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Modified 9 Cr–1 Mo is an ideal candidate preferred for high temperature applications in power plants. In this study, three P91 welds of 12 mm thickness are produced using Gas Tungsten Arc Welding (GTAW), Cold Metal Transfer (CMT) and Pulsed-CMT (P-CMT) processes. The impact toughness is evaluated in the as-welded as well as in the PWHT (760 °C-2 h) condition. It is found that P-CMT process resulted in the highest toughness in both the conditions. The heat input was maximum in the case of GTAW (800 J/mm) welds and minimum in CMT (330 J/mm). Even though P-CMT (380 J/mm) has heat input slightly above CMT, the former is compensated by higher welding speeds. Electron microscopy analysis revealed the presence of fine M23C6 and MX precipitates. Among the welds, P-CMT had minimal amount of the precipitates whereas GTAW welds had the maximum. The dimple morphology observed in the ruptured surface significantly varied and P-CMT process had finer dimples indicating finer weld microstructures and enhanced mechanical properties. Keywords: P-CMT, P91, Weld, PWHT, Heat input, Toughness

The immune pathways that define treatment response and non-response in lupus nephritis (LN) are unknown. To characterize these intra-kidney pathways, transcriptomic analysis was done on protocol kidney biopsies obtained at flare (initial biopsy (Bx1)) and after treatment (second biopsy (Bx2)) in 58 patients with LN. Glomeruli and tubulointerstitial compartments were isolated using laser microdissection. RNA was extracted and analyzed by nanostring technology with transcript expression from clinically complete responders, partial responders and non-responders compared at Bx1 and Bx2 and to the healthy controls. Top transcripts that differentiate clinically complete responders from non-responders were validated at the protein level by confocal microscopy and urine ELISA. At Bx1, cluster analysis determined that glomerular integrin, neutrophil, chemokines/cytokines and tubulointerstitial chemokines, T cell and leukocyte adhesion genes were able to differentiate non-responders from clinically complete responders. At Bx2, glomerular monocyte, extracellular matrix, and interferon, and tubulointerstitial interferon, complement, and T cell transcripts differentiated non-responders from clinically complete responders. Protein analysis identified several protein products of overexpressed glomerular and tubulointerstitial transcripts at LN flare, recapitulating top transcript findings. Urine complement component 5a and fibronectin-1 protein levels reflected complement and fibronectin expression at flare and after treatment. Thus, transcript analysis of serial LN kidney biopsies demonstrated how gene expression in the kidney changes with clinically successful and unsuccessful therapy. Hence, these insights into the molecular landscape of response and non-response may help align LN management with the pathogenesis of kidney injury., (Copyright © 2022 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Gene fusions involving the neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2, and NTRK3, are well established oncogenic drivers in a broad range of pediatric and adult tumors. These fusions are also important actionable markers, predicting often dramatic response to FDA approved kinase inhibitors. Accurate interpretation of the clinical significance of NTRK fusions is a high priority for diagnostic laboratories, but remains challenging and time consuming given the rapid pace of new data accumulation, the diversity of fusion partners and tumor types, and heterogeneous and incomplete information in variant databases and knowledgebases. The ClinGen NTRK Fusions Somatic Cancer Variant Curation Expert Panel (SC-VCEP) was formed to systematically address these challenges and create an expert-curated resource to support clinicians, researchers, patients and their families in making accurate interpretations and informed treatment decisions for NTRK fusion-driven tumors. We describe a system for NTRK fusion interpretation (including compilation of key elements and annotations) developed by the NTRK fusions SC-VCEP. We illustrate this stepwise process on examples of LMNA::NTRK1 and KANK1::NTRK2 fusions. Finally, we provide detailed analysis of current representation of NTRK fusions in public fusion databases and the CIViC knowledgebase, performed by the NTRK fusions SC-VCEP to determine existing gaps and prioritize future curation activities., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Introduction: Membranous nephropathy (MN) is a common cause of adult nephrotic syndrome that progresses to end-stage kidney disease in up to 40% of cases. It is an autoimmune disease characterized by glomerular subepithelial deposits containing IgG. In experimental MN, these deposits activate complement and cause kidney damage. The role of complement in human MN is less clearly defined. To address this, the current study focused on the role of complement in 2 independent primary (p) MN cohorts., Methods: Glomeruli were isolated by laser capture microdissection and analyzed by mass spectrometry, focusing on complement proteins, from kidney biopsy specimens from a pMN cohort (n = 11) and from normal controls (n = 5). Immunohistological staining of kidney biopsy specimens for complement proteins was also done. In a second pMN cohort (n = 13), urine levels of Ba, C5a, and C5b-9 (membrane attack complex [MAC]) were measured., Results: Mass spectrometry identified 8 complement pathway components (C1q, C3, C4, C5, C6, C7, C8, and C9) and 5 complement regulators (complement receptor type 1 [CR1], factor H [FH], FH-related protein 2 [FHR2], vitronectin, and clusterin). All complement levels were significantly higher in the MN groups than in the control group, except the level of CR1, which was lower. All pMN biopsy specimens showed negative or trace staining for C1q, positive staining for C3 and C4, and positive staining for at least 1 component of the lectin pathway. Urine Ba, C5a, and MAC were present in pMN, and their levels correlated ( r Ba,C5a  = 0.87, r Ba,MAC  = 0.89, and r C5a,MAC  = 0.97, P  = .001 for each correlation)., Conclusion: Elevated glomerular levels of C3, C4, and components of MAC (C5b-9) and absent or decreased levels of the complement regulator CR1, along with increased levels of complement activation products in the urine, support the involvement of complement in the pathogenesis of MN. These data raise the possibility that anti-complement therapies may be effective in some forms of MN., (© 2020 International Society of Nephrology. Published by Elsevier Inc.)

