc cells might be due to energy deficiency occurring at different levels of neural hierarchy. Levodopa (LDOPA), a precursor of dopamine, which is used as a symptom-relieving treatment for PD, leads to outcomes that are both positive and negative. Several researchers suggested that LDOPA might be harmful to SNc cells due to oxidative stress. The role of LDOPA in the course of PD pathogenesis is still debatable.New MethodWe hypothesize that energy deficiency can lead to LDOPA-induced toxicity (LIT) in two ways: by promoting dopamine-induced oxidative stress and by exacerbating excitotoxicity in SNc. We present a multiscale computational model of SNc-striatum system, which will help us in understanding the mechanism behind neurodegeneration postulated above and provides insights for developing disease-modifying therapeutics.ResultsIt was observed that SNc terminals are more vulnerable to energy deficiency than SNc somas. During LDOPA therapy, it was observed that higher LDOPA dosage results in increased loss of somas and terminals in SNc. It was also observed that co-administration of LDOPA and glutathione (antioxidant) evades LDOPA-induced toxicity in SNc neurons.Comparison with Existing MethodsOur proposed multiscale model of SNc-striatum system is first of its kind, where SNc neuron was modelled at biophysical level, and striatal neurons were modelled at spiking level.ConclusionsWe show that our proposed model was able to capture LDOPA-induced toxicity in SNc, caused by energy deficiency.

BACKGROUND The main aim of our study was to compare and evaluate the stress response, postoperative recovery and postoperative pain in laparoscopic procedures compared to conventional open surgical procedures. MATERIALS AND METHODS A prospective study was done in 100 patients undergoing surgery for inguinal hernia, symptomatic cholelithiasis and subacute appendicitis. The study was conducted in the Department of General Surgery, Government Kilpauk Medical College and Hospital for a period of six months from January 2015 to June 2015. The study group of 100 patients was divided into 2 groups, each group comprising 50 patients. The first group consisted of 50 patients who underwent conventional open surgical procedure and second group consisted of 50 patients who underwent minimally invasive laparoscopic procedure. The stress response in the two groups was compared on the basis of preoperative and postoperative serum cortisol, glucose and C - reactive protein (CRP) levels, duration of hospital stay and postoperative wound infections. RESULTS Compared to the open surgical group, the stress response in laparoscopic group was less as shown by the difference in mean cortisol level in both the groups. It was also seen that the post op recovery is also faster and incidence of postoperative wound infection is also less in the laparoscopic group compared to the open conventional group. CONCLUSION On the basis of our study one can conclude the laparoscopic surgical procedure is associated with less stress, less pain, less anxiety, early recovery and less hospital stay compared to conventional open procedures.

BACKGROUND In India, pancreatitis seems to be more common among alcoholics. Being a developing nation, most of the affected families live in poverty. So, the hospital expenses in treatment of pancreatitis are a burden to them. Many investigations are required for calculating the severity scoring systems will increase the patient's cost. In order to predict the severity of the disease earlier, a simple scoring system is evaluated using routine blood count which will enable us to provide aggressive treatment for those progressing to severe pancreatitis and lower the morbidity and mortality. MATERIALS AND METHODS A prospective collection of data among 100 sequential patients admitted with a diagnosis of pancreatitis based on Atlanta criteria are enrolled and data collected for severity, amylase, lipase, CECT, serum creatinine, and neutrophil lymphocyte ratio, at the time of admission, 24 hours, 48 hours and analyzed using independent variable t test. RESULTS Out of 100 patients 96% were males, alcohol was the leading cause 98%, severe pancreatitis was noted in 20% mortality was 4%, NLR was progressively increasing from 12 to 15 in severe group compared to 4 to 6 in mild group the difference was significant (p value – 0.004). CONCLUSION The overall mortality due to acute pancreatitis has remained 10-15% in the past 20 years. Accurate predictors of the severity of acute pancreatitis are important because they influence clinical decision making. Neutrophilic Lymphocytic Ratio (NLR) was calculated among these patients and was found to be increased in acute pancreatitis. It was significantly higher in severe pancreatitis patients than the mild pancreatitis patients. It is thus a cost effective tool. NL R is a simple indicator of the prognosis of pancreatitis which would help in providing aggressive treatment to those patients progressing to severe pancreatitis.

