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The aim of this research work is to enhance the machining characteristics and geometrical tolerances of Si3N4–TiN ceramic composite using a copper electrode as the EDM tool. The investigation encompassed a comprehensive exploration of various machining parameters, including polarity, current (amp), pulse on time (µs), pulse off time (µs), dielectric pressure (Kg/cm2), gap voltage (v), spark gap (mm), and servo speed (m/s), utilizing a Taguchi L18 orthogonal array. Throughout the EDM process, meticulous scrutiny was applied to output characteristics such as Material Removal Rate (0.0354 gm/min), Tool Wear Rate (0.001035 gm/min), Wear Ratio (22.625), Surface Roughness (0.117 µm), Top Radial Overcut (0.043 mm), Bottom Radial Overcut (-0.214 mm), top diameter of the drilled hole (5.087 mm), bottom diameter of the drilled hole (4.572 mm), Taper Angle (0.458 deg), Circularity (0.039 mm), Cylindricity (0.034 mm), Perpendicularity (0.007 mm), and Run Out (0.036 mm). The higher pulse current promotes the formation of a stable plasma channel which results in increasing the material removal rate. The improved flushing action helps to minimize the recast layer, leading to a smoother surface finish and reduced surface roughness. The experimental results demonstrate that as the spark gap increases from 0.18 mm to 0.25 mm, the Runout, Electrode Wear Rate, ROC Bottom, ROC Top, and Taper Angle drastically reduce. [ABSTRACT FROM AUTHOR]

Aluminum matrix composites are widely employed in aerospace, military, automobile, and transport applications. The high-strength with low-weight materials are required to fulfill the requirement of high-performance applications. The low-weight materials are reinforced with hard reinforcements to obtain high-strength-to-weight properties for using high-performance applications. The process parameters of fabrication technique define the mechanical and tribological properties. Many types of optimization tools are used for optimizing the process parameters of fabrication method. In this research, the aluminum alloy 7050 and boron carbide are selected as matrix material and reinforcement material. The fabrication of Al7050/B4C composites is produced by the stir casting method. The optimization on stir casting process parameters is done by using the Taguchi approach. The L9 orthogonal array is chosen for this investigation. The chosen input stir casting process parameters are wt% B4C, stirring time (10, 15, and 20 min), stirring speed (300, 350, and 400 rpm), and melting temperature (700, 750, and 800°C). The microhardness is selected as a valuable response parameter for optimizing the stir casting process parameters. The influencing stir casting process parameter sequence is determined by using mean table. The influencing parameters of stir casting on microhardness are stirring speed, stirring time, wt% B4C, and melting temperature. The 9 wt% of boron carbide addition increases the microhardness, and it is higher than the other wt%. The optimum combination of input process parameter combination is 9 wt% boron carbide, 750°C melting temperature, 350 rpm stirring speed, and 15 min stirring time (A3B2C2D2). The percentage of microhardness value improvement is 20.3%. [ABSTRACT FROM AUTHOR]

Byline: S. Thirugnanam, S. Vinodh, S.R. Devadasan One of the techniques that have been dominating the Total Quality Management (TQM) era is Quality Circle Programme (QCP). Several benefits of QCP have been reported in the literature. In particular, QCPs' problem-solving ability is highly appreciated. Today's intense competition demands innovation rather than mere solving of problems. This situation envisages the integration of innovation management principles with QCP. In order to fulfil this imperative, a technique named innovative Quality Circle (innovative QC) has been proposed in this paper. After describing its framework, the implementation features of innovative QC is presented with the help of a case study. Since it is foreseen that innovative QC's sustainability will be ensured by making use of the Decision Support System (DSS) concept, a DSS named Innovative Quality Circle Programme (IQCP) is presented. The article concludes by citing the need for conducting practical case studies on innovative QC to improve its practical compatibility.

The effective utilization of natural fibers is the main objective of the present research work. But natural fibers alone is not to meet the required strength properties. Hence, one more artificial material is to be added for obtaining required strength. The study undergone on sisal-glass fiber reinforced polymer composites, it is developed by heat compression moulding techniques and their mechanical properties such as tensile, flexural and impact strength are evaluated experimentally under the ASTM standards. The binding properties, internal crack and fiber alignments are examined by morphological test. It is observed that, the tensile strength of sisal/glass fiber composites produce 255.80 MPa. It is approximately same strength (260.10 MPa) of artificial fiber composites. Hence, the use of artificial fibers are minimized by addition of natural fiber which reduces cost of materials and utilization of natural resources. From the SEM test, fiber misalignments are over loading of fibers on composites leads decline in strength. The moisture and wax content of natural fiber may decrease hardness value (23.0 RHN). [ABSTRACT FROM AUTHOR]

