NOSH-aspirin (NBS-1120) inhibits estrogen receptor negative breast cancer in vitro and in vivo by modulating redox-sensitive signaling pathways.

Estrogen receptor (ER)-negative breast cancers are known to be aggressive and unresponsive to anti-estrogen therapy, and triple negative breast cancers are associated with poor prognosis and metastasis. Thus, new targeted therapies are needed. FOXM1 is abundantly expressed in human cancers and implicated in protecting tumor cells from oxidative stress by reducing the levels of intracellular reactive oxygen species (ROS). Aspirin, a prototypical anti-cancer agent with deleterious side effects, has been modified to release nitric oxide and hydrogen sulfide, called NOSH-aspirin (NOSH-ASA), generating a 'safer' class of new anti-inflammatory agents. We evaluated NOSH-ASA against (ER)-negative breast cancer using cell lines and a xenograft mouse model. NOSH-ASA strongly inhibited growth of MDA-MB-231 and SKBR3 breast cancer cells with low IC50s of 90{plus minus}5 and 82{plus minus}5 nM, respectively, with marginal effects on a normal breast epithelial cell line. NOSH-ASA inhibited cell proliferation, caused G0/G1 phase arrest, increased apoptosis, and was associated with increases in ROS. In MDA-MB-231 cell xenografts, NOSH-ASA reduced tumor size markedly, which was associated with reduced proliferation (decreased PCNA expression), induction of apoptosis (increased TUNEL positive cells), and increased ROS, while NF-kB and FoxM1 that were high in untreated xenografts were significantly reduced. mRNA data for FoxM1, p21 and CyclinD1 corroborated with the respective protein expressions and arrest of cells. Taken together, these molecular events contribute to NOSH-ASA mediated growth inhibition and apoptotic death of (ER)-negative breast cells in vitro and in vivo. Additionally, as a ROS-inducer and FOXM1-inhibitor, NOSH-ASA has potential as a targeted therapy. Significance Statement In this investigation, we examined the cellular effects and xenograft tumor inhibitory potential of NOSH-aspirin, an NO and H2S-donating hybrid, against ER-negative breast cancer, which currently lacks effective therapeutic options. The induction of reactive oxygen species and subsequent downregulation of FOXM1 represents a plausible mechanism contributing to the observed decrease in cell proliferation and concurrent increase in apoptosis. NOSH-ASA demonstrated a remarkable reduction in tumor size by 90% without inducing any observable gross toxicity, underscoring its promising translational potential.

Assessment of the Efficacy of TMJ Arthroscopy-Assisted Masseter Nerve Avulsion on Hemimasticatory Spasm: An Original Research.

The goal of this study is to find a cure for the masticatory muscle disease known as hemimasticatory spasm (HMS). This retrospective investigation intends to find a more efficient therapeutic approach for HMS patients by examining the clinical effectiveness of masseteric nerve avulsion performed on HMS using a temporomandibular arthroscope. A clinical study was piloted where the subjects were treated for masseter nerve avulsion by TMJ arthroscopy. The follow-up was done till 2 years, and the subjects were evaluated for the various characteristics like difficulties, masticatory abilities, and various sounds at the joint for the various functions of the joint. The diagnosis was done using the electrophysiological electromyogram (EMG) at the designated time intervals. There was a complete remission in all the subjects. The masseter nerve avulsion was effective since the scores lowered. Within 3 years of the operation, electrophysiological EMG depicted no discharge potential with a high frequency, and the total efficiency when paired with the clinical effectiveness was deemed acceptable. The maximal masseter power between the treated and nontreated sides was comparable. The mastication, on comparing, was also as effective as the normal side; however, lower mastication was noted in the first year. The avulsed nerve tissues lacked any apparent demyelination. Masseteric nerve avulsion with temporomandibular arthroscope assistance provided acceptable and stable total effectiveness for the intervention of the hemimasticatory spasm. While the strength of the muscle of the afflicted side was only marginally reduced, its masticatory effectiveness was optimally preserved.

Assessment of Pain Management After Orthognathic Surgery by the Administration of Montelukast: An Original Research.

