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Objectives: Cow urine ark (CUA), known as “Amrita” as mentioned in Ayurveda, contains‎ anti-hyperglycemic and antioxidant effects. Therefore, we designed the present study to evaluate the lipid ‎lowering activity of CUA and its possible implication in metabolic syndrome.‎ Materials and Methods: Thirty guinea pigs of either sex were divided into five groups: Group 1 and 2 serving as a vehicle ‎and sham control, received normal and high fat diet for 60 days respectively; Group 3, 4 and 5 ‎received high fat diet for 60 days with CUA 0.8 ml/kg, 1.6 ml/kg and rosuvastatin (1.5 mg/kg) on the‎last 30 days of study period, respectively. Serum lipid profile (total cholesterol, triglycerides, LDL-‎C, VLDL-C, HDL-C, total Cholesterol/HDL-C) and serum enzymes (ALT, AST, ALP, LDH and CK-MB) ‎were performed in each group at the beginning and end of the study. Histological study of liver and ‎kidney was done in each group. Results: CUA (0.8 ml/kg) significantly decreased the serum triglycerides and VLDL-C, but CUA (1.6 ml/kg) ‎decreased the total serum Cholesterol, triglycerides and VLDL-C (p < 0.05). Higher dose (1.6 ml/kg) of ‎CUA also increased HDL-C level, significantly (p < 0.05). CUA reduced serum AST, ALP and LDH ‎level, which was statistically significant as well, while it also decreased the accumulation of lipid in hepatocytes as ‎compared to sham control.‎ Conclusions: CUA reduced triglycerides, increased HDL-C and found to be hepatoprotective in ‎animals that are on a high fat diet.

Objective: To investigate the anti-urolithiatic effect of aqueous extract of leaves of Bryophyllum pinnatum (B. pinnatum) on ethylene glycol-induced renal calculi. Materials and Methods: Thirty-six Wistar male rats were randomly divided into six equal groups. group A animals received distilled water for 28 days. Group B to group F animals received 1% v/v ethylene glycol in distilled water for 28 days and group B served as ethylene glycol control. Groups C and D (preventive groups) received aqueous extract of leaves of B. pinnatum 50 and 100 mg/kg intraperitoneally, respectively for 28 days. Groups E and F (treatment groups) received aqueous extract of leaves of B. pinnatum 50 and 100 mg/kg intraperitoneally, respectively from 15th to 28th day. On days 0 and 28, 24 hrs urine samples were collected for urinary volume and urinary oxalate measurement. On day 28, blood was collected for serum creatinine and blood urea level monitoring. All animals were sacrificed and kidneys were removed, weighed, and histopathologically evaluated for calcium oxalate crystals deposition. Results: Administration of aqueous extract of leaves of B. pinnatum reduced urine oxalate level significantly, as compared with Group B (p

Background: Clinically significant enlargement of the thyroid gland by amyloid deposition is rare. A case study of 22-year-old lady with gradual enlargement of the thyroid gland has been presented. Routine haemological, biochemical test including thyroid function tests were normal. Ultrasonographic findings were nonspecific. Amyloid goiter has to be differentiated from other types of goitre and malignancy. FNAC was found to be suspicious for the presence of amyloid. Special staining with thioflavin T confirmed amyloid deposition.

The complex regional pain syndrome (CRPS) I is a neurogenic pain syndrome that is characterized by pain, vasomotor and dystrophic changes and often motor impairments. The etiology of the condition resides in multiple theories, and diagnosis can be difficult and therapy focuses on pain management and restoration of physical function. The conservative treatment includes both non-pharmacological and pharmacological methods, and invasive therapy is centered on sympathetic and somatic blocks. We report a case of CRPS type-I in a 15-year-old young boy following repeated trauma to right elbow, which was successfully managed by a stellate ganglion block and continuous interscalene brachial plexus block and function restored to its full extent.

Abstract The study performed by Zhou et al. (World J Surg Oncol 15:104, 2017) titled “Clinical and prognostic significance of HIF-1α overexpression in oral squamous cell carcinoma: a meta-analysis” attempts to highlight hypoxia-inducible factor-1 alpha as a possible prognostic marker in oral squamous cell carcinoma (OSCC). We would like to underline a few points which may affect such a conclusion. The correlations between HIF-1α expression and tumour size as well as tumour stage are debatable. Further, the subgroup analysis incorporating Australia and Europe into a single subgroup limits the viability of the prognostic analysis of HIF-1α. We also suggest future studies in the same research area to analyse head and neck squamous cell carcinoma instead of OSCC, to ameliorate the limitations encountered by Zhou et al., due to the scarcity of relevant clinical data and a low number of studies about OSCC.