The foremost objective of this research work is to implement Artificial Neural Network (ANN), to improve spark erosion machining performance of aluminum alloy AA 6061 hybrid composites by controlling the process constraints, which is suitable for bio medical applications. Aluminum composites are mostly used to replace the conventional materials attributable to their less weight, notable wear and corrosion resistances. These composites are used in automotive, aerospace, electronics and bio medical applications. Machining of aluminium composites using conventional machining technique is one of the major challenges because of the presence of hard particles in aluminium matrix. Unconventional machining techniques have been preferred for machining aluminium composites to enhance better surface quality. In the present study the composite specimen was processed through stir casting and machining was carried out using spark erosion machining, by varying four process constraints with the application of design of experiments. ANN trained with multi-layer feed forward through the error back- propagation training algorithm, was used to model the network and predict the material removal rate (MRR) of the composite. The outcomes exposed that the projected values found from the ANN model were in good agreement with the investigational values and to study the machining characteristics of composites, the model could be effectively applied. [ABSTRACT FROM AUTHOR]

HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of Human Immunodeficiency Virus (HIV) infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption (IEBD). Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for IEBD biomarkers, inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). During the chronic phase of treated SIV infection, elevated levels of plasma IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP). Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10 and 12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV + ART phase along with a trend of increase in the frequencies of activated CD14 + CD16 + intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could fuel metabolic syndrome. Further research is needed to understand the mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated metabolic complications, enabling targeted interventions in people with HIV.

HIV-induced persistent immune activation is a key mediator of inflammatory comorbidities such as cardiovascular disease (CVD) and neurocognitive disorders. While a preponderance of data indicate that gut barrier disruption and microbial translocation are drivers of chronic immune activation, the molecular mechanisms of this persistent inflammatory state remain poorly understood. Here, utilizing the nonhuman primate model of HIV infection with suppressive antiretroviral therapy (ART), we investigated activation of inflammasome pathways and their association with intestinal epithelial barrier disruption and CVD pathogenesis. Longitudinal blood samples obtained from rhesus macaques with chronic SIV infection and long-term suppressive ART were evaluated for biomarkers of intestinal epithelial barrier disruption (IEBD), inflammasome activation (IL-1β and IL-18), inflammatory cytokines, and triglyceride (TG) levels. Activated monocyte subpopulations and glycolytic potential were investigated in peripheral blood mononuclear cells (PBMCs). Higher plasma levels of IL-1β and IL-18 were observed following the hallmark increase in IEBD biomarkers, intestinal fatty acid-binding protein (IFABP) and LPS-binding protein (LBP), during the chronic phase of treated SIV infection. Further, significant correlations of plasma IFABP levels with IL-1β and IL-18 were observed between 10-12 months of ART. Higher levels of sCD14, IL-6, and GM-CSF, among other inflammatory mediators, were also observed only during the long-term SIV+ART phase along with a trend of increase in frequencies of activated CD14 + CD16 + intermediate monocyte subpopulations. Lastly, we found elevated levels of blood TG and higher glycolytic capacity in PBMCs of chronic SIV-infected macaques with long-term ART. The increase in circulating IL-18 and IL-1β following IEBD and their significant positive correlation with IFABP suggest a connection between gut barrier disruption and inflammasome activation during chronic SIV infection, despite viral suppression with ART. Additionally, the increase in markers of monocyte activation, along with elevated TG and enhanced glycolytic pathway activity, indicates metabolic remodeling that could accelerate CVD pathogenesis. Further research is needed to understand mechanisms by which gut dysfunction and inflammasome activation contribute to HIV-associated CVD and metabolic complications, enabling targeted interventions in people with HIV.

The emergence of combination antiretroviral therapy (cART) has greatly transformed the life expectancy of people living with HIV (PWH). Today, over 76% of the individuals with HIV have access to this life-saving therapy. However, this progress has come with a new challenge: an increase in age-related non-AIDS conditions among patients with HIV. These conditions manifest earlier in PWH than in uninfected individuals, accelerating the aging process. Like PWH, the uninfected aging population experiences immunosenescence marked by an increased proinflammatory environment. This phenomenon is linked to chronic inflammation, driven in part by cellular structures called inflammasomes. Inflammatory signaling pathways activated by HIV-1 infection play a key role in inflammasome formation, suggesting a crucial link between HIV and a chronic inflammatory state. This review outlines the inflammatory processes triggered by HIV-1 infection and aging, with a focus on the inflammasomes. This review also explores current research regarding inflammasomes and potential strategies for targeting inflammasomes to mitigate inflammation. Further research on inflammasome signaling presents a unique opportunity to develop targeted interventions and innovative therapeutic modalities for combating HIV and aging-associated inflammatory processes.

