Comparative assessment of immunogenicity of recombinant insulin Aspart from BioGenomics and its originator NovoRapid® in adult patients with type 2 diabetes mellitus.

OBJECTIVES: To assess and compare the immunogenicity of recombinant Insulin Aspart [manufactured by BioGenomics Limited (BGL-ASP)] with its originator NovoRapid® (manufactured by Novo Nordisk) in adult patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: BGL-IA-CTP301 study was a randomized, open label, parallel group, multicenter phase-III clinical study to compare the efficacy and safety of recombinant Insulin Aspart 100 U/mL [manufactured by BioGenomics Limited (BGL-ASP)] with its reference medicinal product (RMP); NovoRapid® [manufactured by Novo Nordisk], in adult patients with Type 2 diabetes mellitus (T2DM). The primary objective of the study was to compare the immunogenicity of BGL-ASP and RMP; NovoRapid® in patient serum samples collected from phase-III clinical study. Immunogenicity was studied as the incidence of patients positive for anti-insulin Aspart (AIA) antibodies, developed against BGL-ASP/RMP at baseline, end of 12 week and end of 24 week of the treatment period. The changes in incidence of patients positive for AIA antibodies post-baseline were also studied to assess and compare the treatment-emergent antibody response (TEAR) between the treatment groups (BGL-ASP and RMP). Statistical evaluation was done by Fisher's exact test to compare the overall incidence of patients positive for AIA antibodies and the TEAR positives observed post-baseline in both the treated groups. An in-vitro neutralizing antibody assay (Nab assay) was also performed to study the effect of AIA antibodies in neutralizing the biological activity/metabolic function of the insulin. The neutralizing potential of AIA was studied by its effect on %glucose uptake. We also evaluated the association between AIA antibody levels and its impact on biological activity by studying the correlation between them. RESULTS: Analysis of immunogenicity data suggested that the percentage of patients positive for AIA antibodies until week 24 was similar and comparable in both the treatment groups, BGL-ASP and RMP; NovoRapid®. The changes in incidence of patients positive for AIA post-baseline in terms of TEAR positives were also similar and comparable between the treatment groups. The results of the Nab assay with confirmed positive AIA samples from BGL-ASP- and RMP-treated groups did not have any negative impact on %glucose uptake by the cells in Nab assay, confirming the absence of neutralizing antibodies in both the treatment groups. The correlation studies also showed absence of association between AIA antibody levels and percentage glucose uptake in both BGL-ASP and RMP-NovoRapid® treatment groups. CONCLUSIONS: The immunogenicity assessment based on the overall incidence of patients positive for AIA, changes in incidence of patients positive for AIA post-baseline, TEAR rates and absence of neutralizing antibodies, were found to be apparently similar and comparable in both the treatment groups (BGL-ASP and RMP). We conclude from our studies that the immunogenicity of BGL-ASP is similar and comparable to RMP and the observed immunogenicity in terms of anti-insulin Aspart antibody levels had no impact on the biological activity of insulin.

Future imaging modalities for the assessment of pancreas allografts a scan of the horizon.

Pancreas transplantation (PT) allows improved glycaemic control for patients with complicated type 1 diabetes mellitus and is most commonly performed simultaneously with a renal transplant. Imaging modalities are critical for the assessment of pancreatic graft dysfunction, as clinical assessment and hyperglycaemia lack robust sensitivity for the transplant clinician. Biopsy represents the most conclusive standard of PT graft assessment but is challenging due to its invasive nature and the potential morbidity associated with the procedure. Innovative imaging technologies offer the opportunity to apply these modalities to improve PT outcomes while using non-invasive technologies to provide a diagnostic sensitivity that traditionally only biopsies can provide. Early graft dysfunction has traditionally been investigated with Computed tomography (CT) and ultrasound (US) scans. We explore adjuncts to these modalities including the application of contrast enhanced ultrasound (CEUS) for routine post-operative graft assessment to inform post-operative treatment strategies. There is currently a dearth of imaging modalities to reliably monitor long term graft function, but the use of innovative functional imaging techniques and how they can be applied to PT is discussed. Perfusion CT and glucose stimulated magnetic resonance imaging (MRI) to detect whole organ function are examined. In addition, early phase developments in beta-cell specific imaging methods to quantify beta-cell mass longitudinally are described. The clinical applications of such tools including Mn2+-enhanced MR and GLP-1R targeted PET/CT are reviewed and may demonstrate opportunities to provide the transplant clinician with greater information to support improved patient care.