Neoplasms arising from the diaphragm are not typically seen in clinical practice, though they may inflict significant morbidity and mortality. In the realm of thoracic surgery, osteochondromas are only encountered at the thoracic wall or vertebra. In this study, we describe a case of an osteochondroma arising from the diaphragm masquerading as a malignant lesion. The tumor was resected via robotic-assisted means and the patient was discharged with no complications., (Copyright © 2020 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Corrective surgery for pectus excavatum often relies on the Haller index (HI), derived from chest roentgenograms or computed tomography; however, this exposes children to potentially unnecessary radiation. Our aim was to develop a novel three-dimensional (3D) optical imaging technique to accurately measure chest wall dimensions in a clinically relevant manner., Methods: Patients with pectus excavatum were imaged using a 3D structured light scanner. Patient characteristics, including height, weight, body mass index, and radiographic HIs (rHI) were recorded. We defined the optical index (OI) as the ratio of the lateral to anterior-posterior measurements obtained from the 3D optical images and compared those to patients' rHIs. Two-thirds of the patients' images were used to develop a predictive model of the rHI, using their OI and biometric data in multilinear regression modeling. The predictive model was applied to the remaining images, and the predicted HIs (pHI) were compared to the rHIs., Results: Optical imaging was performed in 42 patients (ages, 5-35 years) with pectus excavatum; of these, 31 had recent chest roentgenograms, with rHIs ranging from 2.00 to 7.20. The OIs derived from the images correlated closely with rHIs (r = 0.850). Our predictive model, using patients' OI, height, and weight, was able to accurately estimate their rHIs with a median error of 8.11% (interquartile range, 3.5%-17.4%)., Conclusions: 3D optical imaging of patients with pectus excavatum is emerging as an alternative method to assess HIs without the use of ionizing radiation. Additional studies will focus on volumetric quantification of chest wall deformities, using the 3D capabilities of this technology., (Copyright © 2019 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