Electrical energy is often wasted through human negligence when people do not switch off electrical appliances such as lighting after leaving a place. Such a scenario often happens in a classroom when the last person leaves the class and forgets to switch off the electrical appliances. Such wastage may not be able to be afforded by schools that are limited financially. Therefore, this research proposed a simple and cost-effective system that can analyze whether there is or is not a human presence in the classroom by applying a counter to count the total number of people entering and leaving the classroom based on the sensing signals of a set of dual PIR sensors only and then correlating this to automatically turn on or off the electrical appliances mentioned. The total number of people identified in the classroom is also displayed on an LCD screen. A TRIZ approach is used to support the ideation of the system. The system can switch on several electrical output loads simultaneously when the presence of people is detected and switch them off when there are no people in the classroom. The proposed system can be expanded to be used in homes, offices, and buildings to prevent the high cost of electricity consumption caused by the negligence of people. This enables smarter control of electricity consumption.

Previous studies have indicated that the loss of CD161-expressing CD4 + Th17 cells is linked to the progression of chronic HIV. These cells are significantly depleted in peripheral blood and gut mucosa of HIV-infected individuals, contributing to inflammation and disruption of the gut barrier. However, the impact of HIV infection on CD161-expressing CD8 + T cells remain unclear. Here, we examined the functions of peripheral blood and mucosal CD161 + CD8 + T cells in the macaque model of HIV infection. In contrast to the significant loss of CD161 + CD4 + T cells, CD161 + CD8 + T cell frequencies were maintained in blood and gut during chronic SIV infection. Furthermore, gut CD161 + CD8 + T cells displayed greater IL-17 production and maintained Th1-type and cytolytic functions, contrary to impaired IL-17 and granzyme-B production in CD161 + CD4 + T cells of SIV-infected macaques. These results suggest that augmented Th17-type effector functions of CD161 + CD8 + T cells during SIV infection is a likely mechanism to compensate for the sustained loss of gut mucosal Th17 cells. Targeting the cytokine and cytolytic effector functions of CD161 + CD8 + T cells in the preclinical setting of chronic SIV infection with antiretroviral therapy has implications in the restoration of gut barrier disruption in persons with HIV infection.

The gut microbiome plays a critical role in maintaining overall health and immune function. However, dysbiosis, an imbalance in microbiome composition, can have profound effects on various aspects of human health, including susceptibility to viral infections. Despite numerous studies investigating the influence of viral infections on gut microbiome, the impact of gut dysbiosis on viral infection and pathogenesis remains relatively understudied. The clinical variability observed in SARS-CoV-2 and seasonal influenza infections, and the presence of natural HIV suppressors, suggests that host-intrinsic factors, including the gut microbiome, may contribute to viral pathogenesis. The gut microbiome has been shown to influence the host immune system by regulating intestinal homeostasis through interactions with immune cells. This review aims to enhance our understanding of how viral infections perturb the gut microbiome and mucosal immune cells, affecting host susceptibility and response to viral infections. Specifically, we focus on exploring the interactions between gamma delta (γδ) T cells and gut microbes in the context of inflammatory viral pathogenesis and examine studies highlighting the role of the gut microbiome in viral disease outcomes. Furthermore, we discuss emerging evidence and potential future directions for microbiome modulation therapy in the context of viral pathogenesis.

The need for power-efficient devices, such as smart sensor nodes, mobile devices, and portable digital gadgets, is markedly increasing and these devices are becoming commonly used in daily life. These devices continue to demand an energy-efficient cache memory designed on Static Random-Access Memory (SRAM) with enhanced speed, performance, and stability to perform on-chip data processing and faster computations. This paper presents an energy-efficient and variability-resilient 11T (E 2 VR11T) SRAM cell, which is designed with a novel Data-Aware Read-Write Assist (DARWA) technique. The E 2 VR11T cell comprises 11 transistors and operates with single-ended read and dynamic differential write circuits. The simulated results in a 45 nm CMOS technology exhibit 71.63% and 58.77% lower read energy than ST9T and LP10T and lower write energies of 28.25% and 51.79% against S8T and LP10T cells, respectively. The leakage power is reduced by 56.32% and 40.90% compared to ST9T and LP10T cells. The read static noise margin (RSNM) is improved by 1.94× and 0.18×, while the write noise margin (WNM) is improved by 19.57% and 8.70% against C6T and S8T cells. The variability investigation using the Monte Carlo simulation on 5000 samples highly validates the robustness and variability resilience of the proposed cell. The improved overall performance of the proposed E 2 VR11T cell makes it suitable for low-power applications.

