Impact of Undernutrition on Tuberculosis Treatment Outcomes in India: A Multicenter, Prospective, Cohort Analysis.

BACKGROUND: Undernutrition is the leading risk factor for tuberculosis (TB) globally. Its impact on treatment outcomes is poorly defined. METHODS: We conducted a prospective cohort analysis of adults with drug-sensitive pulmonary TB at 5 sites from 2015-2019. Using multivariable Poisson regression, we assessed associations between unfavorable outcomes and nutritional status based on body mass index (BMI) nutritional status at treatment initiation, BMI prior to TB disease, stunting, and stagnant or declining BMI after 2 months of TB treatment. Unfavorable outcome was defined as a composite of treatment failure, death, or relapse within 6 months of treatment completion. RESULTS: Severe undernutrition (BMI <16 kg/m2) at treatment initiation and severe undernutrition before the onset of TB disease were both associated with unfavorable outcomes (adjusted incidence rate ratio [aIRR], 2.05; 95% confidence interval [CI], 1.42-2.91 and aIRR, 2.20; 95% CI, 1.16-3.94, respectively). Additionally, lack of BMI increase after treatment initiation was associated with increased unfavorable outcomes (aIRR, 1.81; 95% CI, 1.27-2.61). Severe stunting (height-for-age z score <-3) was associated with unfavorable outcomes (aIRR, 1.52; 95% CI, 1.00-2.24). Severe undernutrition at treatment initiation and lack of BMI increase during treatment were associated with a 4- and 5-fold higher rate of death, respectively. CONCLUSIONS: Premorbid undernutrition, undernutrition at treatment initiation, lack of BMI increase after intensive therapy, and severe stunting are associated with unfavorable TB treatment outcomes. These data highlight the need to address this widely prevalent TB comorbidity. Nutritional assessment should be integrated into standard TB care.

Development and Validation of a LC-MS/MS Method for the Profiling of Impurities Formed during Stress Study of Antifungal Agent-Efinaconazole.

Liquid chromatography interfaced with mass spectroscopy (LC-MS) is a sensitive and effective analytical method that combines high-resolution separation as well as specific mass detection of impurities in formulated products and as well as in active pharmaceutical ingredient (API). In this study, LC-MS/MS was used to determine impurities formed during the stability period of Efinaconazole (EFZ, a triazole antifungal agent). The method was validated for its assay parameters such as specificity, linearity, accuracy, precision and also for solution stability. The calibration curve was found to be linear for the concentration range from 0.5 µg/mL to 30 µg/mL. A thorough investigation was performed by exposing Efinaconazole (1 mg/mL) to various stress conditions such as hydrolysis (acid and alkaline), oxidation, photolysis and temperature at various time intervals to achieve 10% degradation. The impurities formed during forced degradation were separated using high-performance liquid chromatography later it was identified using LC-MS/MS technique. The obtained results showed that EFZ is prone to oxidation when exposed to a 3% aqueous medium of hydrogen peroxide solution and quite stable in all the remaining stress conditions for a longer period.

Aloe vera and its two bioactive constituents in alleviation of diabetes -proteomic & mechanistic insights.

ETHNOPHARMACOLOGICAL RELEVANCE: Aloe barbadensis Miller, commonly known as Aloe vera has been used since time immemorial for treatment of various diseases such as cancer, inflammatory disorders, diabetes, wound healing etc. AIM: Diabetes mellitus is a complex disorder and understanding the molecular mechanisms involved is a key to identify different markers for early diagnosis of the disease. The proteomic approach offers a plethora of opportunities to identify markers and targets involved in pathogenesis of diabetes. The present study was undertaken to understand the mechanism of action of Aloe vera and its two constituents (Carbohydrates and Polypeptides) in the alleviation of diabetes in streptozotocin-induced diabetic rats through a proteomics approach. METHODS: Different groups of rats were fed with Aloe vera extract, carbohydrate fraction and peptide/polypeptide fraction for three weeks. The diabetic rats fed with Aloe vera and its two fractions restored the glucose and insulin levels to normal. The plasma of the rats was depleted with IgG and albumin and proteomic analysis was carried out. Apolipoproteins (dyslipidemia), complement factors (inflammatory pathways), zonulin (intestinal permeability), anti-oxidant related proteins were selected in this study as these are involved in the progression of diabetes. RESULTS: It was observed that Aloe vera extract is involved in the alleviation of diabetes through these pathways while the carbohydrate fraction alleviates diabetes through an anti-oxidant mechanism and glucose uptake while the polypeptide fraction alleviates diabetes through the restoration of intestinal permeability by reduced zonulin levels. CONCLUSION: The constituents of Aloe vera works different pathways involved in diabetes and the synergistic effect of these constituents make Aloe vera extract a prospective candidate, which can alleviate diabetes through regulation of the pathways involved in the progression of diabetes.