Introduction: Opioid may cause undue risk after surgical procedures like orthognathic surgeries. The present study was aimed to determine how the preoperative administration of oral montelukast affected the degree of postoperative discomfort following bimaxillary orthognathic surgery (BOS). Methodology: This study included all skeletal class III subjects scheduled for BOS. The participants were split into placebo and montelukast groups at random. Every patient received a 10-mL serving of apple juice an hour prior to the surgery; however, for the intervention group, a montelukast 10 mg pill was dissolved in the juice. The same surgical team and general anesthetic guidelines were used for all procedures. The visual analog scale (VAS) was used to calculate postoperative pain at designated intervals. The significance level for the statistical analysis was determined using the Statistical Package for the Social Sciences (SPSS) version 23. Results: The control subjects had a higher level of pain at all the intervals than the intended drug test group. Also, the control group needed more analgesics than the test group. There was one observation made that the length of the surgery had an impact on the postoperative pain. Conclusion: Preoperative montelukast medication may be useful in minimizing postoperative discomfort following bimaxillary orthognathic surgery. More research is required for greater relevance.

Knowledge of Pelvic Floor Dysfunction in African American and Afro-Caribbean Women Seeking Medical Care in a Primary Care Ambulatory Setting.

IMPORTANCE: Approximately one fourth of U.S. community-dwelling women will develop a pelvic floor dysfunction (PFD) within their lifetimes. Prior research has revealed that knowledge of PFD was low to moderate in the general population and lower among Black patients. OBJECTIVE: This study aimed to assess the proficiency of urinary incontinence and pelvic organ prolapse (POP) in self-identified African American and Afro-Caribbean adult (age ≥ 18 years) female patients seeking medical care in our ambulatory setting. STUDY DESIGN: In this cross-sectional study, we administered the Prolapse and Incontinence Knowledge Questionnaire to patients in primary care and gynecology ambulatory settings at an academic medical center in Central Brooklyn. We used a multivariable Poisson regression model to find characteristics of the participants that are associated with proficiency in Prolapse and Incontinence Knowledge Questionnaire domains. RESULTS: A total of 266 survey participants self-identified as African American or Afro-Caribbean. Overall, using a multivariable model, knowledge of POP was significantly higher among African Americans than Afro-Caribbeans, and 75.5% of our patients reported that they would seek information on urinary incontinence and POP from a medical provider (gynecologist or primary care doctor) compared with other alternatives (eg, internet, 19.6%). CONCLUSIONS: These findings highlight subgroups that could benefit from provider-initiated education regarding PFD. Furthermore, although Black patients are often homogenized in research studies, differences may exist within subgroups likely because of varying interplays of structural racism and other social determinants of health, which may serve as an area of future research.

Barriers to Urogynecologic Care for Racial and Ethnic Minority Women: A Qualitative Systematic Review.

IMPORTANCE: Studies have sought to evaluate factors that have perpetuated disparities in health care, including urogynecologic care. However, there remains a lack of understanding of barriers to care specific to racial/ethnic minority populations. OBJECTIVES: We aimed to report identified barriers to urogynecologic care (eg, care for symptoms/diagnoses of urinary incontinence [UI], accidental bowel leakage [ABL], and pelvic organ prolapse [POP]) for underrepresented racial and ethnic minority (URM) women in the United States. STUDY DESIGN: We conducted a systematic search for studies through 5 electronic bibliographic databases. Inclusion criteria for eligible studies included the following: (1) studies reporting barriers to care for those with urogynecologic symptoms/diagnoses, (2) publication date year 2000 or later. Exclusion criteria included study cohorts with children, exclusively non-U.S. populations, cohorts without URM participants, and studies without qualitative research methodology. Study methodology, characteristics, as well as barriers and facilitators to urogynecologic care were captured using a thematic synthesis approach. RESULTS: There were 360 studies identified. Twelve studies met criteria: 6 had study populations with UI, 3 with POP, 2 on UI and/or POP, and 1 on ABL. There were 7 focus group studies (total 44 groups, n = 330), 4 interview studies (total 160 interviews, n = 160), and 1 had both (10 interviews, 6 groups, n = 39). Most studies reported on patient-associated barriers (n = 10/12) and physician/provider-associated barriers (n = 10/12), whereas only half reported system-associated barriers (n = 6/12). CONCLUSION: Identified barriers to urogynecologic care for URM populations were examined. Findings likely do not fully reflect barriers to urogynecologic care for URM populations. Comprehensive evaluation of social determinants of health and systemic racism within studies is needed to understand the unique barriers present for racially/ethnically diverse populations.