Awareness of breast cancer has been increasing due to early detection, but the advanced disease has limited treatment options. There has been growing evidence on the role of miRNAs involved in regulating the resistance in several cancers. We performed a comprehensive systematic review and meta-analysis on the role of miRNAs in influencing the chemoresistance and sensitivity of breast cancer. A bibliographic search was performed in PubMed and Science Direct based on the search strategy, and studies published until December 2018 were retrieved. The eligible studies were included based on the selection criteria, and a detailed systematic review and meta-analysis were performed based on PRISMA guidelines. A random-effects model was utilised to evaluate the combined effect size of the obtained hazard ratio and 95% confidence intervals from the eligible studies. Publication bias was assessed with Cochran’s Q test, I2 statistic, Orwin and Classic fail-safe N test, Begg and Mazumdar rank correlation test, Duval and Tweedie trim and fill calculation and the Egger’s bias indicator. A total of 4584 potential studies were screened. Of these, 85 articles were eligible for our systematic review and meta-analysis. In the 85 studies, 188 different miRNAs were studied, of which 96 were upregulated, 87 were downregulated and 5 were not involved in regulation. Overall, 24 drugs were used for treatment, with doxorubicin being prominently reported in 15 studies followed by Paclitaxel in 11 studies, and 5 drugs were used in combinations. We found only two significant HR values from the studies (miR-125b and miR-4443) and our meta-analysis results yielded a combined HR value of 0.748 with a 95% confidence interval of 0.508−1.100; p-value of 0.140. In conclusion, our results suggest there are different miRNAs involved in the regulation of chemoresistance through diverse drug genetic targets. These biomarkers play a crucial role in guiding the effective diagnostic and prognostic efficiency of breast cancer. The screening of miRNAs as a theragnostic biomarker must be brought into regular practice for all diseases. We anticipate that our study serves as a reference in framing future studies and clinical trials for utilising miRNAs and their respective drug targets.

Head and Neck Cancer (HNC) is the sixth most common type of cancer across the globe, with more than 300,000 deaths each year, globally. However, there are currently no standardised molecular markers that assist in determining HNC prognosis. The literature for this systematic review and meta-analysis were sourced from multiple bibliographic databases. This review followed PRISMA guidelines. The Hazard Ratio (HR) was selected as the effect size metric to independently assess overall survival (OS), disease-free survival (DFS), and prognosis. Subgroup analysis was performed for individual highly represented miRNA. A total of 6843 patients across 50 studies were included in the systematic review and 34 studies were included in the meta-analysis. Studies across 12 countries were assessed, with China representing 36.7% of all included studies. The analysis of the survival endpoints of OS and DFS were conducted separately, with the overall pooled effect size (HR) for each being 1.825 (95% CI 1.527−2.181; p < 0.05) and 2.596 (95% CI 1.917−3.515; p < 0.05), respectively. Subgroup analysis was conducted for impact of miR-21, 200b, 155, 18a, 34c-5p, 125b, 20a and 375 on OS, and miR-21 and 34a on DFS. The pooled results were found to be statistically significant for both OS and DFS. The meta-analysis indicated that miRNA alterations can account for an 82.5% decrease in OS probability and a 159.6% decrease in DFS probability. These results indicate that miRNAs have potential clinical value as prognostic biomarkers in HNC, with miR-21, 125b, 34c-5p and 18a, in particular, showing great potential as prognostic molecular markers. Further large scale cohort studies focusing on these miRNAs are recommended to verify the clinical utility of these markers individually and/or in combination.

Purpose: To evaluate effect of ethanolic extract of Pedalium murex Linn. fruits on experimentalmodel of calcium oxalate nephrolithiasis.Materials and Methods: Thirty-six male Wistar albino rats were randomly divided in 6 groups.Normal controls received distilled water for 28 days. Other five groups received ethylene glycol(1% v/v) in distilled water for 28 days. Pedalium murex ethanolic extract was given 200 mg/kgand 400 mg/kg orally in distilled water for 28 days in prophylactic groups (III and IV) and from15th to 28th days in treatment groups (V and VI). The urea, creatinine, random blood sugar, aspartateaminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin and calcium weremeasured on 28th day. 24 hr urinary oxalate and volume were measured on day 0 and 28. On day28, kidneys were removed, weighed and subjected to histopathological examination. Calcium oxalatecrystallization was evaluated by renal histopathology and in-vitro method of mineralization.All parameters were analyzed by Kruskal-Wallis or one-way ANOVA with post-hoc test.Results: Pedalium murex showed significant improvement in renal function and kidney weight inprophylactic groups as compared to ethylene glycol controls. It did not show any effect on urinaryoxalate, urine volume and any other serological parameters. Calcium oxalate crystallization wassignificantly reduced in all the Pedalium murex treated groups (P < .05). Calcium oxalate and phosphatemineralization were also inhibited by 33% and 57%.Conclusion: Ethanolic extract of Pedalium murex fruits possess significant activity for preventionof renal calculi.