The mammalian target of rapamycin (mTOR) and associated phosphatidylinositol 3-kinase/AKT/mTOR signaling pathway is commonly up-regulated in cancer, including bladder cancer. mTOR complex 2 (mTORC2) is a major regulator of bladder cancer cell migration and invasion, but the mechanisms by which mTORC2 regulates these processes are unclear. A discovery mass spectrometry and reverse-phase protein array-based proteomics dual approach was used to identify novel mTORC2 phosphoprotein targets in actively invading cancer cells. mTORC2 targets included focal adhesion kinase, proto-oncogene tyrosine-protein kinase Src, and caveolin-1 (Cav-1), among others. Functional testing shows that mTORC2 regulates Cav-1 localization and dynamic phosphorylation of Cav-1 on Y14. Regulation of Cav-1 activity by mTORC2 also alters the abundance of caveolae, which are specialized lipid raft invaginations of the plasma membrane associated with cell signaling and membrane compartmentalization. Our results demonstrate a unique role for mTORC2-mediated regulation of caveolae formation in actively migrating cancer cells., (Copyright © 2019 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Objective: Non-invasive brain stimulation (NIBS), such as repetitive TMS (rTMS) and transcranial direct current stimulation (tDCS), are promising neuromodulatory priming techniques to promote task-specific functional recovery after stroke. Despite promising results, clinical application of NIBS has been limited by high inter-individual variability. We propose that there is a possible influence of neuromodulation on cerebral blood flow (CBF), as neurons are spatially and temporally related to blood vessels. Transcranial Doppler (TCD), a clinically available non-invasive diagnostic tool, allows for evaluation of CBF velocity (CBFv). However, little is known about the role of neuromodulation on CBFv., Methods: A systematic review of literature to understand the effects of NIBS on CBFv using TCD in stroke was conducted., Results: Twelve studies fit our inclusion criteria and are included in this review. Our review suggested that CBFv and/or vasomotor reactivity maybe influenced by rTMS dosage (intensity and frequency) and the type of tDCS electrode montage., Conclusion: There is limited evidence regarding the effects of NIBS on cerebral hemodynamics using TCD and the usefulness of TCD to capture changes in CBFv after NIBS is not evident from this review. We highlight the variability in the experimental protocols, differences in the applied neurostimulation protocols and discuss open questions that remain regarding CBF and neuromodulation., Significance: TCD, a clinically accessible tool, may potentially be useful to understand the interaction between cortical neuromodulation and CBFv., (Copyright © 2018 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.)

Background: Rheumatic mitral stenosis constitutes a major cause of acquired heart disease complicating pregnancy in India. In the present study, we have studied the fetal and maternal outcomes of women undergoing balloon mitral valvotomy during pregnancy., Methods and Results: 49 pregnant ladies were included in this study in whom balloon mitral valvotomy was performed. The mean age of these patients was 25.7±3.1 years. The mean gestational age was 23.5±5.2 weeks (12-36 weeks). The procedure was successful in 48 patients (95.9%). Mean two-dimensional MVA increased from baseline value of 0.93±0.17cm 2 to 1.75±0.27cm 2 (p value <0.0001). Pre-procedure peak pulmonary artery pressure was 43.05±15.88mmHg, which decreased to 22.31±6.36mmHg (p value <0.0001). Hemodynamic data showed pre-BMV left atrial mean pressure of 29.6±6.6mmHg, which decreased to 13.7±4.8mmHg after the procedure (p value <0.0001). Mean fluoroscopy time was 6.4±1.2min. There was no maternal mortality in our study. One procedure had to be abandoned, because of failed septal puncture. One of the patients developed cardiac tamponade and another patient developed severe mitral regurgitation, which were managed medically. The patient who developed severe mitral regurgitation later underwent mitral valve replacement. Post-procedure follow-up showed an improvement in NYHA status by at least one class in 81.3% of patients. Thirty-nine (81.3%) patients had a term normal vaginal delivery and 8 (16.7%) underwent cesarean section for obstetric indications. One of the patients had abortion on the second day of the procedure., Conclusion: Percutaneous mitral valvotomy during pregnancy is safe and provides excellent symptomatic relief and hemodynamic improvement. This should be considered as the treatment of choice when managing pregnant women with severe mitral stenosis., (Copyright © 2016 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Binding of intercellular adhesion molecule-1 to the β2-integrin leukocyte function associated antigen-1 (LFA-1) is known to induce cross-talk to the α4β1 integrin. Using different LFA-1 monoclonal antibodies, we have been able to study the requirement and mechanism of action for the cross-talk in considerable detail. LFA-1-activating antibodies and those inhibitory antibodies that signal to α4β1 induce phosphorylation of Thr-758 on the β2-chain, which is followed by binding of 14-3-3 proteins and signaling through the G protein exchange factor Tiam1. This results in dephosphorylation of Thr-788/789 on the β1-chain of α4β1 and loss of binding to its ligand vascular cell adhesion molecule-1. The results show that with LFA-1 antibodies, we can activate LFA-1 and inhibit α4β1, inhibit both LFA-1 and α4β1, inhibit LFA-1 but not α4β1, or not affect LFA-1 or α4β1 These findings are important for the understanding of integrin regulation and for the interpretation of the effect of integrin antibodies and their use in clinical applications., (© 2016 by The American Society of Hematology.)

