Phase 2A Learnings Incorporated into RewinD-LB, a Phase 2B Clinical Trial of Neflamapimod in Dementia with Lewy Bodies.

BACKGROUND: In an exploratory 91-participant phase 2a clinical trial (AscenD-LB, NCT04001517) in dementia with Lewy bodies (DLB), neflamapimod showed improvement over placebo on multiple clinical endpoints. To confirm those results, a phase 2b clinical study (RewinD-LB, NCT05869669 ) that is similar to AscenD-LB has been initiated. OBJECTIVES: To optimize the choice of patient population, primary endpoint, and biomarker evaluations in RewinD-LB. DESIGN: Evaluation of the efficacy results from AscenD-LB, the main results of which, and a re-analysis after stratification for absence or presence of AD co-pathology (assessed by plasma ptau181), have been published. In addition, the MRI data from a prior phase 2a clinical trial in Early Alzheimer's disease (AD), were reviewed. SETTING: 22 clinical sites in the US and 2 in the Netherlands. PARTICIPANTS: Probable DLB by consensus criteria and abnormal dopamine uptake by DaTscan™ (Ioflupane I123 SPECT). INTERVENTION: Neflamapimod 40mg capsules or matching placebo capsules, twice-a-day (BID) or three-times-a-day (TID), for 16 weeks. MEASUREMENTS: 6-test Neuropsychological Test Battery (NTB) assessing attention and executive function, Clinical Dementia Rating Sum-of-Boxes (CDR-SB), Timed Up and Go (TUG), International Shopping List Test (ISLT). RESULTS: Within AscenD-LB, patients without evidence of AD co-pathology exhibited a neflamapimod treatment effect that was greater than that in the overall population and substantial (cohen's d effect size vs. placebo ≥ for CDR-SB, TUG, Attention and ISLT-recognition). In addition, the CDR-SB and TUG performed better than the cognitive tests to demonstrate neflamapimod treatment effect in comparison to placebo. Further, clinical trial simulations indicate with 160-patients (randomized 1:1), RewinD-LB conducted in patients without AD co-pathology has >95% (approaching 100%) statistical power to detect significant improvement over placebo on the CDR-SB. Preliminary evidence of positive treatment effects on beta functional connectivity by EEG and basal forebrain atrophy by MRI were obtained in AscenD-LB and the Early AD study, respectively. CONCLUSION: In addition to use of a single dose regimen of neflamapimod (40mg TID), key distinctions between phase 2b and phase 2a include RewinD-LB (1) excluding patients with AD co-pathology, (2) having CDR-SB as the primary endpoint, and (3) having MRI studies to evaluate effects on basal forebrain atrophy.

Abdominal wall reconstruction (AWR) for post-trauma laparotomy ventral hernia and follow-up assessment of functional quality of life (QOL): experience of a level-1 trauma centre in India.

PURPOSE: The aim of this study was to examine the postoperative outcomes and follow-up QOL of patients after AWR at a level-1 trauma centre in India. METHODS: The study cohort included AWR patients treated between January 2011 and July 2022. The Activities Assessment Scale (AAS) was used to measure QOL, and the Ventral Hernia Recurrence Inventory (VHRI) was used to determine the occurrence of recurrence. In patients suspected of having recurrence, thorough clinical examination and relevant imaging were performed to confirm or rule out recurrence. RESULTS: Out of 89 patients, 35 patients whose complete perioperative and follow-up data were available were enrolled. The mean age of the patients was 28 (SD, 9) years. The mean defect size was 14. 9 (SD, 7) cm. The mean time from laparotomy to AWR surgery was 21 months. During the postoperative course, 37% of patients developed complications, such as SSI and seroma. The mean follow-up time was 53 (SD, 43) months. Upon comparing procedures involving the mesh placed in the sublay position with procedures involving the mesh placed in other positions, no statistically significant difference in the recurrence rate (one in each group, p = 0.99), surgical complication rate (33% v/s 66%, p = 0.6), or mean AAS QOL score (94.7 v/s 98, p = 0.4) was observed. The specificity of the VHRI for diagnosing recurrence was 79%. CONCLUSION: Overall, the recurrence rate was low in these patients despite the presence of large hernia defects. Long-term QOL was not affected by the specific procedure used. Timely planning and execution are more important than the specific repair approach for post-trauma laparotomy ventral hernia.