Microbial and physicochemical assessment of irrigation water treatment methods.

AIMS: The presence of foodborne pathogens in preharvest agricultural water has been identified as a potential contamination source in outbreak investigations, driving markets and auditing bodies to begin requiring water treatment for high-risk produce. Therefore, it is essential that we identify water treatment methods which are effective as well as practical in their application on farm. METHODS AND RESULTS: In this work, we evaluated two sanitizers which are most prominent in preharvest agricultural water treatment (calcium hypochlorite (free chlorine: 3-5 ppm) and peracetic acid (PAA: 5 ppm)), an EPA registered antimicrobial device (ultraviolet light (UV)), in addition to a combination approach (chlorine + UV, PAA + UV). Treatments were evaluated for their ability to inactivate total coliforms and generic Escherichia coli and consistency in treatment efficacy over 1 h of operation. Physicochemical variables were measured along with microbial populations at 0, 5, 15, 30, 45 and 60 min of operation. Escherichia coli and coliform counts showed a significant (P < 0·05) reduction after treatment, with combination and singular treatments equally effective at inactivating E. coli and coliforms. A significant increase (P < 0·05) in oxidation-reduction potential was seen during water treatment (Chlorine; UV + Chlorine), and a significant reduction (P < 0·05) in pH was seen after PAA and PAA + UV treatments (60 min). CONCLUSION: Overall, the results indicate that all treatments evaluated are equally efficacious for inactivating E. coli and coliforms present in surface agricultural water. SIGNIFICANCE AND IMPACT OF THE STUDY: This information when paired with challenge studies targeting foodborne pathogens of interest can be used to support grower decisions when selecting and validating a preharvest agricultural water treatment programme.

Sonographic assessment of nerve blood flow in diabetic neuropathy.

AIMS: To undertake sonographic assessment of nerve blood flow in people with Type 2 diabetes and correlate the findings with neuropathy severity scores and electrophysiological measurements. METHODS: Median and tibial nerve ultrasound scans were undertaken in 75 people with diabetes and 30 aged-matched controls without diabetes, using a high-resolution linear probe at non-entrapment sites. Nerve blood flow was quantified using power Doppler techniques to obtain the vessel score and the maximum perfusion intensity. Neuropathy severity was assessed using a total neuropathy score. RESULTS: Diabetic nerves had higher rates of nerve blood flow detection (28%) compared to the control group (P < 0.0001). Significant correlations were found between nerve blood flow measurements and nerve size (P <0.001), reported sensory symptoms (P < 0.05) and neuropathy severity scores (P < 0.001). The cohort with diabetes had significantly larger median (8.5 ± 0.3 mm2 vs 7.2 ± 0.1 mm2 ; P < 0.05) and tibial nerves (18.0 ± 0.9 mm2 vs 12.8 ± 0.5 mm2 ; P < 0.05) compared with controls. CONCLUSION: Peripheral nerve hypervascularity is detectable by ultrasonography in moderate to severe diabetic neuropathy with prominent sensory dysfunction.

Downregulation of Notch4 - a prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma / Regulação descendente de Notch4 - um marcador prognóstico na distinção entre carcinoma verrucoso oral e carcinoma de células escamosas oral

Abstract Introduction: Oral verrucous carcinoma is a special form of well-differentiated squamous cell carcinoma which possesses specific clinical, morphologic and cytokinetic features that differ from other types of oral cancers and hence diagnosis requires immense experience in histopathology. Hence it is certainly important to distinguish such a lesion from other oral tumors as treatment strategies vary widely between them. Objective: In search of a critical diagnostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma, Notch4 receptor, one of the key regulatory molecules of the Notch signaling family has been aberrantly activated in the progression of several types of tumors. However its function in oral verrucous carcinoma remains unexplored. Thus the present study aims in determining the differential expression pattern of Notch4 in oral verrucous carcinoma and oral squamous cell carcinoma. Methods: Ten patients reported positive for oral cancer (5 patients with oral verrucous carcinoma and 5 patients with oral squamous cell carcinoma). Five normal tissue samples were also obtained and evaluated for clinicopathological parameters and immunohistochemistry, western blotting and real time polymerase chain reaction for Notch4 expression. Results: Our results reveal that the expression of Notch4 was considerably high in oral squamous cell carcinoma lesions compared to normal tissue, whereas in oral verrucous carcinoma, irrespective of the clinicopathological features, complete regulação descendente of Notch4 was observed. Conclusions: These preliminary findings strongly support the fact that Notch4 is downregulated in oral verrucous carcinoma and could be considered as a suitable prognostic marker in distinguishing oral verrucous carcinoma from oral squamous cell carcinoma. This distinguishing marker can help in improving therapeutic options in patients diagnosed with oral verrucous carcinoma.