Prevalence of eczema among older persons: A population-based cross-sectional study.

Background There are very few population-based studies on the prevalence of eczema among older persons Aims To estimate the prevalence and types of eczema in those aged 65 years or more in the community and to evaluate the effectiveness of community-based interventions for case finding. Methods In the first stage of this cross-sectional survey, trained health workers of a non-governmental organization surveyed the eligible population and identified persons likely to have eczema. In the second stage, dermatologists examined such persons to ascertain the diagnosis. Statistical analysis was done using Epi Info software version 7. Prevalence of eczema was expressed in percentages. Chi-square test was used for comparing the difference in prevalence of eczema in various age groups and sex. Results Health workers identified 98 persons as possible cases of eczema after interviewing 385 older persons in the community. Among them 95 persons were examined by dermatologists and 44 were confirmed to have eczema (diagnostic accuracy of health workers = 46.3%).Point prevalence of eczema was 11.4% (44/385). Prevalence was similar in males and females. It was greater (18.2 %) among persons aged 81 years or more. Asteatotic eczema, gravitational eczema and lichen simplex chronicus were the more common types of eczema. Limitations: Possible underestimation of the prevalence rates due to limited medical knowledge of health workers; limited facilities for examination and investigations at the medical camps and home visits. Conclusion There appears to be a considerable burden of eczema among older persons in the community. A community-based approach involving non-governmental organizations has the potential to identify cases and offer care close to their homes.

Dermatitis Artefacta Presenting with Localized Alopecia of Right Eyebrow and Scalp.

Dermatitis artefacta (DA) and trichotemnomania are self-inflicted dermatoses often preceded by psychosocial stressful events. A 38-year-old female presented with sudden loss of hair in the right frontal area along with discoloration and edema of skin. On examination, there was complete loss of hair involving the right frontal area and the lateral half of right eyebrow with skin over that area appearing scalded, edematous, bruised, and discolored. After a detailed medical and psychological evaluation, a clinical diagnosis of DA with trichotemnomania was made. A tactful multidisciplinary approach is essential in managing such patients as outright referral to a psychiatrist could be counterproductive.

Systematic assessment of the various controversies, difficulties, and current trends in the reestablishment of lost occlusal planes in edentulous patients.

Accurate occlusal plane orientation is an essential factor in the fabrication of complete denture prosthesis. Over the years, it has received a number of methodologies by several researchers utilizing various anatomical landmarks however none of them is considered as perfect that could orient ideal occlusal plane. The presented literature review is an attempt to enlighten historical perspectives, pioneer researches, different controversies, difficulties and current trends for re-establishment of lost occlusal plane in edentulous patients. An extensive literature search was performed using Medline/PubMed interface and other scholarly research bibliographic databases using Medical Subject Headings. Studies describing research studies, case series and assorted clinical reports were retrieved and evaluated from 1963 to 2013. Most of the studies have suggest and evidence to consider Camper's plane for artificial orientation of occlusal plane however there is a substantial lack of genuine long term studies and authentic data that could recommend a single reliable landmark for perfect occlusal plane reorientation in a variety of cases.

Methicillin-resistant Staphylococcus aureus colonization and disease severity in atopic dermatitis: a cross-sectional study from South India.

BACKGROUND: Colonization by methicillin-resistant Staphylococcus aureus (MRSA) in atopic dermatitis is little studied but has therapeutic implications. It may have a role in disease severity given the additional virulence factors associated. AIMS: Our aims were to record the proportion of patients with MRSA colonization in atopic dermatitis and to ascertain if any association exists between MRSA colonization and disease severity. METHODS: An observational cross-sectional study involving children aged≤12 years with atopic dermatitis attending the outpatient department of Government Medical College, Kottayam was conducted. Socio-demographic data, exacerbating factors and risk factors for hospital care-associated MRSA were documented. Extent of atopic dermatitis was recorded using a standardized scale (Eczema Area Severity Index, EASI). Skin swabs were taken from anterior nares and the worst affected atopic dermatitis sites for culture and sensitivity. RESULTS: Of the 119 subjects recruited during the study period (November 2009-April 2011), Staphylococcus aureus was isolated from 110 (92.4%) patients and MRSA from 30 (25.21%) patients. A total of 18 patients with MRSA had risk factors for healthcare associated-MRSA. The patients whose cultures grew MRSA were found to have significantly higher EASI score when compared to those patients colonized with methicillin sensitive Staphylococcus aureus (P < 0.01). Presence of Staphylococcus aureus, early age of onset, presence of food allergies, seasonal exacerbation and inadequate breastfeeding did not seem to influence disease severity. CONCLUSIONS: There is a high degree of prevalence of MRSA (25.2%) in atopic dermatitis and presence of MRSA is associated with increased disease severity. Further studies are needed to validate these findings.