Combination Therapy for Alzheimer's Disease: Perspectives of the EU/US CTAD Task Force.

Combination therapy is expected to play an important role for the treatment of Alzheimer's disease (AD). In October 2018, the European Union-North American Clinical Trials in Alzheimer's Disease Task Force (EU/US CTAD Task Force) met to discuss scientific, regulatory, and logistical challenges to the development of combination therapy for AD and current efforts to address these challenges. Task Force members unanimously agreed that successful treatment of AD will likely require combination therapy approaches that target multiple mechanisms and pathways. They further agreed on the need for global collaboration and sharing of data and resources to accelerate development of such approaches.

Physical Properties and Theoretical Study of NixCo3-xO4 (0 ≤ x ≤ 1.5) Nanostructures as High-Performance Electrode Materials for Supercapacitors.

Study evaluates the electrochemical performance of off-stoichiometric NixCo3-xO4 compounds. The off-stoichiometric samples were prepared via hydrothermal technique by systematically varying Co/Ni molar ratio. Physical and electrochemical properties of NixCo3-xO4 were observed to be stoichiometry dependent. The increase in Ni/Co ratio in NixCo3-xO4 leads to the morphological transformation from fibrous bundles to urchin like nanospheres with a concomitant increase in the surface area reaching up to 132 m2/g. The optimal specific capacitance of 225 F/g at a current density of 1 A/g and 524 F/g at 10 mV/s scan rate was observed of x 1.0 sample, with an increased retention capacity ∼120% measured at 2 A/g current density. The hybrid density functional theory (DFT) calculations of the electronic density of states identified Ni1.0Co2O4 with optimal band-gap of 2.38 eV with an expectation of displaying higher electrocapacitive performance. Experimentally, Ni0.92Co2.08O4 displayed superior electrocapacitive performance among all Ni/Co ratio in NixCo3-xO4. The DFT study also predicted Ni preference to the octahedral site, which is in-line with the observed increase in ferromagnetic nature, decreased lattice parameter, and increased structural disorder with increasing Ni/Co ratio. The improved electrochemical performance of NixCo3-xO4 (x > 0) is attributed to the mesoporous hierarchical structure, with a high electroactive surface which can effectively improve structural stability, and reduce the ionic and electron diffusion length. Compared to the pure Co3O4, the reduction of Co content in NixCo3-xO4 is desired due to the high cost and toxicity of Co element.

Predicting Neonatal Hyperbilirubinemia Using First Day Serum Bilirubin Level in Late Preterm and Term Healthy Newborn.

Hyperbilirubinemia is a common problem during the neonatal period and is the most common reason for readmission after early hospital discharge of the healthy near term and term infants. This early discharge policy along with limited follow-up facilities in developing countries and inadequate communication between physicians and parents necessitates a prognostic test to predict hyperbilirubinemia in these newborns; for early and effective management and prevention of potential complication before it occurred. This observational analytical study was done to determine the predictability of day1 total serum bilirubin (TSB) level as a screening test and identify the best cutoff value which would predict neonates likely to develop significant hyperbilirubinemia. The study was carried out in the Department of Neonatology and Department of Gynecology and Obstetrics, Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, Bangladesh from 1st April 2013 to 31st March 2014. A TSB level of ≥17mg/dl after 72 hours was defined as significant hyperbilirubinemia. By purposive sampling method, 100 healthy late preterm and term neonates fulfilling the inclusion criteria were enrolled and 89 were finally analyzed. Among 89 neonates 14(15.74%) developed significant hyperbilirubinemia (Group II) and 75(84.26%) did not develop hyperbilirubinemia (Group I). Mean time of sample collection was similar in both groups. Mean TSB level on day1 was significantly higher in Group II (5.97±1.74mg/dl) than Group I (3.19±1.4mg/dl). By using ROC (Receiver Operating Characteristic) analysis, TSB level of 5.65mg/dl on day 1 has the best combination of sensitivity (86%) and specificity (91%) to predict neonates at risk of significant hyperbilirubinemia (AUC-0.880, p=0.001). At this cut-off PPV was 63% and NPV 97%. Total serum bilirubin level on first day of life predicts neonates at risk of subsequent significant hyperbilirubinemia and late preterm and term babies with TSB level of ≥5.65mg/dl on day 1 of life should be followed up strictly either in the hospital or in the outpatient department on day 5.

