Disulfide HMGB1 acts via TLR2/4 receptors to reduce the numbers of oligodendrocyte progenitor cells after traumatic injury in vitro.

Traumatic brain injury (TBI) is associated with poor clinical outcomes; autopsy studies of TBI victims demonstrate significant oligodendrocyte progenitor cell (OPC) death post TBI; an observation, which may explain the lack of meaningful repair of injured axons. Whilst high-mobility group box-1 (HMGB1) and its key receptors TLR2/4 are identified as key initiators of neuroinflammation post-TBI, they have been identified as attractive targets for development of novel therapeutic approaches to improve post-TBI clinical outcomes. In this report we establish unequivocal evidence that HMGB1 released in vitro impairs OPC response to mechanical injury; an effect that is pharmacologically reversible. We show that needle scratch injury hyper-acutely induced microglial HMGB1 nucleus-to-cytoplasm translocation and subsequent release into culture medium. Application of injury-conditioned media resulted in significant decreases in OPC number through anti-proliferative effects. This effect was reversed by co-treatment with the TLR2/4 receptor antagonist BoxA. Furthermore, whilst injury conditioned medium drove OPCs towards an activated reactive morphology, this was also abolished after BoxA co-treatment. We conclude that HMGB1, through TLR2/4 dependant mechanisms, may be detrimental to OPC proliferation following injury in vitro, negatively affecting the potential for restoring a mature oligodendrocyte population, and subsequent axonal remyelination. Further study is required to assess how HMGB1-TLR signalling influences OPC maturation and myelination capacity.

Patterns of hysterectomy in India: a national and state-level analysis of the Fourth National Family Health Survey (2015-2016).

OBJECTIVE: The National Family Health Survey-4 in India provided the first nationally representative estimates of hysterectomy among women aged 15-49. This paper aims to examine the national and state-level age-specific prevalence of hysterectomy, individual and household level factors associated with the procedure, and state-level indicators that may explain variation across states. DESIGN: Cross-sectional, nationally representative household survey. SETTING: National Family Health Survey was conducted across all Indian states and union territories between 2015 and 2016. POPULATION: The survey covered 699 686 women between the ages of 15 and 49 years. METHODS: Descriptive analyses and multivariate logistic regression. MAIN OUTCOME MEASURES: Women who reported ever having a hysterectomy and age at hysterectomy. RESULTS: Age-specific prevalence of hysterectomy was 0.36% (0.33,0.39) among women aged 15-29; 3.59% (3.45,3.74) among women aged 30-39; and 9.20% (8.94,9.46) among women 40-49 years. There was considerable variation in prevalence by state. Four states reported age-specific prevalence similar to high-income settings. Approximately two-thirds of hysterectomies were conducted in private facilities, with similar patterns across age groups. At the national level, higher age and parity (at least two children); not having had formal schooling; rural residence (adjusted odds ratio [AOR] 1.36; 95% CI 1.27,1.45; P < 0.01) and higher wealth status were associated with higher odds of hysterectomy. Previously sterilised women had lower odds (AOR 0.64; 95% CI 0.61,0,68; P < 0.01) of reporting hysterectomy. Exploratory analyses suggest state-level factors associated with prevalence of hysterectomy include caesarean section, female illiteracy, and women's employment. CONCLUSIONS: Hysterectomy patterns among women aged 15-49 in India indicate the critical need to ensure treatment options for gynaecological morbidity and to address hysterectomy among young women in particular. FUNDING: This study was part of the RASTA initiative of the Population Council's India country office under the Evidence Project supported by USAID. TWEETABLE ABSTRACT: Hysterectomy patterns in India highlight the need for alternatives to treat gynaecological morbidity among younger women.

One year failure rates for de-novo ventriculo-peritoneal shunts in under 3-month-old children.