Cor triatriatum sinistrum is an extremely rare congenital heart disease. It is even more uncommon in adults, and clinically significant mitral valve lesion complicating cor triatriatum is distinctly rare. Wong et al reported for the first time the rare combination of cor triatriatum sinister associated with severe mitral regurgitation and abnormal tensor apparatus of the mitral valve. We report a similar case and used the term Wong's anomaly for the syndrome, having membranous type of cor triatriatum sinistrum, severe mitral regurgitation and hypoplasia of the papillary muscles and short chordae. Color Doppler Echocardiography showed peculiar 'helmet sign' of mitral regurgitation, wherein the mitral regurgitation color jet fills the distal atrial chamber and abruptly ends in a horizontal plane as it is halted by the intra-atrial membrane., (Copyright © 2015 Cardiological Society of India. Published by Elsevier B.V. All rights reserved.)

Background: Transcranial direct current stimulation (tDCS), an emerging technique of noninvasive brain stimulation, has shown to produce beneficial neural effects in consequence with improvements in motor behavior. There are not many studies examining the use of tDCS for lower limb motor control and learning. Most studies using tDCS for facilitating lower limb motor coordination have applied tDCS to the lower limb motor cortex (M1). As the cerebellum is also critically involved in movement control, it is important to dissociate the effect of tDCS on the cerebellum and M1 with respect to lower limb motor control before we begin the application of tDCS as a neuromodulatory tool., Objective/hypothesis: The purpose of this study was to determine the effects of cerebellar vs. motor cortical tDCS on short term ankle visuomotor learning in healthy individuals., Methods: Eight healthy individuals practiced a skilled ankle motor tracking task while receiving either facilitatory anodal tDCS to cerebellum, inhibitory cathodal tDCS to cerebellum, facilitatory anodal tDCS to M1, inhibitory cathodal tDCS to M1 or sham stimulation. Pre- and post-measures of changes in cortical excitability of the tibialis anterior muscle and measures of tracking accuracy were assessed., Results: Anodal cerebellar, cathodal cerebellar, and anodal M1 stimulation improved target-tracking accuracy of the ankle. This was not dependent on the observed changes in motor cortical excitability of the tibialis anterior muscle., Conclusion(s): Polarity independent effects of tDCS on cerebellum were observed. The present study shows that modulation effects of tDCS can occur because of changes in the cerebellum, a structure implicated in several forms of motor learning, providing an additional way in which tDCS can be used to improve motor coordination., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Biologically accurate mouse models of human cancer have become important tools for the study of human disease. The anatomical location of various target organs, such as brain, pancreas, and prostate, makes determination of disease status difficult. Imaging modalities, such as magnetic resonance imaging, can greatly enhance diagnosis, and longitudinal imaging of tumor progression is an important source of experimental data. Even in models where the tumors arise in areas that permit visual determination of tumorigenesis, longitudinal anatomical and functional imaging can enhance the scope of studies by facilitating the assessment of biological alterations, (such as changes in angiogenesis, metabolism, cellular invasion) as well as tissue perfusion and diffusion. One of the challenges in preclinical imaging is the development of infrastructural platforms required for integrating in vivo imaging and therapeutic response data with ex vivo pathological and molecular data using a more systems-based multiscale modeling approach. Further challenges exist in integrating these data for computational modeling to better understand the pathobiology of cancer and to better affect its cure. We review the current applications of preclinical imaging and discuss the implications of applying functional imaging to visualize cancer progression and treatment. Finally, we provide new data from an ongoing preclinical drug study demonstrating how multiscale modeling can lead to a more comprehensive understanding of cancer biology and therapy., (Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Purpose: Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases., Methods: Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM(1,2,6), MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases., Results: A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM(1,2,6), MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM(1,2,6), 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases., Conclusion: Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients.