Purpose To investigate the anti-urolithiatic effect of cow urine ark (medicinal distilled cow urine) on ethylene glycol (EG) induced renal calculi. Materials and Methods 36 male Wistar rats were randomly divided into 6 equal groups. Group I animals served as vehicle control and received distilled water for 28 days. Group II to VI animals received 1% v/v EG in distilled water for 28 days. Group II served as EG control. Group III and IV (preventive groups) received cow urine ark orally for 28 days in doses of 1 mL/kg and 2 mL/kg, respectively. Group V and VI (treatment groups) received 1 mL/kg and 2 mL/kg cow urine ark orally, respectively from 15th to 28th days. 24-hour urine samples were collected on day 0 and 28. Urine volume and oxalate levels were measured. On day 28, blood was collected for biochemical parameters. Animals were sacrificed and kidneys were harvested, weighed and histopathologically evaluated for calcium oxalate (CaOx) crystals. To calculate the percentage of inhibition of mineralization, simultaneous flow static in-vitro model was used. Results EG significantly increased urine oxalate, serum creatinine, blood urea level; kidney weight and CaOx deposits. Provision of cow urine ark resulted in significantly lower levels of urine oxalate, serum creatinine, blood urea and CaOx depositions as compared to Group II. (p value < 0.05) It also significantly restored kidney weight. (p value < 0.05) Cow urine ark inhibited 40% and 35% crystallization of CaOx and calcium phosphate, respectively. Conclusion Cow urine ark is effective in prevention and treatment of EG induced urolithiasis in Wistar rats.

Adult Treatment Panel (ATP), an expert panel to supervise cholesterol management was set up under the aegis of National Cholesterol Education Program (NCEP) in 1985. Since then NCEP-ATP has been revising and framing guidelines to enable clinician to deliver better treatment to cardiovascular patients and to educate general people. As a result, considerable reduction in cardiovascular related deaths has been observed in recent times. All three ATP guidelines viz. ATP-I, ATP-II and ATP-III have targeted low density lipoprotein as their primary goal. The ATP-III guideline was updated in the light of evidences from 5-major clinical trials and was released in 2004. It added therapeutic lifestyle changes, concept of risk equivalents, Framingham CHD-risk score non-high density lipoprotein cholesterol (non-HDL-C) as secondary target and gave strong emphasis on metabolic risk factors. The earlier treat-to-target paradigm faced fierce criticism from clinicians across the globe because of insufficient proof of safety and benefits of treating patients with respect to an individual′s low density lipoprotein (LDL) level. Further, demonstration of non-HDL-C and total cholesterol/HDL-C ratio as strong predictors of overall cardiovascular risk foresees new guidelines. A tailored-treatment approach was suggested instead of LDL-C target based treatment approach which was soundly based on direct clinical trials evidences and proposes treatment based on individual′s overall 5- to 10-year cardiovascular risk irrespective of LDL-C level, leading to lower number of people on high dose/s of statins. Recent report of the Cholesterol Treatment Trialist′s Collaborators meta-analysis strongly supported primary prevention of LDL with statins in low risk individuals and showed that its benefits completely outweighed its known hazards. Markers other than LDL-C like apolipoprotein B, non-HDL-C and total cholesterol/HDL-C ratio would take precedence in the risk assessment and strong emphasis would be given on tailored-treatment approach in the upcoming ATP-IV guideline.

The association of gonadal dysgenesis and Mayer-Rokitansky-Kuster-Hauser syndrome is very rare. We report a 21-year-old phenotypical female who presented with primary amenorrhea and underdeveloped secondary sexual characteristics. Hormonal evaluation revealed hypergonadotropic hypogonadism. Her karyotype was 46XX. Laparoscopy of pelvis revealed absent uterus, normal fallopian tubes and bilateral streak ovaries, which were biopsied and histopathology was consistent with the findings of gonadal dysgenesis. We searched PubMed for similar reports in the literature and details of all the cases were analyzed and reported here.

The developing countries are having an abruptly growing number of drug resistant tuberculosis cases. Multidrug-resistant tuberculosis (MDR-TB) is a type of TB in which the strain of Mycobacterium tuberculosis is resistant to at least Isoniazid and Rifampicin, the two most effective of the four first-line TB drugs (the other two drugs being Ethambutol and Pyrazinamide). The management of such cases is complex and requires a treatment for 24-27 months. The current guidelines available for the management of this type of TB are largely based on the second line TB drugs which are relatively costly, less efficacious and are associated with greater sideeffects. The introduction of newer drugs to cater to the high mortality and early sputum culture conversion in the MDR-TB cases is an absolute essential. In the present article, the authors discuss about the introduction of a newer drug named Bedaquiline for the control of MDR-TB.