Objectives: Few surveys have focused on physician moral distress, burnout, and professional fulfilment. We assessed physician wellness and coping during the COVID-19 pandemic., Design: Cross-sectional survey using four validated instruments., Setting: Sixty-two sites in Canada and the United States., Subjects: Attending physicians (adult, pediatric; intensivist, nonintensivist) who worked in North American ICUs., Intervention: None., Measurements and Main Results: We analysed 431 questionnaires (43.3% response rate) from 25 states and eight provinces. Respondents were predominantly male (229 [55.6%]) and in practice for 11.8 ± 9.8 years. Compared with prepandemic, respondents reported significant intrapandemic increases in days worked/mo, ICU bed occupancy, and self-reported moral distress (240 [56.9%]) and burnout (259 [63.8%]). Of the 10 top-ranked items that incited moral distress, most pertained to regulatory/organizational ( n = 6) or local/institutional ( n = 2) issues or both ( n = 2). Average moral distress (95.6 ± 66.9), professional fulfilment (6.5 ± 2.1), and burnout scores (3.6 ± 2.0) were moderate with 227 physicians (54.6%) meeting burnout criteria. A significant dose-response existed between COVID-19 patient volume and moral distress scores. Physicians who worked more days/mo and more scheduled in-house nightshifts, especially combined with more unscheduled in-house nightshifts, experienced significantly more moral distress. One in five physicians used at least one maladaptive coping strategy. We identified four coping profiles (active/social, avoidant, mixed/ambivalent, infrequent) that were associated with significant differences across all wellness measures., Conclusions: Despite moderate intrapandemic moral distress and burnout, physicians experienced moderate professional fulfilment. However, one in five physicians used at least one maladaptive coping strategy. We highlight potentially modifiable factors at individual, institutional, and regulatory levels to enhance physician wellness., Competing Interests: Dr. Burns disclosed that the Canadian Critical Care Society (CCSS) paid for the statistical analyses. Dr. Lorens received funding from the CCCS. Drs. Lorens and Kerlin disclosed work for hire. Drs. Viglianti, Kohn, Peltan, and Schnapp received support for article research from the National Institutes of Health (NIH). Dr. Fox-Robichaud’s institution received funding from the Canadian Institutes of Health Research and Hamilton Academic Hospitals. Dr. Mathews’ institution received funding from the National Heart, Lung, and Blood Institute (NHLBI); he received funding from Roivant/Kinevant Sciences. Dr. Jain is supported by the National Institute on Aging (NIA) T32AG019134, the Pepper Scholar Award from Yale Claude D. Pepper Older American Independence Center (P30AG021342), NIA of the NIH GEMSSTAR Award (R03AG078942), Parker B. Francis Fellowship Award, and Yale Physician-Scientist Development Award. Drs. Akgun and Crothers disclosed government work. Dr. Gershengorn received funding from the American Thoracic Society (ATS), Gilead Sciences, and Southeastern Critical Care Summit. Dr. Martin’s institution received funding from BARDA; he received funding from Genetech. Dr. Stapleton disclosed that she is chair of DSMB for Altimmune and a member of the ATS Board of Directors 2019–2021 (elected to Chair the Critical Care Assembly which includes a position on the Board). Dr. Attia’s institution received funding from the NHBLI (NHLBI K23 HL129888 and R03 [pending]), the Centers for Aids Research, and Pediatric HIV/AIDS Cohort Study. Dr. Maddux’s institution received funding from the National Institute of Child Health and Human Development (K23HD096018) and the Francis Family Foundation. Dr. Bagshaw received funding from Baxter and Bioporto. Dr. Crothers’ institution received funding from the NIH and Veteran’s Affairs. Dr. Peltan’s institution received funding from Regeneron and Asahi Kasei Pharma; he received funding from the NIH (K23GM129661) and Janssen. Dr. Schnapp received funding from UptoDate and Elsevier. Dr. Kraft’s institution received funding from the NIH, the American Lung Association, Sanofi, and AstraZeneca Consulting; she received funding from Sanofi, Astra-Zeneca, Chiesi Speaking, and UptoDate; she disclosed she is a cofounder and Chief Medical Officer of RaeSedo LLC. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Introduction: Cochlear implantation is a safe surgery for restoration of hearing in profoundly deaf children. Following cochlear implantation, children undergo rehabilitation (or 'habilitation' for those without previous hearing). The device is programmed after the surgery, so that the user can hear sounds through it and through rehabilitation training, the heard sounds are made to understand., Objective: Our study was aimed at analysing the role of satellite habilitation centres following cochlear implantation by analysing the outcomes following habilitation and comparing it with the outcomes of the main centre and correlating it with the percentage of attendance of classes. Our study also aims to compare the attendance of implant patients from outside the geographical area of the main centre before and after starting the satellite centre., Materials and Methods: 1004 profoundly deaf children (6 years and below) who had undergone cochlear implantation and completed 12months of habilitation in our institution from July 2013 to December 2019 were retrospectively analysed. The outcomes of all the centres were assessed by comparing the baseline CAP with CAP scores at 12 months and baseline SIR with SIR scores at 12 months. The outcomes of the main centre and satellite centres were also compared. The outcomes were correlated with percentage of attendance of classes., Observation: The overall attendance in all the centres was between 75 and 80%. Both main and satellite centres showed statistically significant good outcomes and this correlates with percentage of attendance., Conclusion: Satellite centres for habilitation across the state has greatly helped to improve the attendance of these patients and outcomes. Reduced drop-out rates and improved speech language outcomes can be achieved by starting satellite centres for habilitation post cochlear implantation in developing countries like India., (Copyright © 2020. Published by Elsevier B.V.)