Neflamapimod: Clinical Phase 2b-Ready Oral Small Molecule Inhibitor of p38α to Reverse Synaptic Dysfunction in Early Alzheimer's Disease.

Neflamapimod (previously code named VX-745) is a clinical phase 2b-ready highly specific inhibitor of the intra-cellular enzyme p38 mitogen activated protein kinase alpha ("p38α") that is being developed as a disease-modifying drug for Alzheimer's disease (AD) that acts via targeting synaptic dysfunction. Neflamapimod was discovered through a proprietary structure-based drug discovery platform at Vertex Pharmaceuticals, and developed previously by Vertex through to phase 2a in rheumatoid arthritis. EIP Pharma licensed the compound in 2014 for development and commercialization as a treatment of central nervous system (CNS) disorders. Neflamapimod is the most advanced in the clinic drug that targets specific molecular mechanisms within neurons that leads to synaptic dysfunction, the pathogenic process that is now considered to be a major driver of the development of memory deficits and disease progression in the early stages of AD. Based on the scientific rationale of targeting synaptic dysfunction and the preclinical data, neflamapimod has the potential to both reverse memory deficits and slow disease progression. Phase 2a clinical data in patients with early-stage AD (MMSE 20-28, biomarker positive) provides evidence that the preclinical science may be translatable to human Alzheimer's, as 6- to 12-weeks of neflamapimod treatment led to significant improvement in episodic memory, the best clinical measure of synaptic dysfunction in AD. A phase 2b six-month placebo-controlled 150-patient clinical study is anticipated to start by end of 2017. This study is designed to definitively demonstrate that neflamapimod reverses memory deficits, and also to provide preliminary evidence that the drug slows disease progression.

Functional Epitopes for Anti-Aquaporin 5 Antibodies in Sjögren Syndrome.

We recently reported the presence of anti-aquaporin 5 (AQP5) immunoglobulin G (IgG) in patients with primary Sjögren syndrome (SS) with a sensitivity of 0.73 and a specificity of 0.68. The aim of this study was to identify functional epitopes for the anti-AQP5 autoantibodies detected in control subjects and patients with SS. Recognition of epitopes by anti-AQP5 autoantibodies in sera ( n = 13 for control and n = 24 for SS) or purified IgG ( n = 1 for control and n = 3 for SS) was evaluated by indirect immunofluorescence (IIF) assay performed in the presence or absence of peptides corresponding to the second transmembrane helix and extracellular loops A, C, and E of AQP5. Functional epitopes were determined by measuring the effects of purified IgG and neutralizing peptides on transepithelial osmotic permeability (PfT) of MDCK cells expressing AQP5. In the IIF assay, 89% of SS samples were inhibited by at least 1 peptide, while only half of control samples were inhibited by any peptide. Overall, SS samples were inhibited by peptides corresponding to extracellular loops A, C, and E by 40% to 50%, whereas control samples were inhibited only by peptides corresponding to loop E by <20%. A cyclized peptide (E1) mimicking loop E was most frequently recognized and best differentiated between the SS and control samples. Incubation of MDCK-AQP5 cells with SS but not with control IgG, significantly decreased PfT, which was reversed by neutralization of IgG binding to any of the extracellular loops. In conclusion, the anti-AQP5 autoantibodies detected in control and SS groups showed differences in fine specificity to the functional epitopes of AQP5. The prevalent recognition of functional epitopes by anti-AQP5 autoantibodies from SS patients suggests that anti-AQP5 autoantibodies act as mediators of glandular hypofunction and are a potential therapeutic target in SS.