The high rate of fatal suicidal behavior in men is an urgent issue as highlighted in the public eye via news sources and media outlets. In this study, we have attempted to address this issue and understand the neural substrates underlying the gender differences in the rate of fatal suicidal behavior. The Interpersonal-Psychological Theory of Suicide (IPTS) has proposed an explanation for the seemingly paradoxical relationship between gender and suicidal behavior, i.e. greater non-fatal suicide attempts by women but higher number of deaths by suicide in men. This theory states that possessing suicidal desire (due to conditions such as depression) alone is not sufficient for a lethal suicide attempt. It is imperative for an individual to have acquired the capability for suicide (ACS) along with suicidal desire in order to die by suicide. Therefore, higher levels of ACS in men may explain why men are more likely to die by suicide than women, despite being less likely to experience suicidal ideation or depression. In this study, we used activation likelihood estimation meta-analysis to investigate a potential ACS network that involves neural substrates underlying emotional stoicism, sensation seeking, pain tolerance, and fearlessness of death along with a potential depression network that involves neural substrates that underlie clinical depression. Brain regions commonly found in ACS and depression networks for males and females were further used as seeds to obtain regions functionally and structurally connected to them. We found that the male-specific networks were more widespread and diverse than the female-specific ones. Also, while the former involved motor regions such as the premotor cortex and cerebellum, the latter was dominated by limbic regions. This may support the fact that suicidal desire generally leads to fatal/decisive action in males while in females, it manifests as depression, ideation and generally non-fatal actions. The proposed model is a first attempt to characterize the neural networks underlying gender differences in suicidal behavior. Future studies should examine the proposed network to better characterize and refine this network using tasks specifically targeted toward constructs underlying ACS.

The world is facing a new pandemic in progress due to a mosquito-borne flavivirus popularly known as Zika virus. The emergence of this new virus is really alarming with the sudden increment in the cases of microcephaly reported from Brazil. The findings attributing the involvement of Zika virus as the reason for congenital deformations in the babies born in afflicted areas have really shocked the world. The present knowledge about this virus is very limited and in the absence of further studies the precautions seems to be the best way of protection from this virus. The present article is a short review about this new virus.

BACKGROUND:One-fifth of the patients on multidrug-resistant tuberculosis treatment at the Drug-Resistant-TB (DR-TB) Site in Gujarat are lost-to-follow-up(LFU). OBJECTIVE:To understand patients' and providers' perspectives on reasons for LFU and their suggestions to improve retention-in-care. DESIGN:Qualitative study conducted between December 2013-March 2014, including in-depth interviews with LFU patients and DOT-providers, and a focus group discussion with DR-TB site supervisors. A thematic-network analysis approach was utilised. RESULTS:Three sub-themes emerged: (i) Struggle with prolonged treatment; (ii) Strive against stigma and toward support; (iii) Divergent perceptions and practices. Daily injections, pill burden, DOT, migratory work, social problems, prior TB treatment, and adverse drugs effects were reported as major barriers to treatment adherence and retention-in-care by patients and providers. Some providers felt that despite their best efforts, LFU patients remain. Patient movements between private practitioners and traditional healers further influenced LFU. CONCLUSION:The study points to a need for repeated patient counselling and education, improved co-ordination between various tiers of providers engaged in DR-TB care, collaboration between the public, private and traditional practitioners, and promotion of social and economic support to help patients adhere to MDR-TB treatment and avoid LFU.

Expectant management for tubal heterotopic pregnancy could be considered as a successful option in a symptom-free patient where the ectopic embryo has a limited craniocaudal length with no cardiac activity. We report the obstetric outcome after expectant management for a right tubal heterotopic pregnancy. Heterotopic pregnancy was first recognized at 6 weeks gestation in a 32-year-old salpingectomized woman with an 8-year history of subfertility who conceived after in utero transfer of three embryos obtained by in vitro fertilization. Expectant management and close ultrasonographic and clinical monitoring were done. The intrauterine pregnancy proceeded unremarkably. A cesarean section was performed for breech presentation, and it allowed the delivery of a healthy 2260-g male infant. The examination of the adnexa showed a pre-rupture of the right fallopian tube.