Background: The obligate intracellular protozoan parasite Toxoplasma gondii infects humans and other warm-blooded animals and establishes a chronic infection in the central nervous system after invasion. Studies showing a positive correlation between anti-Toxoplasma antibodies and incidences of brain cancer have led to the notion that Toxoplasma infections increase the risk of brain cancer. However, molecular events involved in Toxoplasma induced brain cancers are not well understood., Presentation of the Hypothesis: Toxoplasma gains control of host cell functions including proliferation and apoptosis by channelizing parasite proteins into the cell cytoplasm and some of the proteins are targeted to the host nucleus. Recent studies have shown that Toxoplasma is capable of manipulating host micro RNAs (miRNAs), which play a central role in post-transcriptional regulation of gene expression. Therefore, we hypothesize that Toxoplasma promotes brain carcinogenesis by altering the host miRNAome using parasitic proteins and/or miRNAs., Testing the Hypothesis: The miRNA expression profiles of brain cancer specimens obtained from patients infected with Toxoplasma could be analyzed and compared with that of normal tissues as well as brain cancer tissues from Toxoplasma uninfected individuals to identify dysregulated miRNAs in Toxoplasma-driven brain cancer cells. Identified miRNAs will be further confirmed by studying cancer related miRNA profiles of the different types of brain cells before and after Toxoplasma infection using cell lines and experimental animals. EXPECTED OUTCOME: The miRNAs specifically associated with brain cancers that are caused by Toxoplasma infection will be identified., Implications of the Hypothesis: Toxoplasma infection may promote initiation and progression of cancer by modifying the miRNAome in brain cells. If this hypothesis is true, the outcome of this research would lead to the development of novel biomarkers and therapeutic tools against Toxoplasma driven brain cancers.

The basal complex in Toxoplasma functions as the contractile ring in the cell division process. Basal complex contraction tapers the daughter cytoskeleton toward the basal end and is required for daughter segregation. We have previously shown that the protein MORN1 is essential for basal complex assembly and likely acts as a scaffolding protein. To further our understanding of the basal complex, we combined subcellular fractionation with an affinity purification of the MORN1 complex and identified its protein composition. We identified two new components of the basal complex, one of which uniquely associated with the basal complex in mature parasites, the first of its kind. In addition, we identified several other novel cytoskeleton proteins with different spatiotemporal dynamics throughout cell division. Since many of these proteins are unique to Apicomplexa this study significantly contributes to the annotation of their unique cytoskeleton. Furthermore, we show that G-actin binding protein TgCAP is localized at the apical cap region in intracellular parasites, but quickly redistributes to a cytoplasmic localization pattern upon egress. © 2012 Wiley Periodicals, Inc., (Copyright © 2012 Wiley Periodicals, Inc.)