Wnt addiction of genetically defined cancers reversed by PORCN inhibition.

Enhanced sensitivity to Wnts is an emerging hallmark of a subset of cancers, defined in part by mutations regulating the abundance of their receptors. Whether these mutations identify a clinical opportunity is an important question. Inhibition of Wnt secretion by blocking an essential post-translational modification, palmitoleation, provides a useful therapeutic intervention. We developed a novel potent, orally available PORCN inhibitor, ETC-1922159 (henceforth called ETC-159) that blocks the secretion and activity of all Wnts. ETC-159 is remarkably effective in treating RSPO-translocation bearing colorectal cancer (CRC) patient-derived xenografts. This is the first example of effective targeted therapy for this subset of CRC. Consistent with a central role of Wnt signaling in regulation of gene expression, inhibition of PORCN in RSPO3-translocated cancers causes a marked remodeling of the transcriptome, with loss of cell cycle, stem cell and proliferation genes, and an increase in differentiation markers. Inhibition of Wnt signaling by PORCN inhibition holds promise as differentiation therapy in genetically defined human cancers.

Patients with prior vertebral or hip fractures treated with teriparatide in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study.

SUMMARY: In patients in the Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) observational study with and without a prior vertebral or hip fracture, the incidence of nonvertebral fractures was lower with >6 months of teriparatide treatment than during the first 6 months. INTRODUCTION: Clinical evidence on the effect of teriparatide in patients with prior fracture is limited. In the DANCE observational study, the incidence of nonvertebral fragility fractures (NVFX) decreased significantly in patients receiving teriparatide for >6 months (6-24 months) versus >0 to ≤6 months (reference period). METHODS: We performed a post hoc analysis to assess the effect of teriparatide 20 µg/day in patients who entered DANCE with prior vertebral or hip fractures. The incidence of patients experiencing a NVFX for four 6-month intervals during and after treatment was compared with the reference period. RESULTS: Overall, 4085 patients received ≥1 dose of teriparatide. Of 3720 with sufficient data for efficacy analysis, 692 had prior vertebral fracture, including 179 with previous kyphoplasty/vertebroplasty; 290 had prior hip fracture. These patients were older, and those with prior vertebral fractures had more comorbid conditions at baseline than those without prior vertebral fractures. The incidence of patients experiencing NVFX declined over time in all patient groups. The fracture incidence rate declined 49 and 46%, respectively, in patients with and without prior vertebral fracture and was 63 and 46% lower in patients with previous kyphoplasty/vertebroplasty and without prior vertebral fracture. NVFX declined 43 and 48% in patients with and without prior hip fracture. The reduced incidence over time was consistent in the subgroups (all interaction p values >0.05). Patients with prior fracture were more likely to experience serious adverse events. CONCLUSION: The incidence of NVFX decreased over time in patients receiving teriparatide in DANCE regardless of prior fracture status.

The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study: 2-year nonvertebral fragility fracture results.