Role of zonulin and GLP-1/DPP-IV in alleviation of diabetes mellitus by peptide/polypeptide fraction of Aloe vera in streptozotocin- induced diabetic wistar rats.

ETHNO-PHARMACOLOGICAL RELEVANCE: The genus Aloe has a long history of usage in medicine. Aloe barbadensis Miller, commonly known as Aloe vera, is said to possess anti-diabetic, anti-inflammatory, anti-cancer, anti-microbial, immunomodulation, wound healing properties. AIM OF THE STUDY: In diabetes mellitus, loss in intestinal permeability is observed with high levels of zonulin and low levels of glucagon-like peptide-1 (GLP-1) leading to hyperglycemia. The aim of the study was to understand the role of peptide/polypeptide fraction (PPF) of Aloe vera in the alleviation of diabetes through maintaining the intestinal permeability by regulating the zonulin and GLP-1 levels. MATERIALS AND METHODS: The PPF of Aloe vera was obtained through trichloroacetic acid precipitation. The anti-diabetic potential of the PPF was tested through DPP-IV inhibition, glucose diffusion assay, and by using Rin-m5F cells. The anti-diabetic potential of the PPF was tested at a dose of 0.450 mg/kg bw in vivo using streptozotocin-induced diabetic Wistar rats. The effect of PPF on fasting plasma glucose, insulin, glucagon, Zonulin, GLP-1, DPP-IV, levels were studied in diabetic rats. The histopathological studies of the pancreas, small intestine, and liver were carried out for organ-specific effects. RESULTS: PPF has the ability to reduce fasting plasma glucose levels with concomitant increase in insulin levels in streptozotocin-induced diabetic rats. It was also observed that increase in GLP-1 levels with a decrease in DPP-IV and zonulin levels thereby mitigating the loss of intestinal permeability. These findings correlate with the small intestine's histopathological observation where the excessive proliferation of epithelium in the small intestine of diabetic rats was reduced after PPF treatment. CONCLUSION: These results suggest that the PPF of Aloe vera alleviates diabetes through islet cell rejuvenation via GLP-1/DPP-IV pathway and thereby suggesting the usage of PPF as an alternate medicine for diabetes mellitus with the possibility to reduce the intestinal permeability and zonulin levels.

Water-soluble Cobalt(II) & Cobalt(III) complexes supported by new triazine Schiff base ligands: Synthesis, structure and biological evaluation.

A new class of triazine ligands (E)-2-(2-(6-methyl-5-oxo-2,5-dihydro-1,2,4-triazin-3-yl)hydrazono)propanoic acid hydrate (HL1.H2O) and (Z)-2-(((E)-4-amino-6-methyl-5-oxo-4,5-dihydro-1,2,4-triazin-3(2H)ylidene)hydrazono)propanoic acid (H2L2) has been synthesized by the condensation reaction of pyruvic acid with diaminoguanidine and triaminoguanidine respectively. The corresponding Schiff base cobalt complexes [Co(L1)2].2H2O (1) and [Co(HL2)(L2)].H2O (2) have also been synthesized and characterized by analytical, thermal, spectroscopic and diffraction studies. Strong field ligand results low spin Co(III) centre in 2, which was evidenced by the shorter bond length of Co(III) complex. In H2L2 there is a choice of coordination modes based on distinct sets of donor atoms, both of which are seen in complex 2, involving either an -NH2 group on position 4 of the triazine ring, or via a ring nitrogen of the triazine itself. The deprotonation of one version of L2 allows the formation of the ligand field stabilized low spin Co(III) in 2. In complex 1, each ligand binds to the metal via pyruvate oxygen, azomethine nitrogen and triazine nitrogen forming two five-membered stable chelate rings. In complex 2, the coordination sphere assembled by two types of coordinating atoms from the same ligand with different conformation. Their binding ability and mode of binding with CT-DNA and BSA was studied by UV- absorption, fluorescence and CD spectroscopy. Density Functional Theory (DFT) studies provide further insights into the mode of binding, structure and mechanism. The HOMO and LUMO energy gap values indicate that both the complexes are prone to interact with CT-DNA and BSA. We have also performed molecular docking calculations to understand the mode of binding and the corresponding results confirm our experimental findings.

Prevalence of rifampicin-resistant Mycobacterium tuberculosis among human-immunodeficiency-virus-seropositive patients and their treatment outcomes.