Digital, Introduction. Switching from polluting (e.g. wood, crop waste, coal) to clean (e.g. gas, electricity) cooking fuels can reduce household air pollution exposures and climate-forcing emissions. While studies have evaluated specific interventions and assessed fuel-switching in repeated cross-sectional surveys, the role of different multilevel factors in household fuel switching, outside of interventions and across diverse community settings, is not well understood. Methods. We examined longitudinal survey data from 24 172 households in 177 rural communities across nine countries within the Prospective Urban and Rural Epidemiology study. We assessed household-level primary cooking fuel switching during a median of 10 years of follow up (∼2005–2015). We used hierarchical logistic regression models to examine the relative importance of household, community, sub-national and national-level factors contributing to primary fuel switching. Results. One-half of study households (12 369) reported changing their primary cooking fuels between baseline and follow up surveys. Of these, 61% (7582) switched from polluting (wood, dung, agricultural waste, charcoal, coal, kerosene) to clean (gas, electricity) fuels, 26% (3109) switched between different polluting fuels, 10% (1164) switched from clean to polluting fuels and 3% (522) switched between different clean fuels. Among the 17 830 households using polluting cooking fuels at baseline, household-level factors (e.g. larger household size, higher wealth, higher education level) were most strongly associated with switching from polluting to clean fuels in India; in all other countries, community-level factors (e.g. larger population density in 2010, larger increase in population density between 2005 and 2015) were the strongest predictors of polluting-to-clean fuel switching. Conclusions. The importance of community and sub-national factors relative to household characteristics in determining polluting-to-clean fuel switching varied dramatically across the nine countries examined. This highlights the potential importance of national and other contextual factors in shaping large-scale clean cooking transitions among rural communities in low- and middle-income countries., Ciencias Médicas y de la Salud

Background Depression is twice more prevalent among women but remains unidentified in primary care. Objective We aimed to estimate the reliability and validity of PHQ-9, when administered by health workers, a cadre of public health staff, posted in primary health centres. We translated PHQ-9 to Malayalam, a language spoken by 30 million people in Kerala, India. Health workers administered PHQ-9 to women (n = 238) aged 18–60 years in a high prevalent primary care setting. Mini International Neuropsychiatric Interview (MINI) was administered by the psychiatrist on the same day to diagnose depressive disorder. Two health workers administered PHQ-9, independently, in a subset of 21 women. Results The internal consistency reliability (Cronbach’s alpha 0.89) and inter-rater reliability (intra class correlation coefficient, 0.94; 95% CI, 0.86–0.95) were high. On ROC analysis, area under curve was 0.92 (95% CI 0.88–0.96). For a cut-off score of ≥9, PHQ-9 had a sensitivity of 82.5%, (95% CI, 72.4–92.6), specificity of 90.1% (95% CI, 84.5–95.6%), positive predictive value of 73.4% (95% CI, 62.4–84.4%) and negative predictive value of 93.9% (95% CI, 90.2–97.6%). The accuracy was 88.2% (84.0–92.4%) and positive likelihood ratio was 8.3. Factor analysis supported a single factor, with eigen value above 1, with high loading for all items (0.73–0.79), except item related to appetite (0.58). This explained 62% of variance in the data. Prevalence of MINI diagnosed depressive disorders was 25%. Conclusion When administered by health workers, PHQ-9 has good reliability and at cut off score ≥9, it has good validity to identify depression in primary care.

Background In low and middle income countries where mental health resources are limited, community based depression intervention models, which can be implemented through the existing health system, are extremely relevant. Objective To test the effectiveness of Community based Depression Intervention Programme (ComDIP), newly developed by us, to reduce severity of depression in women, compared to the treatment as usual (TAU). Methods An RCT (Trial registration Number: CTRI/2011/08/001978, Clinical Trials Registry -India) was conducted in a primary care setting in Trivandrum, Kerala, South India. Health workers screened 422 women, aged 18–60 years, using PHQ-9. Sixty women with HAM-D (Hamilton Depression Rating scale) score above 19 were randomized to receive either ComDIP or TAU. Primary care physicians and health workers together implemented ComDIP which had psycho-social intervention and drug treatment. Those in TAU arm were referred to available mental health services. Primary outcome was measured at 8 weeks, by HAM-D. Results At baseline and 8 weeks, mean (SD) HAM-D scores were 29.2 (5.8) and 12.2 (9.3) respectively among women in ComDIP; and 28.6 (5.1) and 21.7 (12.4) respectively among those in TAU (p = 0.02, effect size = 0.82). Conclusions ComDIP, implemented through existing health system is an effective public health programme to manage women with depression in primary care.

A 19-year-old castrated male Arab/Quarter horse presented with an extensive history of cutaneous metastatic melanoma. Over a period of 8 months, a total of 8 doses of plasmid DNA vaccine expressing the Streptococcus pyogenes emm55 gene (pAc/emm55) were administered intratumorally at 300 μg/dose via a needless injector. Upon completion of the vaccination protocol, the size of the injected lesions, on average, were reduced by 40.3% from the initial size measurements. Lesions that were not injected were reduced by 47.6%. The overall reduction in total tumor burden was 42.3%. Tumor regression was also associated with the augmentation of antimelanoma IgG antibody response, thus implying that an induction of an effective antimelanoma response would be of great advantage in the management of equine melanoma.