Resumo Introdução: O carcinoma verrucoso de cavidade oral é uma forma especial de carcinoma de células escamosas bem diferenciada que tem características clínicas, morfológicas e citocinéticas específicas que diferem de outros tipos de cânceres orais. Por essa razão, o diagnóstico requer grande experiência em histopatologia. Portanto, é certamente importante distingui-lo de outros tumores orais, pois as respectivas estratégias de tratamento variam muito. Objetivo: Em busca de um marcador de diagnóstico crítico na distinção entre o carcinoma verrucoso e o carcinoma de células escamosas de cavidade oral, o receptor Notch4, uma das principais moléculas reguladoras da família de sinalizadores Notch, foi ativado de maneira anormal na progressão de vários tipos de tumores. No entanto, sua função no carcinoma verrucoso permanece inexplorada. Assim, o presente estudo tem como objetivo determinar o padrão de expressão diferencial de Notch4 no carcinoma verrucoso e de células escamosas de cavidade oral. Método: Dez pacientes tiveram resultado positivo para câncer oral (cinco pacientes com carcinoma verrucoso e cinco pacientes com carcinoma de células escamosas) e cinco amostras normais foram também obtidas. Além da avaliação dos parâmetros clínico-patológicos, foram feitos análise imuno-histoquímica, Western Blot e reação de polimerase em cadeia em tempo real para a expressão de Notch4. Resultados: Nossos resultados revelam que a expressão de Notch4 foi consideravelmente alta em carcinomas de células escamosas em comparação com os tecidos normais, enquanto que no carcinoma verrucoso, independentemente das características clínico-patológicas, observou-se regulação descendente completa de Notch4. Conclusão: Esses achados preliminares apoiam fortemente o fato de que Notch4 estava regulado para baixo no carcinoma verrucoso oral e poderia ser considerado um marcador prognóstico adequado para distinguir entre carcinoma verrucoso e carcinoma de células escamosas de cavidade oral. Esse marcador distintivo pode ajudar a melhorar as opções terapêuticas em pacientes com diagnóstico de carcinoma verrucoso oral.

Prevalence and sociodemographic determinants of tobacco use in four countries of the World Health Organization: South-East Asia region: findings from the Global Adult Tobacco Survey.

INTRODUCTION: Tobacco use is a leading cause of deaths and Disability Adjusted Life Years lost worldwide, particularly in South-East Asia. Health risks associated with exclusive use of one form of tobacco alone has a different health risk profile when compared to dual use. In order to tease out specific profiles of mutually exclusive categories of tobacco use, we carried out this analysis. METHODS: The Global Adult Tobacco Survey (GATS) data was used to describe the profiles of three mutually exclusive tobacco use categories ("Current smoking only," "Current smokeless tobacco [SLT] use only," and "Dual use") in four World Health Organization South-East Asia Region countries, namely Bangladesh, India, Indonesia and Thailand. GATS was a nationally representative household-based survey that used a stratified multistage cluster sampling design proportional to population size. Prevalence of different forms of usage were described as proportions. Logistics regression analyses was performed to calculate odds ratios (OR) with 95% confidence intervals. All analyses were weighted, accounted for the complex sampling design and conducted using SPSS version 18. RESULTS: The prevalence of different forms of tobacco use varied across countries. Current tobacco use ranged from 27.2% in Thailand to 43.3% in Bangladesh. Exclusively smoking was more common in Indonesia (34.0%) and Thailand (23.4%) and less common in Bangladesh (16.1%) and India (8.7%). Exclusively using SLT was more common in Bangladesh (20.3%) and India (20.6%) and less common on Indonesia (0.9%) and Thailand (3.5%). Dual use of smoking and SLT was found in Bangladesh (6.8%) and India (5.3%), but was negligible in Indonesia (0.8) and Thailand (0.4%). Gender, age, education and wealth had significant effects on the OR for most forms of tobacco use across all four countries with the exceptions of SLT use in Indonesia and dual use in both Indonesia and Thailand. In general, the different forms of tobacco use increased among males and with increasing age; and decreased with higher education and wealth. The results for urban versus rural residence were mixed and frequently not significant once controlling for the other demographic factors. CONCLUSION: This study addressed the socioeconomic disparities, which underlie health inequities due to tobacco use. Tobacco control activities in these countries should take in account local cultural, social and demographic factors for successful implementation.