Multidrug resistant (MDR) and extensively drug resistant tuberculosis (TB) are a threat to the TB control programs in developing countries, and the situation is worsened by the human immunodeficiency virus (HIV) pandemic. This study was performed to correlate treatment outcome with the resistance patterns in HIV-seropositive patients coinfected with pulmonary TB. Sputum specimens were collected from 1643 HIV-seropositive patients and subjected to microscopy and liquid culture for TB. The smear- and culture-positive Mycobacterium tuberculosis isolates were subjected to Genotype MTBDRplus assay version 2.0. The M. tuberculosis culture-positivity rate was 39.44% (648/1643) among the 1643 HIV-seropositive patients and the overall MDR-TB rate was 5.6% (36/648). There were 421 newly diagnosed and 227 previously treated patients, among whom, MDR-TB was associated with 2.9% and 10.57% cases, respectively. The rate of rifampicin monoresistant TB among the cases of MDR-TB was 2.31% (15/648) and the rate of combined rifampicin and isoniazid resistance was 3.24% (21/648). The cure and death rates among the 20 registered cases were 30% (6/20) and 35% (7/20), respectively. Five cases were on treatment and two cases were defaulters among the 20 registered cases. High death rate (13, 36.1%, 95% confidence interval 20.8-53.8) was observed in this study among the patients who had mutations at the 530-533 codons. The present study emphasized the prerequisite to monitor the trend of drug-resistant TB in various mutant populations in order to timely implement appropriate interventions to curb the threat of MDR-TB.

Comorbidities in pulmonary tuberculosis cases in Puducherry and Tamil Nadu, India: Opportunities for intervention.

BACKGROUND: We aimed to define characteristics of TB patients in Puducherry and two districts of Tamil Nadu, India and calculate the population attributable fractions (PAF) of TB from malnutrition and alcohol. METHODS: New smear-positive TB cases were enrolled into the Regional Prospective Observational Research for Tuberculosis (RePORT India) cohort. Census and National Family Health Survey data were used for comparisons. RESULTS: Data were analyzed for 409 participants enrolled between May 2014-June 2016; 307 (75.1%) were male, 60.2% were malnourished (body mass index [BMI] <18.5 kg/m2), and 29.1% severely malnourished (BMI <16). "Hazardous" alcohol use (based on AUDIT-C score) was reported by 155/305 (50.8%) of males. Tuberculosis cases were more likely than the Puducherry population to be malnourished (62.6% v 10.2% males and 71.7% v 11.3% of females; both p<0.001), and male cases were more likely to use alcohol than male non-cases (84.4% v 41%; p < .001). The PAF of malnutrition was 57.4% in males and 61.5% in females; the PAF for alcohol use was 73.8% in males and 1.7% in females. CONCLUSIONS: Alcohol use in men and malnutrition are helping drive the TB epidemic in Southern India. Reducing the TB burden in this population will require efforts to mitigate these risk factors.

Leptin receptor antagonism of iNKT cell function: a novel strategy to combat multiple myeloma.

A hallmark of bone marrow changes with aging is the increase in adipocyte composition, but how this impacts development of multiple myeloma (MM) is unknown. Here, we report the role of the adipokine leptin as master regulator of anti-myeloma tumor immunity by modulating the invariant natural killer T (iNKT) cell function. A marked increase in serum leptin levels and leptin receptor (LR) expression on iNKT cells in MM patients and the 5T33 murine MM model was observed. MM cells and leptin synergistically counteracted anti-tumor functionality of both murine and human iNKT cells. In vivo blockade of LR signaling combined with iNKT stimulation resulted in superior anti-tumor protection. This was linked to persistent IFN-γ secretion upon repeated iNKT cell stimulation and a restoration of the dynamic antigen-induced motility arrest as observed by intravital microscopy, thereby showing alleviation of iNKT cell anergy. Overall our data reveal the LR axis as novel therapeutic target for checkpoint inhibition to treat MM.

A comparison of 7-day versus 10-day course of low-dose dexamethasone for chronically ventilated preterm infants.

OBJECTIVE: The objective of the study was to compare the effect of two different dexamethasone regimens on respiratory outcomes of ventilator-dependent preterm infants. STUDY DESIGN: Retrospective study of ventilated preterm infants <29 weeks gestational age treated with either 7-day or 10-day dexamethasone course. Primary outcome was days to successful extubation. Other outcomes included rate of successful extubation and need for repeat steroid therapy. RESULTS: Fifty-nine infants were identified; 32 (54%) received 7 days of dexamethasone and 27 (46%) received 10 days of dexamethasone. Both groups had comparable baseline demographics and clinical characteristics. Mean time to successful extubation was similar between the two groups (5.1±2.7 days in 7-day group and 6.0±3.7 days in 10-day group, P=0.42). Successful extubation by end of treatment (56% versus 67%, P=0.44) and need for repeat steroid therapy (47% versus 33%, P=0.43) were also similar. CONCLUSION: 7-day and 10-day course of dexamethasone have comparable efficacy in facilitating extubation of ventilator-dependent preterm infants.

MDR-TB in Puducherry, India: reduction in attrition and turnaround time in the diagnosis and treatment pathway.