The primary objective of this study was to find the performance of the 2009 probable case definition of dengue and compare it with the definition given by the WHO-SEAR expert group in 2011.A cross-sectional study was conducted in Thiruvananthapuram district of Kerala, which is hyperendemic for dengue. A consecutive series of 851 participants defined by the selection criteria were recruited from the primary, secondary, and tertiary health care settings. Sensitivity, specificity, predictive values, and likelihood ratios of the clinical case definitions were calculated using reverse transcriptase-polymerized chain reaction (RT-PCR) as gold standard in case of fever less than or equal to 5 days and serology (IgM positivity) for fever5 days. Diagnostic odds ratio (DOR) was also calculated as a single indicator of performance of the case definition.The 2009 World Health Organization (WHO) case definition had a sensitivity of 76·4% (69·6-82·1) and negative predictive value of 87·5%. The 2011 WHO-SEAR expert group case definition had a higher sensitivity of 87·9% (82·2-91·9) but lower negative predictive value of 86·6%. The three independent criteria which were significantly associated with dengue were thrombocytopenia less than 150,000 (OR 2·80), leukopenia (OR 2·28), and absence of backache (OR 2·68). The performance of 2009 case definition was better (DOR 2·4) than the 2011 WHO-SEAR expert group case definition. This was further enhanced when thrombocytopenia was specified as platelet count less than 150,000 (DOR2·7). When 'no backahe' was added as an additional criteria, the performance of both definitions improved.The 2009 WHO case definition has better discriminatory power than the 2011 WHO-SEAR expert group case definition. The performance of 2009 WHO case definition is enhanced by specifying thrombocytopenia as platelet count less than 150,000. The inclusion of 'no backache' further improves the discriminatory power. This may be more useful in primary care settings, to rule out dengue.

Objective Diabetes mellitus and depression are major public health problems and are significantly linked with each other. This research study intends to assess for undiagnosed depression and its predictors among adult diabetic patients. Methods A cross-sectional study was done among 100 patients with type 2 diabetes mellitus attending the diabetic clinic of a tertiary care hospital. Depression was assessed using Patient Health Questionnaire-9 (PHQ-9). Chi-square test was performed and odds ratios (OR) with 95% confidence interval (95% CI) were obtained. Mann Whitney U and Pearson correlation tests were done. Logistic regression was carried out to determine the predictors of depression and adjusted odds ratios with 95% confidence intervals were obtained. Results The prevalence of depression was 49% (95% CI 39.1–58.9%). The predictors of depression were female gender, elevated fasting blood sugar (FBS) level, physical disability and lack of physician's advice about lifestyle modifications. FBS values were significantly higher in depressed individuals as compared to the non-depressed (p value 0.002). A positive correlation (r = 0.38, p value 0.01) was obtained between PHQ-9 scores and the FBS values of the diabetic subjects. Conclusions Subjects with diabetes are highly prone for comorbid depression. Physicians should be sensitive towards the need for assessing for possible depression and its risk factors in diabetic patients.

Acute Renal Failure is an intractable problem, which can be actively and effectively managed, but can be prevented only to a little extent. Acute renal failure requiring dialysis is associated with high mortality and morbidity. In a study conducted by analyzing the literature and taking 15897 acute renal failure patients, it was found that mortality rates in most studies exceeded 30% [1]. Despite technical advancements in the management of acute renal failure over the last 50 years, mortality rates seem to have remained unchanged at around 50% [1]. In Kerala, the studies on acute renal shut down are sparse. Also the clinicodemographic profile of patients with acute renal failure varies in different parts of the world. Our objective was to study the clinicodemographic profile of acute renal failure patients who underwent renal replacement therapy and to identify the determinants of outcome at discharge or death. The present study is a retrospective cohort of 107 patients who required renal replacement therapy in Medical College, Thiruvananthapuram. The relevant data were collected from the case records of patients by a data collection sheet. Outcome was taken as survived or expired at the time of discharge or death. Continuous variables were represented as means and standard deviations. The statistical significance assessed by Odds ratio and Chi-square test. The present study had a mortality of 32.7% with women more prone. The average age of the subjects was 43.16±16.45 years. Univariate analysis of the variables with the outcome like women gender (p=0.490), pre-morbidities (p=0.079), only one comorbidity in a patient (p=0.769), oliguria on the day of Ist dialysis (p=0.549), oliguria on the next day of the Ist dialysis (p=0.363) and Liano’s score 0.3 & above on the day of Ist dialysis (p=0.065) were associated with increased mortality. Ages 45 years & above (p=0.006), sepsis syndrome (p=0.0008), more than one co-morbidity in a patient (p=0.032) and Liano’s score on the day after the Ist dialysis (p=0.024) were associated with obvious increase in mortality, which were statistically significant. Snake envenomation had the best prognosis (p=0.037) and serum creatinine level had weak association with outcome (p=0.065). The study conducted on 107 patients revealed 32.7% mortality. Snake envenomation had the best prognosis and sepsis syndrome the worst. Age 45 years & above and women gender were bad prognostic indicators. Pre-morbidities, co-morbidities and oliguria were probable bad indicators. Liano’s score 0.3 and above was a good predictor of mortality. Unfortunately, serum creatinine level had only weak association with the outcome.