Introduction: Ventriculo-peritoneal shunts (VPS) are still the mainstay treatment for hydrocephalus in children. It is generally accepted that VPS failure and infection rates are higher for neonates than for older children. We compared our 1-year failure and infection rates in under 3-month-old children compared with older children in our department. Results: We identified 58 children under 3 months of age who underwent VPS insertion between January 2007 and December 2016. They had a 29.3% (17) shunt failure rate over the first year. There were two confirmed shunt infections (3.4%). Discussion: The 1-year shunt failure rate at our institution for VPS insertion in children over 3 months is 26.1% and the infection rate is 4.3% (9). The literature suggests that the outcome for VPS in younger children is worse than for older children. Our work shows similar outcomes for all children compared to those under 3 months at time of VPS insertion alone. Conclusion: Children under 3-months-old undergoing VPS insertion should not automatically expect an increased 1-year failure or infection rate compared with older children. The reasons for this may be as a result of increased subspecialisation, the more widespread use of antibiotic-impregnated catheters and improved neonatal care.

How are gender inequalities facing India's one million ASHAs being addressed? Policy origins and adaptations for the world's largest all-female community health worker programme.

BACKGROUND: India's accredited social health activist (ASHA) programme consists of almost one million female community health workers (CHWs). Launched in 2005, there is now an ASHA in almost every village and across many urban centres who support health system linkages and provide basic health education and care. This paper examines how the programme is seeking to address gender inequalities facing ASHAs, from the programme's policy origins to recent adaptations. METHODS: We reviewed all publically available government documents (n = 96) as well as published academic literature (n = 122) on the ASHA programme. We also drew from the embedded knowledge of this paper's government-affiliated co-authors, triangulated with key informant interviews (n = 12). Data were analysed thematically through a gender lens. RESULTS: Given that the initial impetus for the ASHA programme was to address reproductive and child health issues, policymakers viewed volunteer female health workers embedded in communities as best positioned to engage with beneficiaries. From these instrumentalist origins, where the programme was designed to meet health system demands, policy evolved to consider how the health system could better support ASHAs. Policy reforms included an increase in the number and regularity of incentivized tasks, social security measures, and government scholarships for higher education. Residential trainings were initiated to build empowering knowledge and facilitate ASHA solidarity. ASHAs were designated as secretaries of their village health committees, encouraging them to move beyond an all-female sphere and increasing their role in accountability initiatives. Measures to address gender based violence were also recently recommended. Despite these well-intended reforms and the positive gains realized, ongoing tensions and challenges related to their gendered social and employment status remain, requiring continued policy attention and adaptation. CONCLUSIONS: Gender trade offs and complexities are inherent to sustaining CHW programmes at scale within challenging contexts of patriarchal norms, health system hierarchies, federal governance structures, and evolving aspirations, capacities, and demands from female CHWs. Although still grappling with significant gender inequalities, policy adaptations have increased ASHAs' access to income, knowledge, career progression, community leadership, and safety. Nonetheless, these transformative gains do not mark linear progress, but rather continued adaptations.

Pituitary xanthogranulomas: clinical features, radiological appearances and post-operative outcomes.

BACKGROUND: Xanthogranulomas are inflammatory masses most commonly found at peripheral sites such as the skin. Sellar and parasellar xanthogranulomas are rare and present a diagnostic challenge as they are difficult to differentiate from other sellar lesions such as craniopharyngiomas and Rathke's cleft cysts pre-operatively. Their radiological imaging features are yet to be clearly defined, and clinical outcomes after surgery are also uncertain. This study reviews clinical presentation, radiological appearances, and clinical outcomes in a cohort of patients with pituitary xanthogranulomas. METHODS: A prospectively maintained pituitary surgery database was screened for histologically confirmed pituitary xanthogranulomas between May 2011-December 2016. Retrospective case note assessments were then performed by three independent reviewers. Patient demographics, clinical presentations, imaging, and clinical outcomes were analysed. RESULTS: During the study period 295 endoscopic endonasal pituitary surgeries were performed. Six patients had confirmed pituitary xanthogranulomas (2%). Patients most commonly presented with visual field deficits and/or endocrine dysfunction. Common imaging features included: a cystic consistency, hyperintensity on T1-weighted MR images, and contrast enhancement either peripherally (n = 3) or homogenously (n = 3). The most common pre-operative endocrine deficits were hyperprolactinaemia and hypoadrenalism (at least one of which was identified in 4/6 patients; 66%). Thirty-three percent (2/6) of patients presented with diabetes insipidus. The most common post-operative endocrinological deficits were adrenocortical dysfunction (66%) and gonadotropin deficiency (66%). Visual assessments normalised in all six patients post-operatively. Gross total resection was achieved in all patients, and at median follow up of 33.5 months there were no cases of tumour recurrence. CONCLUSIONS: The prevalence of pituitary xanthogranulomas in our series is higher than that suggested in the literature. Surgery restored normal vision to all cases, however four patients (67%) required long-term hormonal replacement post-operatively. Imaging features such peripheral rim enhancement, a suprasellar tumour epicentre, and the absence of both calcification or cavernous sinus invasion were identified as potential indicators that together should alert clinicians to the possibility of pituitary xanthogranuloma when assessing patients with cystic sellar and parasellar tumours.