Background: Nosocomial Acinetobacter infections are an increasing concern in intensive care units (ICU)., Objectives: To study the demographic and clinical characteristics and the outcomes of ICU patients with Acinetobacter infections., Methods: A retrospective, 1-year audit of all Acinetobacter infections diagnosed in ICU patients between January 1 and December 31, 2009., Results: Acinetobacter infection occurred in 94 patients (108 episodes). The most common site of infection was the respiratory tract (83 patients, 76.85%), with medical patients being more susceptible than surgical patients to Acinetobacter lung infections (P=0.04), particularly late-onset ventilator-associated pneumonia (VAP) (P=0.04). The majority (63.8%) of infections were acquired in the ICU, and patients with ICU acquired infections were intubated significantly longer than the other patients (P=0.02). Seventy percent of the infections were caused by multidrug-resistant (MDR) strains, and the overall crude mortality rate was over 70%. The most important factors affecting mortality were the duration of intubation (P=0.001) and the inappropriate use of antibiotics (P=0.021) after diagnosis of the infection., Conclusions: Acinetobacter infections are highly prevalent in the ICU, with medical patients being more susceptible to lung infections, particularly late-onset VAP. The early and appropriate selection of antibiotics is the most important determinant of survival among these patients., (Copyright © 2012 King Saud Bin Abdulaziz University for Health Sciences. Published by Elsevier Ltd. All rights reserved.)

Currently, cancer therapy remains limited by a "one-size-fits-all" approach, whereby treatment decisions are based mainly on the clinical stage of disease, yet fail to reference the individual's underlying biology and its role driving malignancy. Identifying better personalized therapies for cancer treatment is hindered by the lack of high-quality "omics" data of sufficient size to produce meaningful results and the ability to integrate biomedical data from disparate technologies. Resolving these issues will help translation of therapies from research to clinic by helping clinicians develop patient-specific treatments based on the unique signatures of patient's tumor. Here we describe the Georgetown Database of Cancer (G-DOC), a Web platform that enables basic and clinical research by integrating patient characteristics and clinical outcome data with a variety of high-throughput research data in a unified environment. While several rich data repositories for high-dimensional research data exist in the public domain, most focus on a single-data type and do not support integration across multiple technologies. Currently, G-DOC contains data from more than 2500 breast cancer patients and 800 gastrointestinal cancer patients, G-DOC includes a broad collection of bioinformatics and systems biology tools for analysis and visualization of four major "omics" types: DNA, mRNA, microRNA, and metabolites. We believe that G-DOC will help facilitate systems medicine by providing identification of trends and patterns in integrated data sets and hence facilitate the use of better targeted therapies for cancer. A set of representative usage scenarios is provided to highlight the technical capabilities of this resource.