Setting: A mixed-methods operational research (OR) study was conducted to examine the diagnosis and treatment pathway of patients with presumptive multidrug-resistant tuberculosis (MDR-TB) during 2012-2013 under the national TB programme in Puducherry, India. High pre-diagnosis and pre-treatment attrition and the reasons for these were identified. The recommendations from this OR were implemented and we planned to assess systematically whether there were any improvements. Objectives: Among patients with presumptive MDR-TB (July-December 2014), 1) to determine pre-diagnosis and pre-treatment attrition, 2) to determine factors associated with pre-diagnosis attrition, 3) to determine the turnaround time (TAT) from eligibility to testing and from diagnosis to treatment initiation, and 4) to compare these findings with those of the previous study (2012-2013). Design: This was a retrospective cohort study based on record review. Results: Compared to the previous study, there was a decrease in pre-diagnosis attrition from 45% to 24% (P < 0.001), in pre-treatment attrition from 29% to 0% (P = 0.18), in the TAT from eligibility to testing from a median of 11 days to 10 days (P = 0.89) and in the TAT from diagnosis to treatment initiation from a median of 38 days to 19 days (P = 0.04). There is further scope for reducing pre-diagnosis attrition by addressing the high risk of patients with human immunodeficiency virus and TB co-infection or those with extra-pulmonary TB not undergoing drug susceptibility testing. Conclusion: The implementation of findings from OR resulted in improved programme outcomes.

Contexte : Une recherche opérationnelle basée sur un mélange de méthodes a été réalisée afin d'étudier le parcours de diagnostic et de traitement des patients atteints d'une tuberculose multirésistante (TB-MDR) présumée (2012­2013) dans le cadre du programme national TB, à Pondichéry, Inde. Nous avons identifié une attrition avant le diagnostic et avant le traitement, ainsi que les raisons de ce problème. Les recommandations de cette recherche opérationnelle ont été mises en œuvre et nous avons prévu d'évaluer systématiquement s'il y avait une amélioration.Objectifs : Parmi les patients présumés atteints de TB-MDR (juillet­décembre 2014), 1) déterminer l'attrition pré-diagnostic et pré-traitement ; 2) déterminer les facteurs associés à l'attrition pré diagnostic ; 3) déterminer le délai depuis l'éligibilité jusqu'au test et du diagnostic à la mise en route du traitement ; et 4) comparer ces résultats à l'étude précédente.Schéma : Etude de cohorte rétrospective impliquant une revue des dossiers.Résultats : Par comparaison aux études précédentes, il y a eu une réduction de l'attrition pré-diagnostique de 45% à 24% (P < 0,001), une attrition pré-traitement de 29% à 0% (P = 0,18), un délai entre l'éligibilité au test d'une médiane de 11 jours contre 10 jours (P = 0,89) et un délai entre le diagnostic et la mise en route du traitement d'une médiane de 38 jours contre 19 jours (P = 0,04). Il y a des perspectives supplémentaires de réduction de l'attrition avant le diagnostic en ciblant les patients à risque de ne pas être testés parmi ceux atteints de TB et le virus de l'immunodéficience humaine et de TB extra-pulmonaire.Conclusion : La mise en œuvre des résultats de la recherche opérationnelle a eu pour résultat une amélioration des résultats du programme.

Marco de referencia: Se llevó a cabo una intervención de investigación operativa con métodos mixtos, con el fin de estudiar la trayectoria del diagnóstico y el tratamiento de los pacientes con presunción clínica de tuberculosis multirresistente (TB-MDR) en el 2012 y 2013 en el contexto del Programa Nacional contra la Tuberculosis de Puducherry, en la India. Se detectaron altas proporciones de abandono antes del diagnóstico y antes de comenzar el tratamiento y se analizaron sus causas. Las recomendaciones de esta investigación operativa se pusieron en práctica y en el presente estudio se prevé una evaluación sistemática que permita valorar si se logró algún progreso.Objetivos: Analizar los siguientes resultados en los pacientes con presunción clínica de TB-MDR (de julio a diciembre del 2014): 1) si ocurrió abandono antes del diagnóstico o del tratamiento; 2) si existieron factores asociados con el abandono antes de definir el diagnóstico; 3) el lapso necesario entre el momento de la presunción clínica hasta la realización de las pruebas diagnósticas y desde la definición del diagnóstico hasta el comienzo del tratamiento; y 4) comparar estos resultados con los datos del estudio anterior.Método: Fue este un estudio retrospectivo de cohortes, con análisis de las historias clínicas.Resultados: En comparación con el estudio anterior, se observó una disminución del abandono antes del diagnóstico de 45% a 24% (P < 0,001) y antes del comienzo del tratamiento de 29% a 0% (P = 0,18); se redujo el lapso entre la presunción clínica y la práctica de las pruebas diagnósticas una mediana de 11 días a 10 días (P = 0,89) y también el lapso entre el diagnóstico y el inicio del tratamiento una mediana de 38 días a 19 días (P = 0,04). Existe aun margen para una mayor disminución de los abandonos anteriores al diagnóstico, si se aborda el alto riesgo de no practicar las pruebas diagnósticas a los pacientes coinfectados por el virus de la inmunodeficiencia humana y la TB y a los pacientes con TB extrapulmonar.Conclusion: La aplicación de los resultados de la investigación operativa tuvo como consecuencia un progreso en los resultados del programa.