The C-terminal domain (CTD) in linker histones antagonizes anti-apoptotic proteins to modulate apoptotic outcomes at the mitochondrion.

The loss of mitochondrial integrity as a consequence of apoptogenic complexes formed on the outer membrane constitutes a key step in controlling progression of apoptotic cascades. Here, we show that multiple members of the linker histone (LH) family of proteins modify apoptotic cascades initiated by the Bcl-2 protein Bak, and impart resistance to its endogenous antagonist Bcl-xL. Our experiments reveal apoptogenic capabilities equivalent to those documented for H1.2 in H1.1 and H1.3 isoforms. Deletion mutants of H1.2 and site-directed mutagenesis of H1.1 and H1.2 implicated the C-terminal domain in apoptogenic activity. In this context, disruption of protein kinase-C activity using chemical inhibitors, dominant-negative approaches and RNA interference coupled with site-directed modifications in H1.1, identified the protein kinase-Cß1 isoform as a repressor of H1.1/H1.3 apoptogenic activity. Finally, a H1.2 C-terminal tail recombinant attenuated Bcl-xl inhibition of Bak-induced apoptosis, suggesting that the C-terminal domain was necessary and sufficient for apoptogenic functions. Thus, integration with apoptotic intermediates (via C-terminal tail interactions) may constitute a more generalized function of LH isoforms in apoptotic cascades.

Genome-wide association study on detailed profiles of smoking behavior and nicotine dependence in a twin sample.

Smoking is a major risk factor for several somatic diseases and is also emerging as a causal factor for neuropsychiatric disorders. Genome-wide association (GWA) and candidate gene studies for smoking behavior and nicotine dependence (ND) have disclosed too few predisposing variants to account for the high estimated heritability. Previous large-scale GWA studies have had very limited phenotypic definitions of relevance to smoking-related behavior, which has likely impeded the discovery of genetic effects. We performed GWA analyses on 1114 adult twins ascertained for ever smoking from the population-based Finnish Twin Cohort study. The availability of 17 smoking-related phenotypes allowed us to comprehensively portray the dimensions of smoking behavior, clustered into the domains of smoking initiation, amount smoked and ND. Our results highlight a locus on 16p12.3, with several single-nucleotide polymorphisms (SNPs) in the vicinity of CLEC19A showing association (P<1 × 10(-6)) with smoking quantity. Interestingly, CLEC19A is located close to a previously reported attention-deficit hyperactivity disorder (ADHD) linkage locus and an evident link between ADHD and smoking has been established. Intriguing preliminary association (P<1 × 10(-5)) was detected between DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, 4th edition) ND diagnosis and several SNPs in ERBB4, coding for a Neuregulin receptor, on 2q33. The association between ERBB4 and DSM-IV ND diagnosis was replicated in an independent Australian sample. Recently, a significant increase in ErbB4 and Neuregulin 3 (Nrg3) expression was revealed following chronic nicotine exposure and withdrawal in mice and an association between NRG3 SNPs and smoking cessation success was detected in a clinical trial. ERBB4 has previously been associated with schizophrenia; further, it is located within an established schizophrenia linkage locus and within a linkage locus for a smoker phenotype identified in this sample. In conclusion, we disclose novel tentative evidence for the involvement of ERBB4 in ND, suggesting the involvement of the Neuregulin/ErbB signalling pathway in addictions and providing a plausible link between the high co-morbidity of schizophrenia and ND.

Comparative clinical dosimetry with X-knife and gamma knife.