Background: The world is experiencing a pandemic of chikungunya which has swept across Indian Ocean and the Indian subcontinent. Kerala the southernmost state of India was affected by the chikungunya epidemic twice, first in 2006 and then in 2007. Kerala has got geography and climate which are highly favorable for the breeding of Aedes albopictus, the suspected vector. Aim: The aim of the study was to highlight the various domestic and environmental factors of the families affected by chikungunya in 2007 in Thiruvananthapuram district (rural) of Kerala. Settings and design:This is a cross-sectional survey conducted in Thiruvananthapuram (rural) district during November 2007. Settings and design: This is a cross-sectional survey conducted in Thiruvananthapuram (rural) district during November 2007 Materials and Methods: Samples were selected from field area under three Primary Health Centers.These areas represent the three terrains of the district namely the highland, midland, and lowland. The sample size was estimated to be 134 houses from each study area.The field area of health workers was selected as clusters and six subcenters from each primary health center were randomly selected (lot method). Results and Conclusions: The proportion of population affected by chikungunya fever is 39.9% (38.9-40.9%). The investigators observed water holding containers in the peri-domestic area of 95.6% of the houses. According to regression (binary logistic) analysis, the area of residence [adjusted odds ratio (OR) = 8.01 (6.06-14.60)], residing in a non-remote area [adjusted OR=0.25 (0.16-0.38)], perceived mosquito menace [adjusted OR=3.07 (2.31-4.64)], and containers/tires outside the house [adjusted OR=5.61 (2.74-27.58)] were the independent predictors of the occurrence of chikungunya in households.

OBJECTIVE—Antilymphocyte serum can reverse overt type 1 diabetes in NOD mice; yet, the therapeutic parameters and immunological mechanisms underlying the ability for this agent to modulate autoimmune responses against β-cells are unclear, forming the rationale for this investigation. RESEARCH DESIGN AND METHODS—A form of antilymphocyte serum, rabbit anti-mouse thymocyte globulin (mATG), was utilized in a variety of in vivo and in vitro settings, each for the purpose of defining the physiological, immunological, and metabolic activities of this agent, with particular focus on actions influencing development of type 1 diabetes. RESULTS—We observed that mATG attenuates type 1 diabetes development in an age-dependent fashion, only proving efficacious at disease onset or in the late pre-diabetic phase (12 weeks of age). When provided at 12 weeks of age, mATG reversed pancreatic insulitis, improved metabolic responses to glucose challenge, and rapidly increased frequency of antigen-presenting cells in spleen and pancreatic lymph nodes. Surprisingly, mATG therapy dramatically increased, in an age-dependent fashion, the frequency and the functional activity of CD4+CD25+ regulatory T-cells. Adoptive transfer/cotransfer studies of type 1 diabetes also support the concept that mATG treatment induces a stable and transferable immunomodulatory repertoire in vivo. CONCLUSIONS—These findings indicate that an induction of immunoregulation, rather than simple lymphocyte depletion, contributes to the therapeutic efficacy of antithymocyte globulin and suggest that time-dependent windows for the ability to delay or reverse type 1 diabetes exist based on the capacity to enhance the functional activity of regulatory T-cells.

Type 1 diabetes is one of the more costly chronic diseases of children and adolescents throughout North America and Europe, exhibiting an average estimated prevalence rate of nearly 0.2%. It occurs in genetically predisposed individuals when the immune system attacks and destroys specifically the insulin-producing beta cells of the pancreatic islets of Langerhans. While routine insulin therapy can provide diabetic patients with their daily insulin requirements, non-compliance and undetected hyperglycemic excursions often lead to subsequent long-term microvascular and macrovascular complications. The only real cure for type 1 diabetes is replacement of the beta cell mass, currently being accomplished through ecto-pancreatic transplantation and islet implantation. Both of these procedures suffer from a chronic shortage of available donor tissue in comparison to the number of potential recipients. To circumvent this need, three alternative approaches are being intensively investigated: (1) the production of surrogate cells by genetically modifying non-endocrine cells to secrete insulin in response to glucose challenge; (2) the trans-differentiation of non-endocrine stem/progenitor cells or mature cells to glucose-responsive adult tissue; and (3) the regulated differentiation of islet stem/progenitor cells to produce large numbers of mature, functional islets. In recent years, each of these approaches has made impressive advances, leading to the most important question, 'how soon will this new science be available to the patient?' In the present review, we discuss some of the recent advances, focusing primarily on the differentiation of islet stem cells to functional endocrine pancreas that may form the basis for future treatment.