Objective: Muscle weakness develops rapidly after stroke, adversely affecting motor performance, and contributing to reduced functional ability. While the contributions of structural and functional alterations in skeletal muscle to post-stroke weakness have been well described, the relationship between motor pathway integrity, measured using both radiological and electrophysiological techniques, and post-stroke muscle weakness is not clear. This study sought to determine the role of corticospinal tract (CST) integrity on knee extensor weakness in chronic stroke survivors., Methods: Knee extensor strength and activation testing were performed at 90° of knee flexion using an interpolated triplet technique. CST integrity was evaluated using data obtained from Diffusion Tensor Imaging and transcranial magnetic stimulation., Results: Recordings in nine stroke subjects indicated substantial knee extensor weakness and activation deficits in the paretic legs of the stroke survivors. Regression analysis revealed that asymmetry in CST integrity was strongly related to between-leg differences in knee strength., Conclusions: The results of this study suggest a strong link between CST integrity and lower extremity strength, and add to the growing evidence of substantial knee extensor weakness and activation impairments in stroke survivors., Significance: The findings from this study further our understanding of the anatomical and neurophysiological contributions to motor impairments after stroke, which may benefit clinicians and researchers in the field of stroke rehabilitation., (Copyright © 2011 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Objective: Knee surgery may alter the neuromuscular response to unexpected perturbations during functional, dynamic tasks. Long latency reflexes (LLR) follow a transcortical pathway and appear to be modifiable by task demands, potentially giving them a role in neuromuscular performance. We examined LLRs of the quadriceps and hamstrings in response to unexpected perturbations in individuals with a repaired anterior cruciate ligament (ACLR) during a weight-bearing task. We also investigated the anticipatory and volitional muscle activity that preceded and followed the LLR to quantify possible reflex adaptations associated with surgical repair., Methods: Twelve females with ACLR and 12 healthy female controls performed a single leg squat maneuver, tracking a sinusoidal target. Random perturbations at the start of the flexion phase yielded tracking errors ("overshoot errors") and triggered compensatory reflex activity., Results: ACLR subjects demonstrated greater overshoot error and knee velocity during unexpected perturbations, increased LLR responses, and reduced absolute anticipatory, short-latency reflex, and voluntary quadriceps activity., Conclusions: ACLR subjects showed impaired response to perturbation and a distinct EMG profile during a dynamic single leg weight-bearing task. Future research will determine the cause of neural adaptations in those with ACLR., Significance: Neuromuscular adaptations may be a viable target for post-ACL injury rehabilitation interventions., (Copyright © 2010 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.)

Mainstream research and the popular media often equate female-headship with household vulnerability, crisis, and disorganization. Epidemic levels of HIV/AIDS in some parts of sub-Saharan Africa compound this portrait of hopelessness. In South Africa, the impact of HIV/AIDS on households depends on race, class, and place. As female-headed households increase in number, we need to better understand how female-heads in poor rural areas contend with AIDS related challenges. We analyze qualitative interviews with 16 female heads and the members of their households in a rural community to examine the response to AIDS-related illness, death, or caring for orphaned children. Our analysis examines female-heads' financial and social resources and how these resources buffer against hardship in households affected by AIDS. We find considerable heterogeneity among rural female-headed households and their access to resources to combat AIDS-related hardship. Our findings have important policy implications both in terms of identifying individual and household vulnerabilities as well as leveraging the potential for resilience for female-heads in rural South African communities., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Because we are interested in non-invasive transcranial brain stimulation as an adjuvant to post-stroke walking therapy, we applied direct current stimulation (tDCS) preferentially to either the left or right lower limb motor cortex (M1) in two separate sessions and assessed the resulting modulation in both cortices., Objective/hypothesis: We hypothesized that tDCS applied preferentially to one lower limb M1 of healthy subjects would induce between-hemisphere opposite sign modulation., Methods: Transcranial magnetic stimulation (TMS) with the coil offset 2 cm either side of vertex was used to assess the percent change in rectified motor evoked potential (MEP) area recorded bilaterally from vastus lateralis (VL) and tibialis anterior (TA) of 10 subjects during weak tonic contraction., Results: ANOVA revealed an up-regulation of the target cortex and a down-regulation of the non-target cortex (p = 0.001) and no effects of hemisphere (left, right) or muscle (TA, VL). Significant modulation was evident in 78% of VL and TA muscles (all p < 0.05). Excitability increased in 60%, but decreased in 18%. For 43% when excitability increased, a simultaneous decrease in excitability was evident in homologous muscle responses providing support for our hypothesis., Conclusions: The results indicate a modest effectiveness and focality of anodal tDCS when applied to lower limb M1, suggesting in a human model that the strength and depth of polarizing cortical currents induced by tDCS likely depend on inter-individual differences in the electrical properties of superficial brain structures.

Interleukin-6 (IL-6) has been shown to rescue enterocytes from hypoxia-induced apoptosis when given orally following hemorrhagic shock. In vitro models using an intestinal epithelial cell line (IEC-6) cultured with lipopolysaccharide (LPS) under low O2 conditions, to mimic intestinal conditions, show that these cells also undergo apoptosis, which can be reduced by subsequent culture with IL-6. To examine further the mechanisms of rescue, we cultured normal rat intestinal epithelial cells (IEC-6) under both normoxic and hypoxic conditions and analyzed their responses to LPS and IL-6. We showed that IEC-6 expressed IL-6 receptor on its surface. Further, IEC-6 cells could be rescued from hypoxia-induced apoptosis by co-culture with IL-6. RNase protection assay (RPA) examination revealed that under hypoxic conditions, IEC-6 cells that were resistant to apoptosis showed reduced fas expression and increased bcl-2 expression after co-culture with LPS+IL-6.