Perioperative factors associated with acute kidney injury after partial nephrectomy.

BACKGROUND: Partial nephrectomy is performed with the aim to preserve renal function. But the occurrence of postoperative acute kidney injury (AKI) can interfere with this goal. Our primary aim was to evaluate associations between pre-specified modifiable factors and estimated glomerular filtration rate after partial nephrectomy. Our secondary aims were to evaluate associations between pre-specified modifiable factors and both serum creatinine concentration and type of nephrectomy. METHODS: The records of 1955 patients who underwent partial nephrectomy were collected. Postoperative estimated glomerular filtration rate (eGFR) was used as the primary outcome measure. Twenty modifiable risk factors were studied. A repeated-measures linear model with autoregressive within-subject correlation structure was used. The interaction between all the factors and type of nephrectomy was also studied. RESULTS: A total of 1187 (61%) patients had no kidney injury, 647 (33%) had stage I, 80 (4%) had stage II, and 41 (2%) had stage III injury. The mean eGFR increased an estimated 0.83 (99.76% CI 0.79-0.88) ml min(-1) 1.73 m(-2) for a unit increase in baseline eGFR. Mean eGFR was 2.65 (99.76% CI: 0.13, 5.18) ml min(-1) 1.73 m(-2) lower in patients with hypertension. Mean eGFR decreased 0.42 (99.76% CI: 0.22, 0.62) ml min(-1) 1.73 m(-2) for a 10-minute longer in duration of procedure and decreased 2.09 (99.76% CI: 1.39, 2.80) ml min(-1) 1.73 m(-2) for a 10-minute longer in ischemia time. It was 3.53 (99.76% CI: 0.83, 6.23) ml min(-1) 1.73 m(-2) lower for patients who received warm ischemia as compared to cold ischemia. CONCLUSION: Potentially modifiable factors associated with AKI in the postoperative period were identified as baseline renal function, preoperative hypertension, longer duration of surgical time and ischaemia time, and warm ischaemia.

Alcohol use disorders among pulmonary tuberculosis patients under RNTCP in urban Pondicherry, India.

BACKGROUND: Alcohol use is implicated in a wide variety of diseases and disorders including TB. OBJECTIVES: To study the prevalence and pattern of alcohol use among the PTB patients registered under RNTCP in urban Pondicherry and the association of various socio-demographic variables with alcohol drinking during treatment. METHODS: A cross-sectional study was conducted among 235 PTB patients from 6 randomly selected urban PHCs of Pondicherry from Jan 2013 to March 2014. Alcohol Use Disorder Identification Test (AUDIT) was used for screening the PTB patients for their severity of alcohol use. Data were entered in Epi-data v3.1 and was analyzed by SPSS v20. Chi-square test and multiple-logistic regression were used. RESULTS: Prevalence of alcohol use among PTB patients at the time of diagnosis was 59% and during treatment was 31.5%. Around 54% PTB patients had alcohol use disorders (AUD) during diagnosis, whereas the same during treatment was 26.4%. Among drinkers at the time of diagnosis (n=139), 80% modified and 20% did not modify their alcohol use even after TB diagnosis. Male gender was significantly associated with alcohol use (p≤0.001). Univariate analysis showed that lower level of education, lower SES, unemployed/unskilled/semiskilled/skilled occupational group, and Category II were significantly associated with alcohol use among male patients (p<0.05). Multivariate analysis showed that none of the variables were associated. CONCLUSIONS: One-third of PTB patients were drinking alcohol during the treatment. Though 80% modified alcohol use after TB diagnosis, the rest 20% did not modify. Necessary interventions need to be planned to screen for alcohol use.

MDR-TB screening in a setting with molecular diagnostic techniques: who got tested, who didn't and why?

SETTING: The Revised National Tuberculosis Control Programme, Puducherry, India, which has facilities for molecular diagnostic technique. OBJECTIVE: To determine pre-diagnostic and pre-treatment attrition among presumptive multidrug-resistant tuberculosis (MDR-TB) patients and reasons for attrition. METHODS: In this mixed-methods study, the quantitative component consisted of retrospective cohort analysis through record review of all presumptive MDR-TB patients recorded between October 2012 and September 2013. The qualitative component included in-depth interviews with key informants involved in programmatic management of drug-resistant tuberculosis services. RESULTS: Of 341 eligible presumptive MDR-TB patients, pre-diagnostic and pre-treatment attrition was respectively 45.5% (155/341) and 29% (2/7). Patients with extra-pulmonary TB (RR = 2.3), those with human immuno-deficiency and TB co-infection (RR = 1.7), those registered during October-December 2012 (RR = 1.3) and those identified from primary/secondary health centres (RR = 1.8) were less likely to be tested. Themes that emerged during the analysis of the qualitative data were 'lack of a systematic mechanism to track referrals for culture and drug susceptibility testing', 'absence of courier service to transport sputum', 'lack of knowledge and ownership among staff of general health system', 'shortage of diagnostic kits' and 'patient non-adherence'. CONCLUSION: Despite the introduction of molecular diagnostic techniques, operational issues in MDR-TB screening remain a concern and require urgent attention.