Type 1 diabetes (T1D) is an autoimmune disease characterized by hyperglycemia following the destruction of the insulin-producing beta cells of the pancreatic islets of Langerhans by the body's own immune system. Although routine insulin injections can provide diabetic patients with their daily insulin requirements, this treatment is not always effective in maintaining normal glucose levels. A true "cure" is considered possible only through replacement of the beta cell mass, by pancreas transplantation, islet implantation, or implantation of nonendocrine cells modified to secrete insulin. With the recent success of islet implantation to reverse T1D, this procedure has become a welcome therapy for T1D patients. Unfortunately, this procedure is hampered by the limited number of transplantation quality pancreata available for the harvesting of islets. This shortage has sparked great interest in finding a replacement for organ donation, primarily the possible use of stem cell-derived islets starting with stem cells, or alternatively the harvesting of nonhuman islets. This review focuses on progress with growing islets in the laboratory from stem cells and a comparison between this developing technology and the current use of islets harvested from nonhuman sources.

Cancer immunotherapies are emerging as promising treatment modalities in the management of the disease. As a result, cancer vaccines are considered to be immensely crucial in preventing recurrence, a well-known nemesis in cancer patients because they have the potential to activate memory antitumor immunity. Due to poor antigenicity and self-tolerance, most tumor antigens require interventional vaccine therapies to provide an adequate "danger" signal to the immune system in order to activate a robust, clinically meaningful antitumor immunity. It has been postulated that this requirement may be achieved by providing bacterial and/or viral immunogens to prime this type of immune response. Briefly, we provide here a method of transfecting whole tumor cells with plasmid DNA encoding an immunogenic bacterial protein such as Emm55, which was derived from Streptococcus pyogenes (S. pyogenes). Subsequent inactivation of the transfected cells by irradiation (100 Gray) prevents replication. This type of whole-cell vaccine, e.g., ImmuneFx™, has demonstrated activity in a murine neuroblastoma model, in canine lymphoma patients with naturally occurring disease, and in many cancer types in companion animals. The protocols described in this chapter provide the necessary materials and methodologies to manufacture such a vaccine.

Chaudhari M, Cornelius JG, Schatz D, Peck AB, Ramiya VK. Pancreatic stem cells: a therapeutic agent that may offer the best approach for curing type 1 diabetes. Abstract: Type 1 (insulin-dependent) diabetes is one of the most costly chronic diseases of children and adolescents in North America and Europe. It occurs in genetically predisposed individuals when the immune system attacks and destroys specifically the insulin-producing beta cells of the pancreatic islets of Langerhans. Although routine insulin injections can provide diabetic patients their daily insulin requirements, non-compliance commonly results in blood glucose excursions that eventually lead to microvascular and macrovascular complications and early death. The only real ‘cure’ for type 1 diabetes is replacement of the beta-cell mass which, today, is either an ectopancreatic transplant or an islet of Langerhans implant. Two new developments may offer additional options: surrogate, non-endocrine cells genetically modified to secrete insulin in response to high blood glucose levels; and stem cells that possess the capacity to differentiate to endocrine pancreas. In this short review, we discuss the efforts currently being made to regulate pancreatic stem cell growth in order to produce large numbers of functional islets that can be used as implants. Hopefully, autologous stem cell-derived islet cell implants without lifelong immunosuppressive therapy may one day be realized.

Ductal structures of the adult pancreas contain stem cells that differentiate into islets of Langerhans. Here, we grew pancreatic ductal epithelial cells isolated from prediabetic adult non-obese diabetic mice in long-term cultures, where they were induced to produce functioning islets containing alpha, beta and delta cells. These in vitro-generated islets showed temporal changes in mRNA transcripts for islet cell-associated differentiation markers, responded in vitro to glucose challenge, and reversed insulin-dependent diabetes after being implanted into diabetic non-obese diabetic mice. The ability to control growth and differentiation of islet stem cells provides an abundant islet source for beta-cell reconstitution in type I diabetes.

Although expressed at very low levels in islets of NOD mice, GAD65 is a candidate islet autoantigen. Two transgenic lines of NOD/Lt mice expressing high levels of human GAD65 from a rat insulin promoter were generated. Transgenes were integrated on proximal chromosome 15 of the A line and on the Y chromosome of the Y line. Transgenic A-line mice were obligate hemizygotes, since homozygous expression resulted in developmental lethality. A twofold higher level of hGAD65 transcripts in A-line islets from young donors was associated with higher GAD protein and enzyme activity levels. Y-line males developed diabetes at a similar rate and incidence as standard NOD/Lt males. In contrast, A-line mice of both sexes exhibited a markedly lowered incidence of diabetes. Insulitis, present in both transgenic lines, developed more slowly in A-line mice and correlated with a reduction in the ratio of gamma-interferon to interleukin-10 transcripts. Splenic leukocytes from young A-line donors transferred diabetes into NOD-scid recipients at a retarded rate compared with those from nontransgenic donors. Further, nontransgenic NOD T-cells transferred diabetes more slowly in NOD-scid recipients that were congenic for A-line transgenes as compared with standard NOD-scid recipients. Primed T-cell responses and spontaneous humoral reactivity to GAD65 failed to distinguish transgenic from nontransgenic mice. Quantitative differences in expression level or insertional mutagenesis are possible mechanisms of protection in the A line.