Objective: To estimate the processing time and neuromuscular delay required to extract and process sensory information from the ankle in order to coordinate an upper extremity movement sequence., Methods: Nineteen able-bodied subjects were tested on their ability to perform a motor task that involved extension of their left index finger when their left ankle was passively plantar flexed at random velocities through a predetermined target angle., Results: We found that the able-bodied subjects were able to adjust their finger responses up to ankle velocities of 70 degrees /s (300 ms). Reaction time, defined as the delay between onset of ankle rotation and how quickly the index finger could be extended, was 215 ms. The processing time and conduction delay was estimated to be approximately 85 ms., Conclusions: These results indicate that the nervous system processes kinesthetic input related to joint rotation of the ankle with the central mechanisms to execute a planned coordinated task with the upper extremity., Significance: The time required to process proprioceptive information from the leg to perform a coordinated task with the upper extremity may vary throughout the lifespan. Understanding the effects of age, exercise, or injury on proprioceptive processing time may have important clinical implications.

Pharmacies have been recommended as alternative sites for the delivery of immunization services, especially to medically underserved adults and children in inner cities and rural areas. Currently, 35 of 50 states in the USA have legalized the administration of vaccines by pharmacists on the basis of certain training requirements and specific protocols. Since the role of pharmacists is expected to expand, it is important to assess the factors that would enable them to improve the delivery of immunization services and the acceptance of these services by communities. It is particularly important for pharmacists to have knowledge of community circumstances and be able to respond to community needs. This case study of a pharmacy immunization programme (PIP) in rural West Virginia assessed how well pharmacists were aware of community circumstances and which community factors affected the utilization of pharmacy-delivered immunizations. Our findings suggest that although pharmacists played important roles as facilitators, hosts and motivators in PIP, they overestimated the trust placed in them by community members. The convenient locations of pharmacies and the convenient times when they offered immunization services were found to be the determining factors of mothers' decisions to take their children to these places for their vaccinations. The study concludes that as the use of pharmacies as sources of immunization is expected to continue to expand, pharmacists should take these factors into consideration when they decide to offer immunizations.

Several independent research studies have shown that consumption of green tea reduces the development of cancer in many animal models. Epidemiological observations, though inconclusive, are suggesting that green tea consumption may also reduce the risk of some cancers in humans. These anti-carcinogenic effects of green tea have been attributed to its constituent polyphenols. Angiogenesis is a crucial step in the growth and metastasis of cancers. We have investigated the effect of the major polyphenolic constituent of green tea, epigallocatechin-3-gallate (EGCG), on the tube formation of human umbilical vein endothelial cells (HUVEC) on matrigel. Tube formation was inhibited by treatment both prior to plating and after plating endothelial cells on matrigel. EGCG treatment also was found to reduce the migration of endothelial cells in matrigel plug model. The role of matrix metalloproteinases (MMP) has been shown to play an important role during angiogenesis. Zymography was performed to determine if EGCG had any effect on MMPs. Zymographs of EGCG-treated culture supernatants modulated the gelatinolytic activities of secreted proteinases indicating that EGCG may be exerting its inhibitory effect by regulating proteinases. These findings suggest that EGCG acts as an angiogenesis inhibitor by modulating protease activity during endothelial morphogenesis., ((c) 2002 Elsevier Science (USA).)