Chemical composition and antibacterial, antifungal, allelopathic and acetylcholinesterase inhibitory activities of cassumunar-ginger.

BACKGROUND: Zingiber montanum (J.Koenig) Link ex A.Dietr. (Zingiberaceae), commonly known as cassumunar-ginger, is a folk remedy for the treatment of inflammations, sprains, rheumatism and asthma. The aim of the present study was to assess the chemical composition, and antibacterial, antifungal, allelopathic and acetylcholinesterase inhibitory activities of the essential oil of Z. montanum originating from India. RESULTS: The hydrodistilled essential oil of Z. montanum rhizome was analyzed using gas chromatography-flame ionization detection and gas chromatography-mass spectrometry. A total of 49 constituents, forming 98.7-99.9% of the total oil compositions, was identified. The essential oil was characterized by higher amount of monoterpene hydrocarbons (32.6-43.5%), phenylbutanoids (27.5-41.2%) and oxygenated monoterpenes (11.4-34.1%). Major constituents of the oil were sabinene (13.5-38.0%), (E)-1-(3',4'-dimethoxyphenyl)buta-1,3-diene (DMPBD) (20.6-35.3%), terpinen-4-ol (9.0-31.3%), γ-terpinene (1.1-4.8%) and ß-phellandrene (1.0-4.4%). The oil was evaluated against eight pathogenic bacteria and two fungal strains. It exhibited low to good antibacterial activity (minimum inhibitory concentration: 125-500 µg mL-1 ) and moderate antifungal activity (250 µg mL-1 ) against the tested strains. The oil reduced germination (69.8%) and inhibited the root and shoot growth of lettuce significantly (LD50 : 3.58 µL plate-1 ). However, it did not demonstrate acetylcholinesterase inhibitory activity up to a concentration of 10 mg mL-1 . CONCLUSIONS: The essential oil of Z. montanum can be used as a potential source of DMPBD, terpinen-4-ol and sabinene for pharmaceutical products. The results of the present study add significant information to the pharmacological activity of Z. montanum native to India. © 2017 Society of Chemical Industry.

Chemical Composition and Allelopathic, Antibacterial, Antifungal, and Antiacetylcholinesterase Activity of Fish-mint (Houttuynia cordataThunb.) from India.

Fish-mint (Houttuynia cordataThunb.), belonging to family Saururaceae, has long been used as food and traditional herbal medicine. The present study was framed to assess the changes occurring in the essential-oil composition of H. cordata during annual growth and to evaluate allelopathic, antibacterial, antifungal, and antiacetylcholinesterase activities. The essential-oil content ranged from 0.06 - 0.14% and 0.08 - 0.16% in aerial parts and underground stem, respectively. The essential oils were analysed by GC-FID, GC/MS, and NMR (1 H and 13 C). Major constituents of aerial-parts oil was 2-undecanone (19.4 - 56.3%), myrcene (2.6 - 44.3%), ethyl decanoate (0.0 - 10.6%), ethyl dodecanoate (1.1 - 8.6%), 2-tridecanone (0.5 - 8.3%), and decanal (1.1 - 6.9%). However, major constituents of underground-stem oil were 2-undecanone (29.5 - 42.3%), myrcene (14.4 - 20.8%), sabinene (6.0 - 11.1%), 2-tridecanone (1.8 - 10.5%), ß-pinene (5.3 - 10.0%), and ethyl dodecanoate (0.8 - 7.3%). Cluster analysis revealed that essential-oil composition varied substantially due to the plant parts and season of collection. The oils exhibited significant allelopathic (inhibition: 77.8 - 88.8%; LD50 : 2.45 - 3.05 µl/plate), antibacterial (MIC: 0.52 - 2.08 µl/ml; MBC: bacteriostatic) and antifungal (MIC: 2.08 - 33.33 µl/ml; MFC: 4.16 - 33.33 µl/ml) activities. The results indicate that the essential oil from H. cordata has a significant potential to allow future exploration and exploitation as a natural antimicrobial and allelopathic agent.