Insulin-dependent diabetes (IDD), being an autoimmune disease, offers several opportunities for immunological interventions that may result either in the reduction of disease severity or in delaying diabetes onset. Among the various experimental preventative approaches, parenteral immunization with islet-specific autoantigens appears to be practically simpler and promising. We have previously shown that immunization with insulin, insulin B chain and B chain epitope (p9–23), but not insulin A chain, in incomplete Freund's adjuvant (IFA) and in alum (with B chain) delayed/prevented diabetes onset in NOD mice. Here we demonstrate the protective efficacy of affinity purified GAD 65 in IFA. While both insulin B chain and GAD 65 significantly delayed the onset of diabetes (P=0.001), a recently described tyrosine phosphatase (IA–2) antigen did not (P=0.38). Interestingly, B chain immunization reduced the incidence of cyclophosphamide (CY)-accelerated diabetes by about 50–55%. We also provide further evidence that B chain, upon increased adsorption to alum, could improve on its protective capacity in NOD mice.

Interventional approaches that have been successful in delaying insulin-dependent diabetes mellitus (IDDM) using antigen-based immunotherapies include parenteral immunization. It has potential for clinical application provided that effective adjuvants suitable for human use can be found. We have previously shown that immunization with insulin and insulin B chain but not A chain in incomplete Freund's adjuvant (IFA) prevented diabetes by reducing IFN-gamma mRNA in the insulitis lesions. In this paper we show that the insulin B chain peptide (p9-23) contain the most protective epitope. Immunization with selected GAD peptides was ineffective. Immunization with B chain but not A chain using alum as adjuvant delayed diabetes onset (P = 0.012), whereas administration of alum alone was not protective. When Diphtheria-Tetanus toxoid-Acellular Pertussis (DTP) vaccine was used as the adjuvant vehicle, DTP itself induced significant protection (P0.003) which was associated with a Th2-like cytokine producing insulitis profile, IL-4 driven IgG1 antibody responses to insulin, GAD in the periphery and an augmentation of the autoimmune response to GAD. The anti-diabetic effect of DTP was enhanced when given with insulin B chain. These results encourage consideration of an approach using alum/DTP and insulin B chain immunization in clinical trials.

All the experimental animal models of insulin-dependent diabetes mellitus (IDDM) and preliminary human trials suggest that insulin can be safely used not only for immediate therapeutic purposes but also in the prevention of the disease. The mechanism of protection induced by insulin prophylaxis may include both ‘β-cell rest’ and induction of immunoregulatory processes. Finally, combined therapies involving oral, subcutaneous and intravenous routes may be of potential advantage in disease prevention. Future studies will have to address these issues.

Gene transfer into pancreatic cells in vivo could be of immense therapeutic benefit in cases of type 1 diabetes (T1D) through the production of molecules capable of interrupting the progression of autoimmunity or promoting regeneration of insulin-secreting beta cells. We adapted a clinically relevant surgical technique (endoscopic retrograde cholangiopancreatography) to deliver rAAV encoding human alpha1-antitrypsin (approved gene symbol SERPINA1) to the pancreas of 3-week-old Fisher 344 rats and C57BL/6 mice. We compared natural as well as bioengineered serotypes of rAAV (rAAV1, rAAV2/Apo, rAAV8) as well as different promoters (chicken beta-actin, human insulin) for their expression in vivo. Rats injected with rAAV1 showed the highest hAAT expression (week 2, rAAV1/CB-AT, 579 +/- 457 ng/ml). In mice, rAAV8 vector delivered the highest serum concentration of hAAT (week 2, rAAV8/CB-AT, 19 +/- 6 microg/ml). The chicken beta-actin promoter provided the highest expression in both rodent experiments. Immunohistochemical staining indicated transduction primarily of pancreatic acinar cells with either the rAAV1/CB-AT vector in the rat or the rAAV8/CB-AT vector in the mouse. This study demonstrates that rAAV vectors can be designed to deliver therapeutic genes efficiently to the pancreas and achieve high levels of gene expression and may be useful in treating pancreatic disorders, including T1D.

Ductal structures of the adult pancreas contain multipotent stem cells that, under controlled in vitro conditions, are able to self-renew and differentiate into functional islets of Langerhans. In vitro-generated islets, whether derived from stem cells of human, porcine, or mouse origin, exhibit temporal changes in mRNA transcripts for islet-associated markers as well as regulated insulin responses following glucose challenge. When in vitro-generated mouse islets were implanted into diabetic mice, neovascularization of the implant material occurred, followed by reversal of insulin-dependent diabetes. The possibility of growing functional islets from adult stem cells provides new opportunities to produce large numbers of islets, even autologous islets, for use as implants.