UNLABELLED: This observational study evaluated the occurrence of nonvertebral fragility fractures (NVFX) in over 4,000 men and women with osteoporosis treated with teriparatide (TPTD). The incidence of new NVFX decreased for patients receiving TPTD treatment for greater than 6 months. No new significant safety findings were observed in this large trial. INTRODUCTION: The Direct Assessment of Nonvertebral Fractures in Community Experience (DANCE) study evaluated the occurrence of NVFX in patients receiving TPTD for osteoporosis in a real-world setting. METHODS: DANCE is a multicenter, prospective, observational trial that examined the long-term effectiveness of TPTD in men and women with osteoporosis whom study physicians judged to be suitable for TPTD therapy. Patients received 20 µg TPTD per day by subcutaneous injection for up to 24 months and were followed for 24 months after treatment cessation. The incidence of patients experiencing a new NVFX, defined as a fracture associated with low trauma, was evaluated during four 6-month periods in both the treatment and cessation phases with >0 to ≤6 months serving as the reference. We also observed the spectrum and occurrence of serious adverse events. RESULTS: Of the 4,167 patients enrolled, 4,085 took one or more doses of TPTD (safety population); 3,720 were included in the efficacy analysis. The incidence of patients experiencing a NVFX was 1.42, 0.91, 0.70, and 0.81 % for the four treatment periods, respectively, and 0.80, 0.68, 0.33, and 0.33 % for the four periods after treatment cessation. Differences for each period were statistically significant compared with the reference period (first 6-month interval, each p < 0.05). No new significant safety findings were observed. CONCLUSIONS: In this study, the incidence of NVFX decreased for patients receiving TPTD for all three treatment periods >6 months compared to 0 to ≤6 months, and this trend persisted throughout the cessation phase. TPTD was generally well tolerated.

SMART phones and the acute respiratory patient.

Definition of Respiratory Failure using PaO2 alone is confounded when patients are commenced on oxygen therapy prior to arterial blood gas (ABG) measurement. Furthermore, classification of Respiratory Failure as Type 1 or Type 2 using PaCO2 alone can give an inaccurate account of events as both types can co-exist. 100 consecutive presentations of acute respiratory distress were assessed initially using PaO2, and subsequently PaO2/FiO2 ratio, to diagnose Respiratory Failure. Respiratory Failure cases were classified as Type 1 or Type 2 initially using PaCO2, and subsequently alveolar-arterial (A-a) gradient. Any resultant change in management was documented. Of 100 presentations, an additional 16 cases were diagnosed as Respiratory Failure using PaO2/FiO2 ratio in place of PaO2 alone (p = 0.0338). Of 57 cases of Respiratory Failure, 22 cases classified as Type 2 using PaCO2 alone were reclassified as Type 1 using A-a gradient (p < 0.001). Of these 22 cases, management changed in 18.

Arzoxifene versus raloxifene: effect on bone and safety parameters in postmenopausal women with osteoporosis.

UNLABELLED: Arzoxifene increased bone mineral density and decreased bone turnover to a significantly greater extent than raloxifene. The hot flush incidence was lower with arzoxifene than raloxifene. INTRODUCTION: To assess the effect of arzoxifene versus raloxifene on change in lumbar spine (LS) bone mineral density (BMD) in postmenopausal women with osteoporosis. METHODS: In this 12-month study (NEXT trial), participants were randomly assigned to arzoxifene 20 mg/day (N = 158) or raloxifene 60 mg/day (N = 162). All received daily calcium and vitamin D. Change in LS BMD was assessed by DXA. Secondary objectives included assessment of femoral neck (FN) and total hip BMD, serum bone turnover markers, and safety. RESULTS: Treatment groups were similar at baseline (mean age 63 years, mean LS BMD T-score -2.9). At 12 months, the increase in LS BMD with arzoxifene was greater than with raloxifene (+2.75% vs. +1.66%), as was FN and total hip BMD (P < 0.05). For LS and FN, this effect was also evident at 6 months. Arzoxifene reduced bone turnover to a greater extent than raloxifene at 3, 6, and 12 months (P < 0.05). The proportion of women reporting ≥ 1 adverse event did not differ between treatment groups, nor did vaginal bleeding. No cases of endometrial polyps, hyperplasia, or cancer were reported. Nasopharyngitis and bronchitis were reported more frequently with arzoxifene versus raloxifene (10.1% vs. 2.5%, and 5.1% vs. 0%, respectively) and new/worsening hot flushes were reported less frequently with arzoxifene (7.0% vs. 16.7%) (P < 0.05). CONCLUSIONS: Arzoxifene increased BMD and suppressed bone turnover to a greater extent than raloxifene and resulted in a lower incidence of new/worsening hot flushes. Based on subsequent findings from a fracture outcome study, this difference did not translate into improved fracture efficacy.