Background: Human immunodeficiency virus (HIV) disclosure offers important benefits to people living with HIV/AIDS. However, fear of discrimination, blame, and disruption of family relationships can make disclosure a difficult decision. Barriers to HIV disclosure are influenced by the particular culture within which the individuals live. Although many studies have assessed such barriers in the U.S., very few studies have explored the factors that facilitate or prevent HIV disclosure in India. Understanding these factors is critical to the refinement, development, and implementation of a counseling intervention to facilitate disclosure. Materials and Methods: To explore these factors, we conducted 30 in-depth interviews in the local language with HIV- positive individuals from the Integrated Counselling and Testing Centre in Gujarat, India, assessing the experiences, perceived barriers, and facilitators to disclosure. To triangulate the findings, we conducted two focus group discussions with HIV medical and non-medical service providers, respectively. Results: Perceived HIV-associated stigma, fear of discrimination, and fear of family breakdown acted as barriers to HIV disclosure. Most people living with HIV/AIDS came to know of their HIV status due to poor physical health, spousal HIV-positive status, or a positive HIV test during pregnancy. Some wives only learned of their husbands′ HIV positive status after their husbands died. The focus group participants confirmed similar findings. Disclosure had serious implications for individuals living with HIV, such as divorce, maltreatment, ostracism, and decisions regarding child bearing. Interpretation and Conclusion: The identified barriers and facilitators in the present study can be used to augment training of HIV service providers working in voluntary counseling and testing centers in India.

No abstract

Background: Thyroid cancer is fairly common. The worldwide annual incidence ranges from 0.5 to 10 cases per 100,000 people. Anaplastic thyroid carcinoma, comprising less than 10% of all thyroid carcinomas, remains one of the most virulent of all cancers in humans with a 10 year survival rate of only 0.1 %. In the present study we looked into the clinical, cytological and histological spectrum of anaplastic carcinoma and compared our experience with recent literature. Materials and Methods: This was a hospital based retrospective study from January 2000 to November 2010. Clinical, cytological and histopathological data of all the diagnosed anaplastic thyroid carcinoma cases were reviewed and analyzed. Results: Of the 59 thyroid malignancies diagnosed in the same period, 7 cases were anaplastic carcinoma. The mean age was 63 years and was predominantly found in females. All of the cases presented with a neck mass that lasted for a mean of 5.7 months. The mean tumor size was 14.9 cm and the most common sub-type was the spindle cell type. Atypical mitosis of more than 5 per high power field and necrosis was noted in all cases. Conclusion: Due to the markedly aggressive nature of this tumor and its association with areas of endemic thyroid disease, early diagnosis and aggressive therapy is essential, especially in the Himalayan and Sub-Himalayan belt. Keywords: Anaplastic carcinoma; Thyroid carcinoma; Spindle cell variant DOI: 10.3126/jpn.v1i1.4451 Journal of Pathology of Nepal (2011) Vol.1, 45-48

Unilateral or bilateral hypoplasia or agenesis of one or both thyroid lobes, with or without isthmic agenesis, is a rare developmental anomaly. Hemiagenesis of the left lobe is far commoner than of the right. Clinically, these patients may be euthyroid, hyperthyroid, or hypothyroid. Ultrasonography is usually able to diagnose this condition easily, as we demonstrate in this case report of a 37-year-old lady with an incidentally detected thyroid nodule who was found to have hemiagenesis of the right lobe and isthmus.

Attempts at organ transplantation have been made since the 19 th century. Renal transplantation is the preferred treatment for end stage renal disease. Renal transplant anaesthesia requires a thorough understanding of the meta-bolic and systemic abnormalities in end stage renal disease, familiarity with transplant medicine and expertise in managing and optimizing these patients for the best possible outcome. Also, the associated co-morbid conditions increase the complexity of anaesthesia, pain management and perioperative morbidity and mortality. Hence, a good perioperative management of these patients includes a multidisciplinary collaboration with well-planned anaesthetic strategies.

Transplantation provides a near normal life and excellent rehabilitation compared to dialysis and is the pre-ferred method oftreatment for end stage renal disease patients. We describe our experiences through a retrospec-tive analysis ol′anaesthesia management of 350 cases of both living related and cadaveric renal transplantation conducted between Jan 2004 -April 2008 at Jaslok Hospital And Research Center. Areas ol′our interest include preoperative patient status, fluid management, hemodynamic stability, anaesthesia management, and perioperative complications. Recent advances in surgical techniques; anaesthesia management and immunosuppressive drugs have made renal transplantation sale and predictable. Preoperative patient optimization, intraoperative physiologi-cal stability and postoperative care of′renal transplant patients have contributed to the success of′renal transplant programme in our hospital.