Effect of PET before liver resection on surgical management for colorectal adenocarcinoma metastases: a randomized clinical trial.

IMPORTANCE: Patients with colorectal cancer with liver metastases undergo hepatic resection with curative intent. Positron emission tomography combined with computed tomography (PET-CT) could help avoid noncurative surgery by identifying patients with occult metastases. OBJECTIVES: To determine the effect of preoperative PET-CT vs no PET-CT (control) on the surgical management of patients with resectable metastases and to investigate the effect of PET-CT on survival and the association between the standardized uptake value (ratio of tissue radioactivity to injected radioactivity adjusted by weight) and survival. DESIGN, SETTING, AND PARTICIPANTS: A randomized trial of patients older than 18 years with colorectal cancer treated by surgery, with resectable metastases based on CT scans of the chest, abdomen, and pelvis within the previous 30 days, and with a clear colonoscopy within the previous 18 months was conducted between 2005 and 2013, involving 21 surgeons at 9 hospitals in Ontario, Canada, with PET-CT scanners at 5 academic institutions. INTERVENTIONS: Patients were randomized using a 2 to 1 ratio to PET-CT or control. MAIN OUTCOMES AND MEASURES: The primary outcome was a change in surgical management defined as canceled hepatic surgery, more extensive hepatic surgery, or additional organ surgery based on the PET-CT. Survival was a secondary outcome. RESULTS: Of the 263 patients who underwent PET-CT, 21 had a change in surgical management (8.0%; 95% CI, 5.0%-11.9%). Specifically, 7 patients (2.7%) did not undergo laparotomy, 4 (1.5%) had more extensive hepatic surgery, 9 (3.4%) had additional organ surgery (8 of whom had hepatic resection), and the abdominal cavity was opened in 1 patient but hepatic surgery was not performed and the cavity was closed. Liver resection was performed in 91% of patients in the PET-CT group and 92% of the control group. After a median follow-up of 36 months, the estimated mortality rate was 11.13 (95% CI, 8.95-13.68) events/1000 person-months for the PET-CT group and 12.71 (95% CI, 9.40-16.80) events/1000 person-months for the control group. Survival did not differ between the 2 groups (hazard ratio, 0.86 [95% CI, 0.60-1.21]; P = .38). The standardized uptake value was associated with survival (hazard ratio, 1.11 [90% CI, 1.07-1.15] per unit increase; P < .001). The C statistic for the model including the standardized uptake value was 0.62 (95% CI, 0.56-0.68) and without it was 0.50 (95% CI, 0.44-0.56). The difference in C statistics is 0.12 (95% CI, 0.04-0.21). The low C statistic suggests that the standard uptake value is not a strong predictor of overall survival. CONCLUSIONS AND RELEVANCE: Among patients with potentially resectable hepatic metastases of colorectal adenocarcinoma, the use of PET-CT compared with CT alone did not result in frequent change in surgical management. These findings raise questions about the value of PET-CT scans in this setting. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00265356.

The state of political priority for safe motherhood in India.

Approximately one-quarter of all maternal deaths occur in India, far more than in any other nation on earth. Until 2005, maternal mortality reduction was not a priority in the country. In that year, the cause emerged on the national political agenda in a meaningful way for the first time. An unpredictable confluence of events concerning problem definition, policy alternative generation and politics led to this outcome. By 2005, evidence had accumulated that maternal mortality in India was stagnating and that existing initiatives were not addressing the problem effectively. Also in that year, national government officials and donors came to a consensus on a strategy to address the problem. In addition, a new government with social equity aims came to power in 2004, and in 2005, it began a national initiative to expand healthcare access to the poor in rural areas. The convergence of these developments pushed the issue on to the national agenda. This paper draws on public policy theory to analyse the Indian experience and to develop guidance for safe motherhood policy communities in other high maternal mortality countries seeking to make this cause a political priority.