A human homologue of high mobility group box 1 (HMGB1) protein was cloned and characterized from the human filarial parasites Wuchereria bancrofti and Brugia malayi. Sequence analysis showed that W. bancrofti HMGB1 (WbHMGB1) and B. malayi HMGB1 (BmHMGB1) proteins share 99 % sequence identity. Filarial HMGB1 showed typical architectural sequence characteristics of HMGB family of proteins and consisted of only a single HMG box domain that had significant sequence similarity to the pro-inflammatory B box domain of human HMGB1. When incubated with mouse peritoneal macrophages and human promyelocytic leukemia cells, rBmHMGB1 induced secretion of significant levels of pro-inflammatory cytokines such as TNF-α, GM-CSF, and IL-6. Functional analysis also showed that the filarial HMGB1 proteins can bind to supercoiled DNA similar to other HMG family of proteins. BmHMGB1 protein is expressed in the adult and microfilarial stages of the parasite and is found in the excretory secretions of the live parasites. These findings suggest that filarial HMGB1 may have a significant role in lymphatic pathology associated with lymphatic filariasis.

Introduction: Despite evidence-based guidelines for venous thromboembolism prevention, substantial variability is found in practice. Many economic evaluations of new drugs for thromboembolism prevention do not occur prospectively with efficacy studies and are sponsored by the manufacturers, raising the possibility of bias. We performed a systematic review of economic analyses of venous thromboembolism prevention in hospitalized patients to inform clinicians and policy makers about cost-effectiveness and the potential influence of sponsorship., Methods: We searched MEDLINE, EMBASE, Cochrane Databases, ACP Journal Club, and Database of Abstracts of Reviews of Effects, from 1946 to September 2011. We extracted data on study characteristics, quality, costs, and efficacy., Results: From 5,180 identified studies, 39 met eligibility and quality criteria. Each addressed pharmacologic prevention: low-molecular-weight heparins versus placebo (five), unfractionated heparin (12), warfarin (eight), one or another agents (five); fondaparinux versus enoxaparin (11); and rivaroxaban and dabigatran versus enoxaparin (two). Low-molecular-weight heparins were most economically attractive among most medical and surgical patients, whereas fondaparinux was favored for orthopedic patients. Fondaparinux was associated with increased bleeding events. Newer agents rivaroxaban and dabigatran may offer additional value. Of all economic evaluations, 64% were supported by manufacturers of a "new" agent. The new agent had a favorable outcome in 38 (97.4%) of 39 evaluations [95% confidence interval [CI] (86.5 to 99.9)]. Among studies supported by a pharmaceutical company, the sponsored medication was economically attractive in 24 (96.0%) of 25 [95% CI, 80.0 to 99.9)]. We could not detect a consistent bias in outcome based on sponsorship; however, only a minority of studies were unsponsored., Conclusion: Low-molecular-weight heparins and fondaparinux are the most economically attractive drugs for venous thromboembolism prevention in hospitalized patients. Approximately two thirds of evaluations were supported by the manufacturer of the new agent; such drugs were likely to be reported as economically favorable.

Expression of receptor for advanced glycation end products (RAGE) plays a key role in the progression of prostate cancer. However, the therapeutic potential of targeting RAGE expression in prostate cancer is not yet evaluated. Therefore in this study, we have investigated the effects of silencing the expression of RAGE by RNAi approach both in vitro and in vivo. The results of this study showed that down regulation of RAGE expression by RNAi inhibited the cell proliferation of androgen-dependent (LNCaP) and androgen-independent (DU-145) prostate cancer cells. Furthermore, targeting RAGE expression resulted in apoptotic elimination of these prostate cancer cells by activation of caspase-8 and caspase-3 death signaling. Of note, the levels of prostate specific antigen (PSA) were also reduced in LNCaP cells transfected with RAGE RNAi constructs. Importantly, the RAGE RNAi constructs when administered in nude mice bearing prostate tumors, inhibited the tumor growth by targeting the expression of RAGE, and its physiological ligand, HMGB1 and by up regulating death receptors DR4 and DR5 expression. Collectively, the results of this study for the first time show that targeting RAGE by RNAi may be a promising alternative therapeutic strategy for treating prostate cancer., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Exocytosis is essential to the lytic cycle of apicomplexan parasites and required for the pathogenesis of toxoplasmosis and malaria. DOC2 proteins recruit the membrane fusion machinery required for exocytosis in a Ca(2+)-dependent fashion. Here, the phenotype of a Toxoplasma gondii conditional mutant impaired in host cell invasion and egress was pinpointed to a defect in secretion of the micronemes, an apicomplexan-specific organelle that contains adhesion proteins. Whole-genome sequencing identified the etiological point mutation in TgDOC2.1. A conditional allele of the orthologous gene engineered into Plasmodium falciparum was also defective in microneme secretion. However, the major effect was on invasion, suggesting that microneme secretion is dispensable for Plasmodium egress.