Context : There is a continuous controversy regarding the obstetric perinatal outcome of twin pregnancies conceived after assisted reproductive techniques (ART). There is an ongoing discussion whether theses parameters may show poorer results as compared to spontaneous conception. Aims: To evaluate the outcome of multifetal pregnancies and to compare maternal and neonatal complications between spontaneously conceived and assisted reproductive therapy. Settings and Design : Prospective case-control study. Materials and Methods :In this prospective case-control study of 2-year duration, obstetric and perinatal outcomes were compared in 36 ART twin pregnancies (Group A) with 138 twins who conceived naturally (Group B). The outcomes were analyzed and used for a comparison between spontaneous and assisted multifetal pregnancies. Statistical Analysis : The continuous variables were analyzed by Student′s t -test and categorical variables were analyzed with Fisher′s exact test. Results : Pregnancy-related complications like pregnancy-induced hypertension, antepartum hemorrhage, were similar in both groups. Incidence of cesarean section, preterm delivery, and hospital stay was significantly more in Group A vs. Group B, P < 0.001. The newborns in the assisted group had more complications than the spontaneous group; most notable were respiratory distress syndrome, newborn intensive care admission, sepsis, and longer hospital stay (4.8 days vs. 1.6 days, P < 0.001). Conclusions : Increased rates of cesarean section and preterm delivery are the main reasons for increased obstetric risk in pregnancies conceived through ART. Preterm birth and neonatal prematurity-related complications were the main cause for longer stay in hospital in ART-conceived twins.

Background: Study of the chronology of criteria of dependence in alcohol dependence syndrome (ADS) can enable us design strategies for the prevention for ADS, which aims at reducing the occurrence of ADS. Objective: To study the age-wise and order-wise chronologies of ICD-10 (DCR) dependence criteria in individuals with ADS. Materials and Methods: Consecutively admitted and consenting inpatients with ICD-10 (DCR) diagnosis of ADS were evaluated in a structured interview after detoxification using Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA)-II. Results: The total sample size was 81. The mean ages at the first onset of alcohol use, development of the first criterion and International Statistical Classification of Diseases and Related Health Problems 10 th Revision (ICD-10) dependence was 18.72 years (SD, 6.84), 24.33 years (SD, 9.21) and 27.51 years (SD, 9.28), respectively. In age-wise chronology, tolerance, loss of control and craving were present in 97.53%, 80.24% and 79%, respectively, of our study sample. In order-wise chronology, either craving (16%) or tolerance (71.6%) was present as the first criterion and the presence of craving (16%), tolerance (21%) or loss of control (18.5%) was observed in the first criterion in 55.5% of the subjects. Conclusions: Knowledge of chronology, its frequencies and time duration between various milestones in the development of the dependence criteria may enable the selection of the target population at an early stage. The pattern of development of dependence may provide us with an opportunity for interventions to reduce the incidence of ADS, as a step toward primary prevention. Adequate training of the primary care personnel and early psychiatric referral may help in the reduction in the incidence of ADS.

Proliferating eukaryotic cells undergo a finite number of cell divisions before irreversibly exiting mitosis. Yet pathways that normally limit the number of cell divisions remain poorly characterized. Here we describe a screen of a collection of 3762 single gene mutants in the yeast Saccharomyces cerevisiae, accounting for 2/3 of annotated yeast ORFs, to search for mutants that undergo an atypically high number of cell divisions. Many of the potential longevity genes map to cellular processes not previously implicated in mitotic senescence, suggesting that regulatory mechanisms governing mitotic exit may be broader than currently anticipated. We focused on an ER-Golgi gene cluster isolated in this screen to determine how these ubiquitous organelles integrate into mitotic longevity. We report that a chronic increase in ER protein load signals an expansion in the assembly of autophagosomes in an Ire1-independent manner, accelerates trafficking of high molecular weight protein aggregates from the cytoplasm to the vacuoles, and leads to a profound enhancement of daughter cell production. We demonstrate that this catabolic network is evolutionarily conserved, as it also extends reproductive lifespan in the nematode Caenorhabditis elegans. Our data provide evidence that catabolism of protein aggregates, a natural byproduct of high protein synthesis and turn over in dividing cells, is among the drivers of mitotic longevity in eukaryotes.