The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures.

UNLABELLED: The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. INTRODUCTION: This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. METHODS: In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 µg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. RESULTS: At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine (p = 0.001) and femoral neck (p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe (p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. CONCLUSIONS: Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate.

Impact of population and latrines on fecal contamination of ponds in rural Bangladesh.

A majority of households in Bangladesh rely on pond water for hygiene. Exposure to pond water fecal contamination could therefore still contribute to diarrheal disease despite the installation of numerous tubewells for drinking. The objectives of this study are to determine the predominant sources (human or livestock) of fecal pollution in ponds and examine the association between local population, latrine density, latrine quality and concentrations of fecal bacteria and pathogens in pond water. Forty-three ponds were analyzed for E. coli using culture-based methods and E. coli, Bacteroidales and adenovirus using quantitative PCR. Population and sanitation spatial data were collected and measured against pond fecal contamination. Humans were the dominant source of fecal contamination in 79% of the ponds according to Bacteroidales measurements. Ponds directly receiving latrine effluent had the highest concentrations of fecal indicator bacteria (up to 106 Most Probable Number (MPN) of culturable E. coli per 100 mL). Concentrations of fecal indicator bacteria correlated with population surveyed within a distance of 30-70 m (p<0.05) and total latrines surveyed within 50-70 m (p<0.05). Unsanitary latrines (visible effluent or open pits) within the pond drainage basin were also significantly correlated to fecal indicator concentrations (p<0.05). Water in the vast majority of the surveyed ponds contained unsafe levels of fecal contamination attributable primarily to unsanitary latrines, and to lesser extent, to sanitary latrines and cattle. Since the majority of fecal pollution is derived from human waste, continued use of pond water could help explain the persistence of diarrheal disease in rural South Asia.

Monoparesis secondary to herpes zoster.

We describe a 90-year-old woman with right upper limb monoparesis secondary to varicella zoster virus infection as a result of extensive inflammatory involvement of the entire brachial plexus at root level. To our knowledge, this is the first report of entire brachial plexus involvement in a living patient of such advanced age. Despite a delay in presentation and thus initiation of treatment, a favourable clinical response was observed.

Pulmonary function status of Kolkata inhabitants of different economic class during rainy and winter seasons.

The pulmonary function status of the Kolkata inhabitants was evaluated during rainy and winter seasons. The pulmonary function tests (PFT) of the 1st study was carried out in the months of July to August when the environment is pollution free and the 2nd study was carried out between November to January when the environment is polluted. In the 1st study a total of 162 (male-88, female-74) inhabitants were investigated and again they were repeated in same way in the 2nd study. To evaluate the respiratory function status, Slow Vital Capacity (SVC), Forced Vital Capacity (FVC) and Peak Expiratory Flow Rate (PEFR) were recorded. Forced expiratory volume in one second (FEV1), forced expiratory volume in 1 sec as the percentage of FVC (FEV1%), forced expiratory flow at 200mL-1200 mL, 25-75% and 75-85% were calculated from the same tracings. Males were having higher mean PFT values compared to females because of sex difference. In the 2nd study PFT values were significantly lower compared to 1st study. According to different durations of stay category the PFT values were significantly reduced in winter season. The regression lines showed decrement as the duration of stay on that area was increased and it was more in 2nd study compared to 1st study. In both studies the PFT values found higher in high economic class of people. Between the same economic class of people PFT values were significantly lower in winter season. Respiratory impairments were also found higher during winter and males were having more impairment compared to females. Respiratory impairments in both sexes were more in winter and low economic class of people had maximum respiratory impairments. In rainy season and winter season the respiratory impairments were less in non-smokers. Males had more respiratory function impairments compared to females.