Determinants of neonatal mortality in rural Haryana: a retrospective population based study.

OBJECTIVE: To identify the determinants of neonatal mortality. STUDY DESIGN: Nested case-control study. STUDY SETTING: 28 villages under the intensive field practice area of Comprehensive Rural Health Services Project, Ballabgarh, Haryana serving a population of 87,016, as on 31st December 2009. The study period was from 2005 to 2009. METHODS: The data were obtained from Health Management Information System and analyzed using multivariate logistic regression analysis. A hierarchical approach was used to analyze the factors associated with neonatal deaths, using community level factors, socio-economic status and biological determinants. The population attributable fractions were estimated for significant variables. RESULTS: The total live births during the study period were 10392 and neonatal deaths were 248. The infant and neonatal mortality rates during the study period were 45.6 and 23.8 per 1000 live births, respectively. Socio-economic determinants (Low educational status of parents [OR 2.1, 95% CI; 1.4, 3.3]; fathers occupation [OR 1.8, 95% CI; 1.0, 3.0]; Rajput caste [OR 2.0, 95% CI; 1.2, 3.4] appeared to explain a major fraction (45.7%) of neonatal deaths. Community level factors (villages with no health facility [OR 1.5, 95% CI; 1.0, 2.1]; villages with population >6000 [OR 1.7, 95% CI; 1.2, 2.5]) were associated with 27.3% of all neonatal deaths. Proximate determinants (early childbearing age of mother (<20 years) [OR 2.0, 95% CI; 1.2, 3.2]) were least important. All the three level of variables seemed to act independently with little mediation among them. CONCLUSION: Neonatal mortality is affected by socioeconomic, community level and proximate biological determinants.

Application and assessment of a robust elastic motion correction algorithm to dynamic MRI.

The purpose of this study was to assess the performance of a new motion correction algorithm. Twenty-five dynamic MR mammography (MRM) data sets and 25 contrast-enhanced three-dimensional peripheral MR angiographic (MRA) data sets which were affected by patient motion of varying severeness were selected retrospectively from routine examinations. Anonymized data were registered by a new experimental elastic motion correction algorithm. The algorithm works by computing a similarity measure for the two volumes that takes into account expected signal changes due to the presence of a contrast agent while penalizing other signal changes caused by patient motion. A conjugate gradient method is used to find the best possible set of motion parameters that maximizes the similarity measures across the entire volume. Images before and after correction were visually evaluated and scored by experienced radiologists with respect to reduction of motion, improvement of image quality, disappearance of existing lesions or creation of artifactual lesions. It was found that the correction improves image quality (76% for MRM and 96% for MRA) and diagnosability (60% for MRM and 96% for MRA).

Living with HIV infection: perceptions of patients with access to care at a non-governmental organization in Chennai, India.

Through interviews, we examined explanatory frameworks of living with HIV infection among 50 HIV-positive individuals (23 women, 27 men) receiving care at a non-governmental organization in Chennai, India. Results were analysed according to three sets of issues, all of which were found to differ by gender: causal beliefs about HIV, impact of HIV, and care/treatment of HIV. HIV-positive participants attributed their infection to biological, moral and social causes, and the physical, financial and relationship dimensions of their lives were impacted upon by the infection. Furthermore, HIV-related stigma evoked fears about isolation and discrimination. Regarding care/treatment, men were most usually first initiated into the healthcare system while women often entered as a consequence of their partner's condition. Non-adherence to medication was reported by 32% of the participants due to financial constraints or side-effects. Although all participants were hopeful about a cure for HIV, women were less positive than men about treatment. Results highlight the importance of a gender-sensitive approach to HIV care, nuanced to accommodate an individual's gender, marital status and social background.

Barriers and facilitators to antiretroviral medication adherence among patients with HIV in Chennai, India: a qualitative study.