Background: Depressed patients who do not respond to second-line antidepressant drugs are characterised as suffering from treatment-refractory depression (TRD). Chronic psychosocial stress hypothalamic–pituitary–adrenal (HPA) axis dysfunction is associated with attenuated responses to antidepressants. Corticosteroid co-administration reduces the increase in forebrain 5-hydroxytryptamine with selective serotonin reuptake inhibitors, whereas antiglucocorticoids have the opposite effect. A Cochrane review suggesting that antiglucocorticoid augmentation of antidepressants may be effective in treating TRD included a pilot study of the cortisol synthesis inhibitor, metyrapone. The Antiglucocorticoid augmentation of antiDepressants in Depression (ADD Study) was a multicentre randomised placebo-controlled trial of metyrapone augmentation of serotonergic antidepressants in patients with TRD. Objective: To determine the efficacy and safety of augmentation of standard serotonergic antidepressants with metyrapone 500 mg twice a day for 3 weeks in patients with TRD. Methods: A total of 165 patients with moderate to severe TRD aged 18–65 years were randomised to metyrapone 500 mg twice daily or placebo for 3 weeks, in addition to ongoing serotonergic antidepressants. The primary outcome was improvement in Montgomery–Åsberg Depression Rating Scale (MADRS) score 5 weeks after randomisation estimated using analysis of covariance. Secondary outcomes included the degree of persistence of treatment effect for up to 6 months, and also safety and tolerability of metyrapone. ADD included substudies investigating the potential mechanism of action of metyrapone, and utilised a comparator group of healthy participants. Results: The estimated mean difference for each of our study outcomes between randomised groups, 5 weeks post randomisation (allowing for variation between centres and whether or not patients originate from primary or secondary care) was MADRS –0.51 [95% confidence interval (CI) –3.48 to 2.46]; Beck Depression Inventory (BDI) –2.65 (95% CI –6.41 to 1.10); Clinical Anxiety Scale 0.46 (95% CI –1.20 to 2.12); State–Trait Anxiety Inventory 1.2 (95% CI –0.6 to 3.0); European Quality of Life-5 Dimensions 0.015 (95% CI –0.069 to 0.099); EuroQol visual analogue scale 5.6 (95% CI –0.7 to 12.0); and Young Mania Rating Scale –0.04 (95% CI –0.52 to 0.45). The differences were not statistically significant and were small in relation to the change from baseline in both groups that was observed immediately after completion of therapy. Endocrinological data required for compliance assessment are not yet available. HPA function, similar in patients and control subjects, was not associated with differing clinical responses. Neuropsychological impairments were found, along with changes in brain structure and function, but no effect of metyrapone was seen on these measures. Discussion: The inclusion criteria led to the sample being broadly representative of patients with TRD, within the UK NHS, with high anxiety and BDI scores. Metyrapone augmentation of antidepressants is not efficacious for outpatients with TRD who are moderately depressed. There was no obvious benefit associated with the use of metyrapone, either on the primary outcome or over the period of follow-up, and this negative result extended to other secondary outcomes. Metyrapone was well tolerated. There were no serious adverse events attributable to it and adverse events were as common with the placebo. HPA axis function was not associated with differing clinical or neuropsychological outcomes. Conclusions: The results of the study suggest that although metyrapone augmentation was well tolerated, it is ineffective in the treatment of refractory depression. This finding is contrary to a previous proof of principle study in more acutely unwell patients. Future research should consider whether or not antiglucocorticoid treatments, such as metyrapone, should be targeted at patients with confirmed hypercortisolaemia. Trial registration: Current Controlled Trials ISRCTN45338259. Funding details: This study was funded by the National Institute for Health Research Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

The use of an implantable cardiac defibrillator has been advocated as the only effective treatment for the management of ventricular fibrillation (VF) in patients with Brugada Syndrome (BrS). However, this device is only useful for terminating VF. Intermittent and/or recalcitrant VF for which lifesaving cardioversion occurs is a problematic situation in this patient population. The immediate use of appropriate antiarrhythmics in the acute setting has proven to be lifesaving. Quinidine has been well established as an effective antiarrhythmic in BrS, while isoproterenol (ISP) has had some recognition as well. The addition of drug therapy to prevent the induction of these arrhythmias has been shown to reduce the morbidity and mortality associated with BrS. It was proven to be especially effective in the presence of early repolarization, evidenced by the reduction or normalization of the early repolarization pattern on ECG. Thus, for the prophylactic management and long term suppression of VF in BrS, further prospective studies should be performed to determine the effectiveness of quinidine and ISP in this patient population.

Effective antiretroviral (ARV) therapy depends on adequate drug exposure, yet methods to assess ARV exposure are limited. Concentrations of ARV in hair are the product of steady-state pharmacokinetics factors and longitudinal adherence. We investigated nevirapine (NVP) concentrations in hair as a predictor of treatment response in women receiving ARVs. In participants of the Women's Interagency HIV Study, who reported NVP use for >1 month from 2003-2008, NVP concentrations in hair were measured via liquid-chromatography-tandem mass-spectrometry. The outcome was virologic suppression (plasma HIV RNA below assay threshold) at the time of hair sampling and the primary predictor was nevirapine concentration categorized into quartiles. We controlled for age, race/ethnicity, pre-treatment HIV RNA, CD4 cell count, and self-reported adherence over the 6-month visit interval (categorized ≤ 74%, 75%-94% or ≥ 95%). We also assessed the relation of NVP concentration with changes in hepatic transaminase levels via multivariate random intercept logistic regression and linear regression analyses. 271 women contributed 1089 person-visits to the analysis (median 3 of semi-annual visits). Viral suppression was least frequent in concentration quartile 1 (86/178 (48.3%)) and increased in higher quartiles (to 158/204 (77.5%) for quartile 4). The odds of viral suppression in the highest concentration quartile were 9.17 times (95% CI 3.2-26, P < 0.0001) those in the lowest. African-American race was associated with lower rates of virologic suppression independent of NVP hair concentration. NVP concentration was not significantly associated with patterns of serum transaminases. Concentration of NVP in hair was a strong independent predictor of virologic suppression in women taking NVP, stronger than self-reported adherence, but did not appear to be strongly predictive of hepatotoxicity.