Respiratory effect related to exposure of different concentrations of arsenic in drinking water in West Bengal, India.

Arsenic toxicity due to drinking of arsenic contaminated water has been one of the worst environmental health hazards. High levels of arsenic have been reported in different natural water sources from West Bengal for more than two decades. Groundwater contamination by arsenic and its adverse effects on the health of a big population in nine districts of West Bengal have been reported. The problems found were mainly related to skin and respiratory, digestive, cardiovascular and nervous systems. The respiratory effects are largely confined to those who had the skin lesion. The present study was undertaken to evaluate the respiratory effects of exposure to different levels of arsenic in drinking water. The water samples were collected from different tube wells and wells in the study area. Analysis of arsenic was done by Atomic Absorption Spectrophotometer with hydride generation system. Based on the consumption of arsenic concentrations in drinking water the populations were divided into three categories, i.e., <=50 microg/L, >50 - <= 150 microg/L and >150 microg/L. Standard techniques of medical examination were applied to elicit signs and recorded in the pre-designed proforma. A written consent was taken from each subject for their voluntary participation in the study. 112 subjects were investigated. The respiratory effect was evaluated by measuring the pulmonary function test (PFT). Vital Capacity (VC) and Forced Vital Capacity (FVC) were measured by Spirovit-SP-10 (Schiller Health Care Pvt Ltd., Switzerland) and Peak Expiratory Flow Rate by Wrights Peak Flow Meter (Clement and Clarke, UK). The PFT values showed gradual decrement among the males following skin pigmentation, keratosis and arsenicosis. The respiratory function impairment among the male subjects found as restrictive type (26.41%), obstructive type (3.77%) and combined type (7.54%), whereas in females only the restrictive type of impairment (10.16%) was found. Restrictive type of impairments among the subjects increased as the concentration of arsenic in drinking water increased, in males 15.78%, 29.41% and 35.29% and in females 4.54%, 5.00% and 23.52% respectively. The pathophysiologic mechanism, by which ingested arsenic leads to impairments of lung function and increased respiratory symptoms, is yet to be understood and needs further investigation.

Synthesis, structure and reactivity of tetranuclear square-type complexes of rhenium and manganese bearing pyrimidine-2-thiolate (pymS) ligands: versatile and efficient precursors for mono- and polynuclear compounds containing M(CO)(3) (M = Re, Mn) fragments.

Reactions of M(2)(CO)(10) (M = Re, Mn) with pyrimidine-2-thiol (pymSH) in the presence of Me(3)NO afford the tetranuclear square-type complexes [M(4)(CO)(12)(micro-kappa(3)-pymS)(4)] (, M = Re; , M = Mn). Both consist of four M(CO)(3) (M = Re, Mn) units, pairs of which are joined by tridentate pyrimidine-2-thiolate ligands. Treatment of with a variety of donor ligands results in cleavage of the square to afford mononuclear species with either a mono- or bidentate pyrimidine-2-thiolate ligand. Triphenylphosphine reacts with to give [Mn(CO)(3)(PPh(3))(kappa(2)-pymS)] () in which the pyrimidine-2-thiolate coordinates in a bidentate fashion. With diamines [M(CO)(3)(kappa(2)-L)(kappa(1)-pymS)] () (M = Re, Mn; L = 2,2'- bipy, 1,10-phen, en) result in which the pyrimidine-2-thiolate binds in a monodentate fashion through sulfur. With diphosphines, complexes with different stoichiometries and pyrimidine-2-thiolate binding modes are obtained depending on the nature of the metal and diphosphine. With dppm and dppe, gives [Re(CO)(2)(kappa(1)-pymS)(kappa(2)-dppm)] () and [Re(CO)(2)(kappa(2)-pymS)(kappa(1)-dppe)(2)] (), respectively, whereas affords [Mn(CO)(2)(kappa(2)-pymS)(kappa(1)-dppm)(2)] () and [Mn(CO)(2)(kappa(2)-pyS)(kappa(2)-dppe)] () under similar conditions. Reactions of with [Os(3)(CO)(10)(NCMe)(2)] affords mixed-metal butterfly clusters [MOs(3)(CO)(13)(micro(3)-kappa(2)-pymS)] () in which the group 7 metal occupies a wing-tip position and the pyrimidine-2-thiolate ligand caps a triangular Os(2)M face. With Ru(3)(CO)(12), carbon-sulfur bond cleavage occurs to give the tetranuclear clusters [MRu(3)(CO)(14)(micro(4)-S)(micro-kappa(1):eta(1)-pym)] () bearing both the extruded sulfur and the heterocyclic ring. The molecular structures of , and have been established by X-ray diffraction allowing the binding mode of the pyrimidine-2-thiolate ligands to be probed.