Antiretroviral therapy (ART) for HIV is increasingly being introduced and utilized in diverse areas of the world. However, little research exists on adherence to ART in different cultural settings, particularly in developing countries such as India. This formative qualitative study examined barriers and facilitators of ART adherence among 60 (49 men, 11 women; 33 taking ART, 27 not currently taking ART) patients receiving HIV primary care at YRG CARE, a nongovernmental organization, in Chennai, India. The average participant reported becoming HIV infected through heterosexual transmission, was between 31 and 40 years old, had over ninth class standard education, was married, and generally had access to medical care; however, we obtained some qualitative data from various other risk categories. Trained ethnographers at the study site conducted in-depth interviews in the local language. These interviews were analyzed for content and ethnographic data. Almost all of the participants discussed the cost of ART as a barrier, with many reporting extended drug holidays, turning to family and/or friends, or taking drastic measures (i.e., selling family jewels, property) for financial assistance. Other barriers centered on privacy and stigma issues, such as disclosure of HIV inhibiting pill-taking and social support. Frequently discussed facilitators of adherence included perceived benefits of ART and proper adherence, perceptions about the consequences of nonadherence, and social support, if available. These data highlight the importance of reducing the cost of antiretroviral medications, involving family members in HIV care, and addressing privacy issues and stigma in counseling interventions in this setting.

Predictors of therapy-related leukemia and myelodysplasia following autologous transplantation for lymphoma: an assessment of risk factors.

We analyzed data on 612 patients who had undergone high-dose chemoradiotherapy (HDT) with autologous stem cell rescue for Hodgkin's disease (HD) and non-Hodgkin's lymphoma (NHL) at the City of Hope National Medical Center, to evaluate the incidence of therapy-related myelodysplasia (t-MDS) or therapy-related acute myeloid leukemia (t-AML) and associated risk factors. A retrospective cohort and a nested case-control study design were used to evaluate the role of pretransplant therapeutic exposures and transplant conditioning regimens. Twenty-two patients developed morphologic evidence of t-MDS/t-AML. The estimated cumulative probability of developing morphologic t-MDS/t-AML was 8.6% +/- 2.1% at 6 years. Multivariate analysis of the entire cohort revealed stem cell priming with VP-16 (RR = 7.7, P = 0.002) to be independently associated with an increased risk of t-MDS/t-AML. The influence of pretransplant therapy on subsequent t-MDS/t-AML risk was determined by a case-control study. Multivariate analysis revealed an association between pretransplant radiation and the risk of t-MDS/t-AML, but failed to reveal any association with pretransplant chemotherapy or conditioning regimens. However, patients who had been primed with VP-16 for stem cell mobilization were at a 12. 3-fold increased risk of developing t-AML with 11q23/21q22 abnormalities (P = 0.006). Patients undergoing HDT with stem cell rescue are at an increased risk of t-MDS/t-AML, especially those receiving priming with VP-16 for peripheral stem cell collection. (Blood. 2000;95:1588-1593)

Association of dietary factors and other coronary risk factors with social class in women in five Indian cities.

The association between social classes, food intake and coronary risk factors was determined. Cross-sectional surveys were conducted in 6-12 urban streets in each of five cities, each one from five different regions of India using similar methods of dietary intakes and criteria of diagnosis. We randomly selected 3257 women aged 25-64 years inclusive, from Moradabad (n = 902), Trivandrum (n = 760), Calcutta (n = 410), Nagpur (n = 405) and Bombay (n = 780). All subjects, after pooling of data, were divided into social class 1 (n = 985), class 2 (n = 790), class 3 (n = 774), class 4 (n = 602) and class 5 (n = 206) based on various attributes of socioeconomic status. Social class 1 was the highest and 5 was the lowest social class. Social classes 1-3 had greater intake of pro-atherogenic foods; total visible fat, milk and milk products, meat and eggs, as well as sugar and confectionery, compared to social classes 4 and 5. The consumption of wheat, rice, millets, fruits, vegetables and legume/total visible fat ratio were inversely associated with social class. Mean body mass index (BMI), obesity, overweight, central obesity and sedentary lifestyle were also significantly more common among subjects from higher social classes. Spearman's rank correlation showed that bodyweight, BMI, wheat, rice, millets, total visible fat, milk and milk products, meat, eggs, sugar and jaggery intakes were significantly correlated with social class. Social class 5 subjects had a lower intake of all foods and a lower BMI, suggestive of a higher rate of undernutrition among them. The findings indicate that the consumption of pro-atherogenic foods and other coronary risk factors are more common in higher social classes compared to lower social classes.