Glycyrrhetinic acid is an active triterpenoid metabolite of glycyrrhizin abundantly present in licorice roots. Glycyrrhetinic acid exists as α and β stereo-isomeric forms. Both stereo-isomeric forms are known to have anti-inflammatory and anticancer activity. However, the effects and anticancer mechanism of α glycyrrhetinic acid in prostate cancer cells has not yet been evaluated. Therefore, we investigated the growth inhibition, induction of apoptosis and the anticancer mechanisms of 18α-glycyrrhetinic acid (AGA), on the androgen-independent metastatic prostate cancer cell line DU-145. Our results showed that AGA inhibited proliferation and growth of these cells by inducing apoptosis as determined by Annexin V and flow cytometry analyses. Our studies also showed that HUVEC tube formation was drastically reduced when cultured in conditioned medium of AGA-treated DU-145 cells. In addition, AGA treatment prevented the invasion of DU-145 prostate cancer cells on matrigel coated transwells via down-regulation of NF-κB (p65), VEGF and MMP-9 expression. Furthermore, AGA treatment also down-regulated the expression of pro-inflammatory cytokine/growth factor genes HMGB1, IL-6 and IL-8 in DU-145 cells. Interestingly, AGA simultaneously upregulated the expression of non-steroidal anti-inflammatory gene-1 (NAG-1) in DU-145 cells suggesting its anti-inflammatory activity on prostate cancer cells. Taken together, the results of this study suggest that AGA may be a promising anticancer agent that merits further investigation for the chemoprevention and treatment of prostate cancer.

Toxoplasmosis is characterized by fast lytic replication cycles leading to severe tissue lesions. Successful host cell invasion is essential for pathogenesis. The division cycle of Toxoplasma gondii is characterized by an unusual cell cycle progression and a distinct internal budding mechanism. To identify essential genes involved in the lytic cycle we devised an insertional gene trapping strategy using the Tet-transactivator system. In essence, a random, active promoter is displaced with a tetracycline regulatable promoter, which if in an essential gene, will result in a conditionally lethal phenotype upon tetracycline addition. We isolated eight mutants with growth defects, two of which displayed modest invasion defects, one of which had an additional cell cycle defect. The trapped loci were identified using expression microarrays, exploiting the tetracycline dependent expression of the trapped genes. In mutant 3.3H6 we identified TCP-1, a component of the chaperonin protein folding machinery under the control of the Tet promoter. However, this gene was not critical for growth of mutant 3.3H6. Subsequently, we identified a suppressor gene encoding a protein with a hypothetical function by guided cosmid complementation. In mutant 4.3B13, we identified TAF250, an RNA polymerase II complex component, as the trapped, essential gene. Furthermore, by mapping the plasmid insertion boundaries we identified multiple genomic rearrangements, which hint at a potential replication dependent DNA repair mechanism. Furthermore, these rearrangements provide an explanation for inconsistent locus rescue results observed by molecular biological approaches. Taken together, we have added an approach to identify and study essential genes in Toxoplasma., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Prostate cancer is the most frequently diagnosed malignancy in men. As cancer progresses from an androgen-sensitive stage to hormone-refractory stage, it turns resistant to androgen ablation therapy. At this stage, effective newer therapies that induce apoptosis are needed for treatment of prostate cancer. DNA oligonucleotides homologous to the telomere 3' overhang (T-oligo) induce apoptosis in several human cancer cells. In the present study, we studied the effect of T-oligo on prostate cancer cells. Our studies showed that androgen-independent DU-145 cells are sensitive to T-oligo in terms of inhibition of proliferation. Moreover, T-oligo induced DU-145 cells to undergo apoptosis. Therefore, our results are encouraging for further investigation in the potential application of T-oligo as a novel therapeutic approach for prostate cancer, especially the androgen-independent.