X-knife and gamma knife techniques are well-established for cranial stereotactic radiosurgery (SRS). Due to differences in their radiation delivery methods, some of the dosimetric parameters of these two techniques differ which may have clinical significance. There are many dosimetric studies comparing linear accelerator based techniques such as X-knife with gamma knife but generally from different institutions. We carried out a retrospective comparative study of the dosimetric parameters of the SRS treatments performed at our centre with X-knife (circular cones) and gamma knife. Our results indicate that the dose conformity and dose fall-off in the vicinity of the target volumes were better for patients treated with gamma knife as compared to X-knife. However, the dose fall-off pattern shows a reversal at a larger distance from the target. It was better for the X-knife as compared to gamma knife in the low dose region.

Simplified minimally invasive parathyroidectomy: a series of 100 cases and review of the literature.

INTRODUCTION: Conventional practice of parathyroidectomy has been collar incision with bilateral neck exploration and a four-gland evaluation. Our local practice involves simplified parathyroidectomy via mini-incision without routine use of intraoperative adjuncts. The aim of this study is to demonstrate that a good success rate can be achieved, which will hopefully encourage more to undertake minimally invasive parathyroid surgery. MATERIALS AND METHODS: A prospective case series of the first 100 patients undergoing minimally invasive parathyroidectomy (MIP) by a single surgeon at a single institution were included. Preoperatively, patients underwent ultrasonography (US) and/or a sestamibi (MIBI) scan for localisation. Parathyroidectomy was performed following an algorithm of intraoperative decisions. Serum calcium and/or parathyroid hormone levels were checked at follow-up. Postoperative normocalcaemia was considered success independent of serum parathyroid hormone levels RESULTS: The patients had a median age of 63 years. Of the 100 patients, 83 were female and 17 male. Seven patients had a conversion to bilateral exploration. The mean operative time for unilateral and bilateral exploration was 42.38 minutes and 76.43 minutes respectively. Separately, a MIBI scan and US lateralised the side of the lesion in 82.8% and 79.5% of cases respectively. When US and the MIBI scan agreed, the predictive accuracy of the side of the lesion was 87.5%. The majority of patients (96%) had a successful return to normocalcaemia. No complications were encountered. CONCLUSIONS: Excellent results are achievable with simplified MIP even without intraoperative adjuncts. Preoperative localisation is helpful in determining the side of incision. Our technique demonstrates a key principle of surgery: to keep things simple.

A hierarchical cascade activated by non-canonical Notch signaling and the mTOR-Rictor complex regulates neglect-induced death in mammalian cells.

The regulation of cellular metabolism and survival by trophic factors is not completely understood. Here, we describe a signaling cascade activated by the developmental regulator Notch, which inhibits apoptosis triggered by neglect in mammalian cells. In this pathway, the Notch intracellular domain (NIC), which is released after interaction with ligand, converges on the kinase mammalian target of rapamycin (mTOR) and the substrate-defining protein rapamycin independent companion of mTOR (Rictor), culminating in the activation of the kinase Akt/PKB. Biochemical and molecular approaches using site-directed mutants identified AktS473 as a key downstream target in the antiapoptotic pathway activated by NIC. Despite the demonstrated requirement for Notch processing and its predominant nuclear localization, NIC function was independent of CBF1/RBP-J, an essential DNA-binding component required for canonical signaling. In experiments that placed spatial constraints on NIC, enforced nuclear retention abrogated antiapoptotic activity and a membrane-anchored form of NIC-blocked apoptosis through mTOR, Rictor and Akt-dependent signaling. We show that the NIC-mTORC2-Akt cascade blocks the apoptotic response triggered by removal of medium or serum deprivation. Consistently, membrane-tethered NIC, and AktS473 inhibited apoptosis triggered by cytokine deprivation in activated T cells. Thus, this study identifies a non-canonical signaling cascade wherein NIC integrates with multiple pathways to regulate cell survival.

Prevalence and associations of hepatitis C viremia in hemodialysis patients at a tertiary care hospital.

Hepatitis C virus (HCV) infection in hemodialysis (HD) is a significant problem. We evaluated the prevalence and associations of HCV viremia in our HD patients. All patients undergoing maintenance HD at our center were tested for HCV RNA by PCR after written informed consent. Detailed history regarding age, sex, and duration of dialysis, frequency of dialysis, blood transfusions in one year, number of dialysis centers, dialyzer reuse/fresh use, and recent laboratory data was recorded. A total of 119 patients (77 males and 42 females) were tested for HCV RNA. Thirty three (27.7%) tested positive. Duration of dialysis was significantly longer in HCV RNA positive group (P = 0.001). 45.2% of patients with duration of dialysis more than 16 months were HCV RNA positive while only 7.4% of patients with dialysis duration

Reactive oxygen species regulate quiescent T-cell apoptosis via the BH3-only proapoptotic protein BIM.