Recent successes in treating type 1 diabetic patients with islet transplantation portends a future need for an increase in available islets. Ductal structures of the adult pancreas contain multipotent stem cells that, under the proper in vitro conditions, can both self-renew and differentiate into functional islets of Langerhans. In vitro-generated islets exhibit temporal changes in mRNA transcripts for islet-associated markers as well as regulated insulin responses following glucose challenge. When implanted into diabetic mice, in vitro-generated islets induce neovascularization and reverse insulin-dependent diabetes. The possibility of growing functional endocrine pancreas from stem cells provides new opportunities to produce large numbers of islets, even autologous islets, for use as implants.

Type 1, insulin-dependent, diabetes is one of the more costly chronic diseases of children, adolescents and adults in Europe and North America. While routine insulin injections currently provide diabetic patients with their daily insulin requirements, blood glucose excursions are common, leading eventually to microvascular and macrovascular complications and early death. A 'cure' for Type 1 diabetes relies on replacement of the beta-cell mass which, today, is accomplished by pancreas transplants or islets of Langerhans implants. Recent advances in the isolation of stem cells that possess the capacity to differentiate to functional endocrine pancreas provide new opportunities to produce large numbers of islets, even autologous islets, that can be used as implants. We discuss briefly this new technology and its meaning for diabetes.

Islet cell antigens have been administered orally and intravenously (I.V.) to NOD mice to assess their abilities to protect from or delay the onset of diabetes, and thereby provide insights that may have therapeutic implications in human trials. Whereas we and others have observed a delay in the onset of diabetes in NOD mice that have been fed with insulin from early life, we report here for the first time that feedings with porcine GAD65 alone (p = 0.226) or in combination with insulin (p = 0.011), have anti-diabetic effects in a prolonged study period (>400 days). While antigen-specific inhibitions of in vitro lymphocytic proliferation responses were seen (p < 0.05), antibody levels were unaffected by oral antigen treatments. IFN-gamma mRNA levels were downregulated in the islet infiltrates following oral antigen treatments while IL-2 and TNF-beta were expressed in all instances. We also observed that I.V. human recombinant GAD65, and porcine GAD given at weaning, delayed diabetes onset (p = 0.004) while similar treatments with a variety of inactive insulin preparations were generally ineffective. These findings thus indicate varying effects of oral and I.V. autoantigen administrations on the development of diabetes in NOD mice, and describe the immunological processes induced by oral autoantigen treatments.

Purpose: The Kudumbashree mission, an initiative of the Government of Kerala state in India, has collaborated with Local Self Governments to set up ‘Buds’, a special school system for individuals with intellectual disability. The objectives of this study were to evaluate the structure and functioning of ‘Buds’ schools, to identify the healthcare needs of the students, and to conceptualise a framework for healthcare provision. Methods: A cross-sectional survey was conducted among 202 children at 11 registered ‘Buds’ schools in Kerala. A multidisciplinary team consisting of a psychiatrist, public health personnel and a social worker from the Medical Colleges of Kerala, visited the institutions. Data collection consisted of abstraction from medical records, interviews with parents, and clinical assessment and prescription of intervention by the specialists concerned. A pre-tested semi-structured questionnaire was used for every child. Using both quantitative and qualitative techniques, the public health personnel in the team evaluated the structure and functioning of the schools. Results: The most commonly associated condition was epilepsy, seen in 11.9% of the children, while 28.2% had behavioural problems. The medicines needed were mainly anti-epileptics and drugs for behavioural problems. Interventions for self help and social skill training were also among the important requirements. The infrastructure and other facilities were poor in many schools, with the average student to teacher ratio at 14:1. While these institutions were well utilised, functioning was good only in 27.2% of the schools. Healthcare services and visits by healthcare personnel were far from adequate. This study proposes a framework in which the Medical Colleges and Health Services can function together to deliver healthcare services to children at these schools, with linkages from the District Mental Health Programme (DMHP). Conclusion and Recommendation: Evidence that these schools are well utilised indicates a need to propagate this initiative in other areas of the state, country and other countries. However, improvements in infrastructure, human resources and other logistics are required. Besides, the healthcare needs of these children have to be addressed. A comprehensive healthcare programme through the existing system, using a multidisciplinary approach, needs to be developed.

Insulin-dependent diabetes (IDD) is a serious, life-long disease replete with life-threatening complications that are not preventable through conventional insulin replacement therapies. The prolonged prodromal period of autoimmunity to beta cell antigens offers multiple intervention opportunities. These can target different steps that precede final destruction of insulin-secreting beta cells and clinical onset of the disease. All current and proposed immunotherapies are experimental procedures that have proven to be protective in animal models, especially the nonobese diabetic (NOD) mouse. This brief review deals with a selected list of nonspecific and autoantigen-specific immunotherapies that may bring hope in the near future to individuals at risk of developing the disease. None are yet proven to be effective in humans.