Mesenchymal stem cells (MSCs) are pleiotropic cells with potential therapeutic benefits for a wide range of diseases. Because of their immunomodulatory properties they have been utilized to treat autoimmune diseases such as multiple sclerosis (MS), which is characterized by demyelination. The microenvironment surrounding MSCs is thought to affect their differentiation and phenotype, which could in turn affect the efficacy. We thus sought to dissect the potential for differential impact of MSCs on central nervous system (CNS) disease in T cell mediated and non-T cell mediated settings using the MOG35-55 experimental autoimmune encephalomyelitis (EAE) and cuprizone-mediated demyelination models, respectively. As the pathogeneses of MS and EAE are thought to be mediated by IFNγ-producing (TH1) and IL-17A-producing (TH17) effector CD4+ T cells, we investigated the effect of MSCs on the development of these two key pathogenic cell groups. Although MSCs suppressed the activation and effector function of TH17 cells, they did not affect TH1 activation, but enhanced TH1 effector function and ultimately produced no effect on EAE. In the non- T cell mediated cuprizone model of demyelination, MSC administration had a positive effect, with an overall increase in myelin abundance in the brain of MSC-treated mice compared to controls. These results highlight the potential variability of MSCs as a biologic therapeutic tool in the treatment of autoimmune disease and the need for further investigation into the multifaceted functions of MSCs in diverse microenvironments and the mechanisms behind the diversity.

Multidrug-resistant Tuberculosis (MDR-TB) is a rising global threat to public health and concerted efforts for its treatment are diluted if the outcomes are not successful, loss to follow up (LFU) being one of them. It is therefore necessary to know the proportion and the associated reasons for LFU and devise effective patient-centered strategies to improve retention in care.A retrospective cohort study was conducted at the MDR-TB treatment site (DR-TB Site)in Central Gujarat among all patients registered from February 2010 to June 2013.LFU patients were defined as those whose treatment was interrupted for two or more consecutive months for any reason. Descriptive statistics, survival analysis and multivariate modeling were used to determine the proportion of patients LFU and to assess associations between LFU and selected demographic and clinical factors.A total of 796 patients were enrolled during the study period; 71.9% were male and the median age was 35 years [Interquartile range (IQR) 27-45].The overall proportion of LFU patients was 153/796 (19.2%).The majority of LFU patients (133/153 i.e.87%) were lost within the first 6 months of treatment. Ambulatory treatment initiation (adjusted Hazards ratio aHR=2.63, CI:1.01-6.86), different providers in IP and CP ( aHR=1.27, CI:1.18-1.38)and culture conversion after more than 4 months of treatment(aHR=1.34, CI: 1.21-1.49)were found to be significantly associated with LFU in multivariate models.A high proportion of LFU among patients on MDR-TB treatment was found in a programmatic setting in India. Clinical but equally important programmatic factors were associated with LFU, accounting for one-fifth of all the outcomes of MDR-TB treatment. Proper training for DOT providers and aggressive counseling and health system strengthening with patient friendly follow up services may help reduce LFU.

A morbidly obese, 45-year-old woman with a body mass index of 47 kg/m 2 , presented with a prolapsed intervertebral disc of the lumbar spine for decompression and fixation. Anesthesia and surgical positioning of morbidly obese patient carries 3 main hazards, namely, morbid obesity, prone position, and airway preservation problems. Morbid obesity has its own hazards of deep vein thrombosis and pulmonary embolus. Here we describe anesthetic management, successfully dealing with the specific problems of this patient due to obesity.

This is a report of anterior osteophytes on the cervical vertebra resulting in distortion of the airway and leading to difficulty during intubation. The osteophytes associated with the syndrome of diffuse idiopathic skeletal hyperostosis were at the C2-3 and C6-7, T1 level and resulted in anterior displacement of the pharynx and the trachea respectively.

We present here a case of vasa previa in a multipara, diagnosed at the time of her late second trimester ultrasonogram. The patient subsequently underwent an elective cesarean section after 37 weeks gestation, giving birth to a healthy child with an uneventful post-partum, neonatal and infant course. At the time of cesarean section, the incision was gradually deepened in layers through the myometrium by utmost care allowing the amniotic sac to protrude through the uterine incision hereby avoiding laceration of the vasa previa and its branches. Fetal exsanguination and a need for blood transfusion as well as a possible adverse neonatal course were therefore avoided.