Effects of arzoxifene on bone mineral density and endometrium in postmenopausal women with normal or low bone mass.

INTRODUCTION: Arzoxifene, a benzothiophene estrogen agonist/antagonist, is being developed for prevention and treatment of osteoporosis and for risk reduction of invasive breast cancer in postmenopausal women. METHODS: The effects of arzoxifene 20 mg/d on bone mineral density (BMD), uterine safety, and overall safety were studied in the FOUNDATION study, a 2-yr randomized, placebo-controlled trial including 331 postmenopausal women with normal to low bone mass. RESULTS: Compared to placebo, arzoxifene significantly increased lumbar spine (+2.9%) and total hip (+2.2%) BMD. Arzoxifene decreased biochemical markers of bone metabolism compared to placebo. Changes in breast density were neutral or slightly decreased in the arzoxifene vs. placebo group. There was no evidence of endometrial hyperplasia or carcinoma in the arzoxifene group as assessed by central review of baseline and follow-up endometrial biopsies. There was no significant change between the groups in endometrial thickness assessed by transvaginal ultrasound. The incidence of uterine polyps and vaginal bleeding was not significantly different between the groups. Vulvovaginal mycotic infection was the only adverse event significantly increased in the arzoxifene vs. placebo group. Hot flushes were not significantly different between the groups. CONCLUSION: In postmenopausal women with normal to low bone mass, arzoxifene 20 mg/d increased BMD at the spine and hip and had a neutral effect on the uterus and endometrium.

Dibenzoylmethane activates Nrf2-dependent detoxification pathway and inhibits benzo(a)pyrene induced DNA adducts in lungs.

Cigarette smoke derived carcinogens have been identified as the main agents implicated in lung carcinogenesis. Epidemiological as well as animal studies have indicated that certain phytochemicals can block the carcinogenic process by enhancing the detoxification of environmental and or dietary carcinogens. Dibenzoylmethane (DBM), a minor constituent of licorice, is a beta-ketone analog of curcumin, a promising chemopreventive agent for colon, breast and skin cancer. The present study was designed to examine the chemopreventive efficacy of DBM in lungs, its global molecular targets and the mechanism of its action. Feeding DBM to A/J mice significantly inhibited benzo[a]pyrene induced DNA adducts in lungs. Further analysis of its global molecular targets in lungs by oligonucleotide microarray revealed expression of several cytoprotective genes including phase II enzymes that are regulated by Nrf2, a basic leucine zipper transcription factor. To decipher if DBM mediates its function via Nrf2 activation, Nrf2 dependent reporter assays were performed. DBM elicited a dose-dependent increase in antioxidant response element (ARE)-driven luciferase reporter activity which correlated with an increase in mRNA expression of NQO1, GSTA2, and GCLC in mouse hepatoma cells, which are well established targets of Nrf2. Conversely, DBM stimulated ARE reporter activity was attenuated by a dominant-negative mutant of Nrf2. Electrophoretic mobility shift assay confirmed that DBM greatly increased the DNA binding activity of Nrf2. In conclusion, DBM mediates the induction of phase II enzymes by Nrf2 activation and inhibits benzo[a]pyrene induced DNA adducts by enhancing its detoxification in lungs.