The survival of quiescent T cells in the peripheral immune system is dependent on signals transmitted from the extracellular environment. The requirement for survival factors is also manifested in vitro, providing a robust system to examine molecular mechanisms underlying T-cell death. We show that peripheral T cells cultured in the absence of survival factors accumulate reactive oxygen species (ROS), upregulate BIM (Bcl-2-interacting mediator of death) and inducible nitric oxide synthase (iNOS) expression, culminating in Fas-independent neglect-induced death (NID). We have examined ROS, iNOS and cytokine modulation of T-cell NID. Antioxidants inhibit BIM induction, caspase activation and apoptosis but do not promote cell cycle entry. iNOS-deficient T cells are protected from apoptosis, implicating iNOS in the regulation of NID via suppression of Bcl-x(L) expression and consequent inhibition of BIM activity. Finally, we show that the prosurvival cytokine IL-7 elevates Bcl-x(L) expression and transcriptionally regulates iNOS but not BIM expression in T cells.

Open labeled, randomized, switch-over study of two fixed doses (10/15mg) of aripiprazole : to evaluate its safety and efficacy in the treatment of Indian patients of schizophrenia.

Aripiprazole is a new anti psychotic with a unique receptor binding profile that combines partial agonistic activity at D2 receptor and 5-HT 1A receptor and potent antagonism at 5-HT 2A receptor. This receptor profile makes it possible for it to act as a dopamine system stabilizer. Based on various short term and long term studies, aripiprazole has been found to be effective in schizophrenia and has no significant adverse effect on QTc prolongation, prolactin, serum lipids, and has a low potential for weight gain. Present study aims to evaluate the efficacy and tolerability of aripiprazole (10-15mg/day) in the treatment of Indian patients of schizophrenia and to see its effect on QTc interval, prolactin levels, serum lipids, plasma sugar and weight gain in these patients. Outpatients with an ongoing/newly diagnosed ICD-10 Schizophrenia (n=136) were randomly assigned to 10 or 15 mg dose of Aripiprazole for a period of six weeks. Clinical response was evaluated by the Positive And Negative Symptoms Scale (PANSS), Clinical Global Impression (CGI) scale and safety was evaluated by observing spontaneously reported adverse events and changes in various laboratory parameters. Switching schizophrenic patients to aripiprazole (10/15 mg) from both conventional and atypical anti-psychotics was safe and well tolerated. Six weeks after switching to aripiprazole, patients showed improvements in PANSS scores (P< 0.001), EPS, prolactin levels and weight over the baseline levels. No difference was seen in the 10 or 15mg dose groups. One hospitalization was reported (due to hepatitis E). Common side effects reported were insomnia, somnolence, nausea, vomiting and diarrhea. Aripiprazole is a safe and effective anti psychotic in Indian patients - both in newly diagnosed, as well as, in patients not responding to or intolerant to other available typical and atypical antipsychotics.

VDAC is a conserved element of death pathways in plant and animal systems.

Programmed cell death (PCD) is very much a part of plant life, although the underlying mechanisms are not so well understood as in animals. In animal cells, the voltage-dependent anion channel (VDAC), a major mitochondrial outer membrane transporter, plays an important role in apoptosis by participating in the release of intermembrane space proteins. To characterize plant PCD pathways by investigating the function of putative components in a mammalian apoptotic context, we have overexpressed a rice VDAC (osVDAC4) in the Jurkat T-cell line. Overexpression of osVDAC4 induces apoptosis, which can be blocked by Bcl-2 and the VDAC inhibitor DIDS. Modifying endogenous VDAC function by DIDS and hexokinase II (HxKII) in Jurkat cells inhibits mitochondria-mediated apoptotic pathways. Finally, we show that DIDS also abrogates heat-induced PCD in cucumber cotyledons. Our data suggest that VDAC is a conserved mitochondrial element of the death machinery in both plant and animal cells.