Contexte : Programme national révisé de Lutte contre la Tuberculose, Pondichéry, Inde, avec une structure de techniques de diagnostic moléculaire.Objectif : Déterminer l'abandon préalable au diagnostic et préalable au traitement et leurs raisons parmi des patients présumés atteints de tuberculose multirésistante (TB-MDR).Méthodes : Dans cette étude utilisant plusieurs méthodes, l'élément quantitatif consistait en une analyse de cohorte rétrospective, grâce à une revue de dossiers, de tous les patients présumés atteints de TB-MDR entre octobre 2012 et septembre 2013. L'élément qualitatif incluait des entretiens approfondis avec des informateurs clés impliqués dans la gestion programmatique des services de TB pharmacorésistante.Résultats : Sur 341 patients présumés TB-MDR éligibles, le taux d'abandon avant le diagnostic et avant le traitement a été de 45,5% (155/341) et 29% (2/7), respectivement. Les patients atteints de TB extra-pulmonaire (RR = 2,3), de coïnfection par le virus de l'immunodéficience humaine et TB (RR = 1,7), inscrits entre octobre et décembre 2012 (RR = 1,3) et identifiés à partir de centres de santé primaires/secondaires (RR = 1,8) avaient moins de chances d'être testés. Les thèmes qui ont émergé lors de l'analyse des données qualitatives ont été « l'absence d'un mécanisme systématique de suivi des patients référés pour culture et test de pharmaco sensibilité ¼, « l'absence de services de coursier pour transporter les crachats ¼, « le manque de connaissances et d'appropriation du personnel de santé en général ¼, « les ruptures de stock de kits de diagnostic ¼ et « la non-adhérence du patient ¼.Conclusion : En dépit de l'introduction de techniques de diagnostic moléculaire, les problèmes opérationnels de dépistage de la TB-MDR restent préoccupants et requièrent une attention urgente.

Marco de referencia: El Programa Nacional Revisado contra la Tuberculosis en Pondicherry, en la India, cuenta con capacidad técnica para realizar pruebas diagnósticas moleculares.Objetivo: Determinar las tasas de abandono anterior al diagnóstico y antes de comenzar el tratamiento y analizar sus causas, en pacientes con presunción clínica de tuberculosis multidrogorresistente (TB-MDR).Método: En el presente estudio se utilizaron métodos mixtos; el componente cuantitativo consistió en un análisis retrospectivo de cohortes, a partir de los expedientes de todos los pacientes atendidos con presunción diagnóstica de TB-MDR entre octubre del 2012 y septiembre del 2013. El componente cualitativo incluyó entrevistas exhaustivas a informantes clave que participaban en la gestión programática de los servicios de tuberculosis farmacorresistente.Resultados: En los 341 pacientes con presunción diagnóstica de TB-MDR, que cumplían las condiciones del estudio, se observó una tasa de abandono anterior al diagnóstico del 45,5% (155/341) y un abandono anterior al comienzo del tratamiento del 29% (2/7). Fue menos probable que se practicaran las pruebas diagnósticas en los pacientes con TB extrapulmonar (RR = 2,3), coinfección por el virus de la inmunodeficiencia humana y TB (RR = 1,7), en los pacientes registrados de octubre a diciembre del 2012 (RR = 1,3) y los pacientes detectados en un centro de atención primaria o secundaria (RR = 1,8). Los aspectos que surgieron durante el análisis cualitativo fueron 'la falta de un mecanismo sistemático de seguimiento de los pacientes remitidos para cultivo y pruebas de sensibilidad a los medicamentos', 'la ausencia de un servicio de mensajería que transporte las muestras de esputo', 'la falta de conocimientos y de apropiación del trabajo en los miembros del personal del sistema de salud general', 'el desabastecimiento de los estuches diagnósticos' y 'el incumplimiento por parte de los pacientes'.Conclusión: Pese a la introducción de las técnicas de diagnóstico molecular, persisten dificultades operativas en la detección de la TB-MDR que precisan atención urgente.

Multivariate combination of magnetization transfer, T2* and B0 orientation to study the myelo-architecture of the in vivo human cortex.