The impact of heart failure and its treatment on specific nutrient requirements is unknown. Furthermore, depletion of water-soluble B vitamins that play key roles in the production of cellular energy in patients with heart failure can contribute to depletion of energy reserves observed in the failing heart. A cross-sectional study recently reported that approximately one third of hospitalized patients with heart failure had tissue levels suggestive of thiamin deficiency (vitamin B-1). Riboflavin (vitamin B-2) and pyridoxine (vitamin B-6) are similar to thiamin in that they are water-soluble, subject to renal excretion, have limited tissue storage, and are dependent on intake. Therefore, it was hypothesized that the status of these B vitamins may also be adversely affected by heart failure. As a result, the prevalence of patients at risk of vitamin B-2 (erythrocyte glutathione reductase activity coefficient > or = 1.2) and B-6 deficiency (plasma B-6 < or = 20 nmol/L) was determined in a cross-section of 100 patients hospitalized with heart failure between April 2001 and June 2002 as well as in a group of volunteers without heart failure. Twenty-seven percent of patients with heart failure had biochemical evidence of vitamin B-2 deficiency, while 38% had evidence of B-6 deficiency. These prevalence rates were significantly higher than those observed in the volunteers without heart failure (2% and 19%, respectively; P < or = 0.02). Use of common B-vitamin-containing supplements by patients with heart failure did not significantly reduce deficiency rates in comparison with those who did not use supplements (B-2 P=0.38 or B-6 P=0.18)). Finally, while 80% of patients with heart failure took diuretics, neither the dose nor the duration of furosemide use was related to the presence of either B-2 or B-6 deficiency. Given the physiologic importance of these vitamins, further investigations aimed at determining the effect of heart failure on specific nutrient requirements as well as the safety and efficacy of B-vitamin supplementation are warranted.

Translationally controlled tumor protein (TCTP) is a novel anti apoptotic protein which is highly expressed in several cancer cell types including prostate cancer. However, studies investigating the role of TCTP in prostate cancer are scarce. Therefore, in this study we evaluated the effect of small interference RNA (siRNA) based knocking down of TCTP gene in prostate cancer cells. Cell proliferation and apoptosis were evaluated. Our results showed that TCTP is highly expressed in LNCaP cells compared to normal prostate epithelial cells. Transfection with TCTP siRNA specifically and drastically reduced the expression of both mRNA and protein levels of TCTP in LNCaP cells. The decreased expression of TCTP was associated with decreased viability of LNCaP cells. Further analysis of the transfected LNCaP cells showed that they undergo apoptosis via caspase-8 and caspase-3 dependent pathways. Results presented herein suggest a potential therapeutic application for prostate cancer by targeting TCTP gene using an siRNA approach.

High mobility group box protein 1 (HMGB1), transcriptional activity regulatory protein is associated with most cancers including prostate cancer. To investigate the effects of down-regulation of HMGB1 expression, we have transfected LNCaP cells with four short hairpin RNA (shRNA) targeting HMGB1 plasmid vectors. Transfection with the four shRNAs efficiently and specifically reduced the HMGB1 expression in LNCaP cells. The gene silencing effects on HMGB1 expression were subsequently confirmed by RT-PCR and immunoblotting analyses. Down-regulation of HMGB1 expression resulted in the inhibition of cell growth in LNCaP prostate cancer cells and the decreased cell number was due to transfected cells undergoing apoptosis via caspase-3-dependent pathways. These findings suggest that HMGB1 is critical for the survival of prostate cancer cells and targeted knockdown of HMGB1 mRNA can be used as a strategy to kill prostate cancer cells. Our findings may have some potential therapeutic relevance for treating prostate cancer.

Over 2 million Americans are currently living with prostate cancer. Current chemotherapeutic strategies are only partially effective in controlling the disease. There is always a need for an effective newer drug for treating prostate cancer. Use of active principles from medically important herbs has proven to be effective in treating various forms of cancers. Glycyrrhizin, a triterpene compound isolated from roots of licorice has been found to exhibit potent in vitro cytotoxic activity against several human cancer cell lines. In this study, we evaluated the effects of glycyrrhizin on the viability of two human prostate cancer cells LNCaP (hormone-dependent) and DU-145 (hormone-independent) in vitro. Cell viability assay showed that glycyrrhizin inhibited the cell proliferation of prostate cancer cells in a time- and dose-dependent manner. The decreased viability of prostate cancer cells was due to apoptosis as confirmed by Annexin-V FITC flow cytometric analyses. Glycyrrhizin also caused DNA damage in DU-145 and LNCaP cells in a time-dependent manner. Caspase-3 and -8 activities were not detected in glycyrrhizin-treated prostate cancer cells suggesting that caspase-independent pathways may be involved in the apoptotic mechanism. Collectively, these studies suggest that glycyrrhizin has therapeutic potential against prostate cancer.