A prospective evaluation of positron emission tomography scanning, sentinel lymph node biopsy, and standard axillary dissection for axillary staging in patients with early stage breast cancer.

BACKGROUND: Positron emission tomography (PET) is a noninvasive imaging modality that can detect malignant lymph nodes. This study determined the sensitivity, specificity, predictive values, and likelihood ratios of PET scanning compared with standard axillary lymph node dissection (ALND) and sentinel lymph node biopsy (SLNB) in staging the axilla in women with early stage breast cancer. METHODS: Women with clinical stage I or II breast cancer had whole body PET scanning before ALND and SLNB, in a prospective, blinded protocol. ALND were evaluated by standard hematoxylin and eosin (H&E) staining techniques, while sentinel nodes were also examined for micrometastatic disease. RESULTS: A total of 98 patients were recruited. PET compared with ALND demonstrated sensitivity of 0.40 (95% CI, 0.16, 0.68), specificity 0.97 (CI, 0.90, 0.99), positive likelihood ratio 14.4 (CI, 3.21, 64.5), positive predictive value 0.75 (CI, 0.35, 0.97), and false-negative rate of 0.60 (CI, 0.32, 0.84). Test properties were similar for PET compared with sentinel nodes positive by H&E staining. A few false-positive scans (0.028, CI, 0.003, 0.097) were seen. Multiple logistic regression analysis found that PET accuracy was better in patients with high grade and larger tumors. Increased size and number of positive nodes were also associated with a positive PET scan. CONCLUSIONS: The sensitivity of PET compared with ALND and SLNB was low, whereas PET scanning had high specificity and positive predictive values. The study suggests that PET scanning cannot replace histologic staging in early stage breast cancer. The low rate of false-positive findings suggests that PET can identify women who can forego SLNB and require full axillary dissection.

The effects of repeated minimal electroconvulsive shock exposure on levels of mRNA encoding fibroblast growth factor-2 and nerve growth factor in limbic regions.

Chronic, but not acute, exposure to minimal electroconvulsive shock (ECS) has been shown to decrease vulnerability to neuronal cell death, without itself causing neuronal damage. One potential mechanism for the neuroprotective effect of ECS is the increase in fibroblast growth factor-2 (FGF-2) which occurs after chronic, but not acute, ECS exposure. This raises the possibility that repeated seizures over a period of several days may alter the transcriptional regulation of FGF-2. To test this hypothesis, the present study compared the effect of acute (1 day) vs. chronic (7 days) ECS treatment on levels of mRNA for FGF-2 in rhinal and frontal cortices, hippocampus, and olfactory bulbs. In addition, mRNA for another prominent neurotrophic factor, nerve growth factor (NGF), was assayed concurrently. At 8 h after acute ECS, mRNA levels increased by 60% for FGF-2 and 136% for NGF in rhinal cortex, 32% for FGF-2 and 36% for NGF in frontal cortex, and by 13% for NGF in hippocampus. After 7 days of ECS treatment the respective increases were 72% and 80%, 53% and 38%, and 28%. No increases were observed in olfactory bulbs after either treatment regimen. The peak increases in FGF-2 mRNA were consistently greater after chronic treatment, but the differences from those seen acutely reached significance in frontal cortex only. However, the duration over which mRNA for FGF-2 was elevated did not differ between the acute and chronic ECS groups. NGF mRNA induction was neither enhanced nor prolonged as a result of chronic ECS as compared to acute ECS treatment. These results suggest that chronic ECS treatment may lead to an enhanced rate of transcription of message for FGF-2 but not for NGF, in selected brain regions. At the same time, the results indicate that chronic ECS treatment induces FGF-2 and NGF mRNA expression in a tissue-specific manner and that this induction is maintained over the 7-day treatment period. The sustained increases in mRNAs for these trophic factors may contribute to the neuroprotective actions of chronic ECS treatment.