Recently, T2* imaging at 7Tesla (T) MRI was shown to reveal microstructural features of the cortical myeloarchitecture thanks to an increase in contrast-to-noise ratio. However, several confounds hamper the specificity of T2* measures (iron content, blood vessels, tissues orientation). Another metric, magnetization transfer ratio (MTR), is known to also be sensitive to myelin content and thus would be an excellent complementary measure because its underlying contrast mechanisms are different than that from T2*. The goal of this study was thus to combine MTR and T2* using multivariate statistics in order to gain insights into cortical myelin content. Seven healthy subjects were scanned at 7T and 3T to obtain T2* and MTR data, respectively. A multivariate myelin estimation model (MMEM) was developed, and consists in (i) normalizing T2* and MTR values and (ii) extracting their shared information using independent component analysis (ICA). B0 orientation dependence and cortical thickness were also computed and included in the model. Results showed high correlation between MTR and T2* in the whole cortex (r=0.76, p<10(-16)), suggesting that both metrics are partly driven by a common source of contrast, here assumed to be the myelin. Average MTR and T2* were respectively 31.0+/-0.3% and 32.1+/-1.4 ms. Results of the MMEM spatial distribution showed similar trends to that from histological work stained for myelin (r=0.77, p<0.01). Significant right-left differences were detected in the primary motor cortex (p<0.05), the posterior cingulate cortex (p<0.05) and the visual cortex (p<0.05). This study demonstrates that MTR and T2* are highly correlated in the cortex. The combination of MTR, T2*, CT and B0 orientation may be a useful means to study cortical myeloarchitecture with more specificity than using any of the individual methods. The MMEM framework is extendable to other contrasts such as T1 and diffusion MRI.

Autophagy inhibits oxidative stress and tumor suppressors to exert its dual effect on hepatocarcinogenesis.

The role of autophagy in carcinogenesis is controversial and apparently complex. By using mice with hepatocyte-specific knockout of Atg5, a gene essential for autophagy, we longitudinally studied the role of autophagy in hepatocarcinogenesis. We found that impairing autophagy in hepatocytes would induce oxidative stress and DNA damage, followed by the initiation of hepatocarcinogenesis, which could be suppressed by the antioxidant N-acetylcysteine. Interestingly, these mice developed only benign tumors with no hepatocellular carcinoma (HCC), even after the treatment with diethylnitrosamine, which induced HCC in wild-type mice. The inability of mice to develop HCC when autophagy was impaired was associated with the induction of multiple tumor suppressors including p53. Further analysis indicated that the induction of p53 was associated with the DNA-damage response. Tumorigenesis studies using an established liver tumor cell line confirmed a positive role of autophagy in tumorigenesis and a negative role of p53 in this process when autophagy was impaired. Our studies thus demonstrate that autophagy is required to maintain healthy mitochondria and to reduce oxidative stress and DNA damage to prevent the initiation of hepatocarcinogenesis. However, once hepatocarcinogenesis has been initiated, its presence is also required to suppress the expression of tumor suppressors to promote the development of HCC.

Prevalence of Diabetes Mellitus among Tuberculosis Patients in Urban Puducherry.

BACKGROUND: Diabetes and Tuberculosis often present together and complicate each other at many levels. A collaborative framework for care and control of diabetes and tuberculosis developed by World Health Organisation and International Union against Tuberculosis and Lung Diseases emphasizes routine bi-directional screening for the two diseases. AIMS: The study was to assess the prevalence of diabetes in tuberculosis patients currently on treatment. MATERIALS AND METHODS: This facility-based cross-sectional study was undertaken in four randomly selected peripheral health institutions providing directly observed treatment short-course, treatment for tuberculosis patients. All cases of tuberculosis, more than 18 years of age were screened for diabetes. Risk factors like age, sex, family history of diabetes, alcohol, smoking and obesity were assessed. RESULTS: The prevalence of diabetes in tuberculosis patients was found to be 29% (known diabetics - 20.7%, new Diabetes cases - 8.3%). Diabetes was significantly associated with older age, family history of diabetes, consumption of alcohol and sputum positivity. CONCLUSIONS: Screening patients with Tuberculosis for fasting blood sugar estimation will help in early detection of diabetes.

Uptake of HIV testing and HIV positivity among presumptive tuberculosis patients at Puducherry, South India.

SETTING: Puducherry, a district in South India with a low prevalence of human immunodeficiency virus (HIV) infection (<1% among antenatal women). OBJECTIVES: 1) To estimate the proportion of patients with known HIV status who were HIV-positive, 2) to describe the demographic and clinical characteristics of patients with unknown HIV status among presumptive TB patients, and 3) to assess the additional workload at HIV testing centres. DESIGN: In this cross-sectional study, consecutive presumptive TB patients attending microscopy centres for diagnosis during March-May 2013 were asked if they knew their HIV status. Patients with unknown HIV status were offered voluntary counselling and HIV testing. RESULTS: Of 1886 presumptive TB patients, HIV status was ascertained for 842 (44.6%); 28 (3.3%) were HIV-positive. The uptake of HIV testing was significantly higher in younger age groups, males, residents of Puducherry and smear-positive TB patients. The median increase in the number of clients tested for HIV per day per testing centre was 1 (range 0-6). CONCLUSION: The uptake of HIV testing was low. HIV prevalence was higher among presumptive TB patients than in antenatal women, and as high as in TB patients. With minimal increase in workload at HIV testing centres, HIV testing could be implemented using existing resources.