Context: Tuberculosis (TB) is a public health emergency, which challenges the health indicators of India. Revised National Tuberculosis Control Programme (RNTCP) of the country has modified the definition of a pulmonary TB suspect so as to include an additional proportion of people with cough of 2 to 3 weeks duration, which will help in reducing the delay in starting treatment. Aims: To estimate the proportion of people with cough of 2-3 weeks duration among the newly diagnosed sputum-positive TB patients. Settings and Design: It is a community-based, cross-sectional study in the geographical setting of Thiruvanathapuram city corporation area, Kerala, India. Materials and Methods: The defined population in this study was tuberculosis cases registered under RNTCP for 1 year after April 2009 at the Thiruvanathapuram Tuberculosis Unit (TU). Simple random sampling procedure was done from the sampling frame, the registry of sputum-positive pulmonary cases. TB patients were interviewed when they came to the DOTS center to start the treatment. Total duration of treatment was the major outcome variable. The study protocol was approved by institutional ethical committee of government medical college, Thiruvananthapuram. Results: Proportion of people having cough of less than 3 weeks duration among newly detected TB patients and eligible for screening as per the new guideline was 32%. The analysis included data of 194 subjects with a mean (standard deviation) age of 47.5 (14.3) years. Male gender (149, 76.8%), an educational level up to secondary school (172, 88.6%), and people who were either unemployed or manual laborers (96, 49.4%) predominated in the study sample. Conclusions: In short, the study revealed that almost one third of recently diagnosed TB patients would not have been considered as 'TB suspect' before the implementation of the new strategic change. The findings support the new definition of pulmonary TB suspect in RNTCP.

Context: Measles imparts high morbidity and mortality in low-income countries with weak health infrastructure. The coverage of measles vaccination in Kerala which is best performing state of India in indicators of health has also not reached the elimination level and outbreaks of measles continue to occur. Aim: The aim of the paper was to study the profile of measles outbreaks in Kerala during the years 2007-2008. Settings and Designs: The study design was cross-sectional and data of the measles surveillance project of Kerala were analyzed . Results: The total number of clinically suspected measles outbreaks in Kerala during the 2-year period of 2007 and 2008 was 29. But only 15(53.6%) were found to be 'measles only' outbreak. The total number of epidemiologically linked measles cases was 718 (314 in 2007 and 404 in 2008). The cases that were immunized but developed the disease were 187 (28.6%), the number of cases that were not immunized was 355 (54.3%) and those whose immunization status was unknown were 112 (17.1%). The mean age of occurrence of disease was higher in the vaccinated group as compared to not vaccinated group. Two deaths were recorded in the study. Conclusions: Significant morbidity and mortality due to measles do occur in the most developed state of India. The epidemics were clustered in some districts. The study indicated an age shift in occurrence of measles cases among who received the vaccination.

Background : In India, indigenous cases of cutaneous leishmaniasis (CL) are mainly confined to the northwestern region. But now, more and more case reports are coming in from other parts of India. In January 2009, a 26-year-old lady residing in a forest area in Thiruvananthapuram district of Kerala State presented with bluish red nodules on her upper extremities, of six months duration, which was clinically more in favor of cutaneous leishmaniasis. She had never gone out of the district of Thiruvananthapuram in her life. Aim : To investigate whether the patient hails from a new endemic focus of cutaneous leishmaniasis. Setting and Design : An epidemiological investigation in the form of a survey was carried out in March 2009 by a multidisciplinary team among 63 persons residing in the Mele Aamala and Aayiramkala forest tribal settlements in Kuttichal Panchayat of Thiruvananthapuram district. Material and Methods : History taking and clinical examination of 38 persons in the area with special consideration to skin lesions was undertaken. Microbiological and histopathological examination of the skin lesions was done. Breeding places of sand fly and possible reservoirs of Leishmania were also simultaneously investigated. Statistical analysis used : The data obtained was tabulated as frequency and percentage. Chi-square test was done to find out the statistical significance of differences in distributions. Results : Out of the 38 persons examined, active lesions were found in 12 persons and six had healed lesions. Tissue samples were obtained from seven out of the 12 suspected cases. Four of them showed Leishman Donovan (LD) bodies in tissue smears. Out of the cultures taken from three patients, one showed promastigote forms in Novy McNeal Nicolle (NNN) medium. Histopathological study was done in five patients and two patients had LD bodies, one had epithelioid cell granuloma and the other two had mixed infiltrate with predominantly macrophages. All the three investigations were carried out in three patients and out of them one showed positivity in all the three investigations and the rest two were positive in tissue smear and histopathological examination. Sandflies collected from the area gave an indirect evidence of its role in the disease transmission in the area. Conclusion : The clinical, microbiological and histopathological evaluation of the skin lesions was consistent with cutaneous leishmaniasis. But none of the patients gave history of travel outside the district before the onset of the disease and no one had newly moved into this area within the last two years. So this may be considered as probably a new focus of cutaneous leishmaniasis