Smoking as an independent risk factor for hepatocellular carcinoma: the Singapore Chinese Health Study.

BACKGROUND: Given the close correlation between smoking and alcohol intake in most epidemiologic studies, it is difficult to exclude the residual confounding effect of alcohol in the association between smoking and hepatocellular carcinoma (HCC). METHOD: We evaluated the association between smoking and risk of HCC in the Singapore Chinese Health Study, a prospective cohort with a low prevalence of alcohol intake. Information on cigarette smoking and alcohol consumption was obtained through in-person interviews conducted at enrolment. RESULTS: After a mean of 11.5 years of follow-up, there were 394 incident cases of HCC. Participants who consumed more than two alcoholic drinks per day showed an increased risk for HCC (hazard ratio (HR)=2.24; 95% confidence interval (CI)=1.46-3.41). After adjusting for alcohol consumption and other potential confounders, current vs never smokers had a statistically significant, increased risk of HCC (HR=1.63; 95% CI=1.27-2.10) that was dose-dependent (number of cigarettes per day, P for trend<0.001). The observed tobacco-HCC association also was duration-dependent (years of smoking in ever smokers, P for trend=0.002). When we excluded daily drinkers from the analysis, all risk estimates remained essentially the same and statistically significant. CONCLUSION: Our findings strongly implicate tobacco smoke as a causal factor of HCC development.

Bone mineral density in patients with end-stage renal disease and its evolution after kidney transplantation.

Renal transplantation is associated with abnormalities of the structure and function of the musculoskeletal system. No data are available on bone health in Indian patients with end-stage renal disease (ESRD) and its evolution after transplantation. Consecutive ESRD patients who underwent living donor renal transplantation were studied prospectively. Bone mineral density (BMD) was measured at lumbar vertebrae using quantitative computed tomography (CT) scan before transplantation and after 3 and 6 months. T and Z scores were calculated by comparing with normal control data, and values were correlated with various clinical and biochemical parameters. Of the 56 patients enrolled (mean age, 33.7 years; 47 males), 40 completed the 6-month follow-up. The vertebral trabecular bone density at the time of transplantation was 172±53 mg/cc and the average Z score was 0.26±1.7. There was a significant decline in BMD at 3 months (11.8%; P<0.0001) and 6 months (16%; P<0.0001) after transplantation. Both T and Z scores showed a significant decline at 3 and 6 months. There was a significant decline in intact parathormone (iPTH) levels after transplantation, but 15 (37.5%) patients continued to have raised iPTH 6 months after transplantation. The iPTH levels at 6 months had significant correlation with BMD decline (r=0.43, P=0.006). We conclude that Indian ESRD patients have relatively well-preserved BMD, but the density declines rapidly after transplantation. A significant proportion of patients exhibit persistent hyperparathyroidism 6 months after transplantation, which correlates with bone loss.

Corticosterone induced morphological changes of hippocampal and amygdaloid cell lines are dependent on 5-HT7 receptor related signal pathway.

Stress is an unavoidable life experience. It induces mood, cognitive dysfunction and plasticity changes in chronically stressed individuals. Among the various brain regions that have been studied, the hippocampus and amygdala have been observed to have different roles in controlling the limbic-hypothalamic-pituitary-adrenal axis (limbic-HPA axis). This study investigated how the stress hormone corticosterone (CORT) affects neuronal cells. The first aim is to test whether administration of CORT to hippocampal and amygdaloid cell lines induces different changes in the 5-HT receptor subtypes. The second goal is to determine whether stress induced morphological changes in these two cell lines were involved in the 5-HT receptor subtypes expression. We now show that 5-HT(7) receptor mRNA levels were significantly upregulated in HT-22 cells, but downregulated in AR-5 cells by exposure to a physiologically relevant level of CORT (50 µM) for 24 h, which was later confirmed by primary hippocampal and amygdaloid neuron cultures. Additionally, pretreatment of cells with 5-HT(7) antagonist SB-269970 or agonist LP-44 reversed CORT induced cell lesion in a dose-dependent manner. Moreover, CORT induced different changes in neurite length, number of neurites and soma size in HT-22 and AR-5 cells were also reversed by pretreatment with either SB-269970 or LP-44. The different effects of 5-HT(7) receptors on cell lines were observed in two members of the Rho family small GTPase expression: the Cdc-42 and RhoA. These observed results support the hypothesis that 5-HT may differentially modulate neuronal morphology in the hippocampus and amygdala depending on the expression levels of the 5-HT receptor subtypes during stress hormone insults.