Background: Population-wide restriction of dietary sodium has been recommended. However, little evidence directly links sodium intake to morbidity and mortality. The aim of this study was to assess the relation of sodium intake to subsequent all-cause and cardiovascular-disease (CVD) mortality in a general population., Methods: The first National Health and Nutrition Examination Survey established baseline information during 1971-75 in a representative sample of 20729 US adults (aged 25-75). 11348 underwent medical examination and nutritional examination based on 24 h recall. Two had no data on sodium intake available. Vital status at June 30, 1992, was obtained for the 11346 participants through interview, tracing, and searches of the national death index. Mortality was examined in sex-specific quartiles of sodium intake, calorie intake, and sodium/calorie ratio. Multiple regression analyses were done to assess the relations with mortality., Findings: There were 3923 deaths, of which 1970 were due to CVD. All-cause mortality (per 1000 person-years; adjusted for age and sex) was inversely associated with sex-specific quartiles of sodium intake (lowest to highest quartile 23.18 to 19.01, p<0.0001) and total calorie intake (25.03 to 18.40, p<0.0001) and showed a weak positive association with quartiles of sodium/calorie ratio (20.27 to 21.71, p=0.14). The pattern for CVD mortality was similar (sodium 11.80 to 9.60, p<0.0019; calories 12.80 to 8.94, p<0.0002; sodium/calorie ratio 9.73 to 11.35, p=0.017). In Cox multiple regression analysis, sodium intake was inversely associated with all-cause (p=0.0069) and CVD mortality (p=0.086) and sodium/calorie ratio was directly associated with all-cause (p=0.0004) and CVD mortality (p=0.0056). By contrast, calorie intake in the presence of the two measures of sodium intake was not independently associated with mortality (all-cause p=0.86; CVD p=0.74). Analysis restricted to participants with no history of CVD at baseline gave similar results., Interpretation: This observational study does not justify any particular dietary recommendation. Specifically, these results do not support current recommendations for routine reduction of sodium consumption, nor do they justify advice to increase salt intake or to decrease its concentration in the diet.

Background: Short-acting calcium antagonists may increase coronary artery morbidity, mortality, and non-cardiovascular complications in hypertensive patients. We assessed whether this association was also true for long-acting calcium antagonists., Methods: We did a case-control study, which was nested within a systematic hypertension control programme for a prospective cohort of 4350 people (first seen 1981-94). Cases (n = 189) were hypertensive patients who had had a first cardiovascular event, including all cardiovascular deaths and hospitalisations, between 1989 and 1995. Controls (n = 189) were individually matched to cases for sex, ethnic origin, age, type of previous antihypertensive treatment, year of entry into the study, and length of follow-up. We collected data on any prescribed drug regimen that was being taken on the event data for cases and on the same date for matched controls. Calcium antagonists were classified by duration of action., Findings: Compared with those on beta-blocker monotherapy, patients on long-acting calcium antagonists (n = 136) had no increased risk of a cardiovascular event (adjusted odds ratio 0.76 [95% CI 0.41-1.43]), whereas patients on short-acting calcium antagonists (n = 27) were at significantly greater risk (adjusted odds ratio 3.88 [1.15-13.11], p = 0.029). Among 38 matched pairs who were both on calcium antagonists, the adjusted risk ratio for short-acting versus long-acting was 8.56 (1.88-38.97), p < 0.01., Interpretation: Long-acting and short-acting calcium antagonists differ in cardiovascular outcomes. Consistent with earlier findings, the use of short-acting calcium antagonists was associated with increased risk of a cardiovascular event. This finding highlights the need to complete on-going clinical trials so that the relative cardiovascular impact of various antihypertensive agents can be assessed.

Reduced-sodium diets are frequently recommended for hypertensive patients. To determine the relation of sodium intake to subsequent cardiovascular disease, 24-h urinary excretion of sodium, potassium, and creatinine and plasma renin activity (PRA) were measured in 2937 mildly and moderately hypertensive patients unmedicated for > or = 3-4 wk. Morbidity and mortality in these treated subjects were ascertained. Subjects were stratified by sex-specific quartiles of urinary sodium excretion; race, cardiovascular status, and blood pressure before and during treatment were similar for each stratum. Patients with lower urinary sodium excretion were thinner, excreted less potassium, and had higher PRA. During an average 3.8-y follow-up, 55 myocardial infarctions (MIs) occurred. Incidence of MIs and urinary sodium excretion were inversely associated in the total population and in males but not in females. In males, age- and race-adjusted MI incidence in the lowest compared with the highest quartile of urinary sodium excretion was 11.5 compared with 2.5 (RR: 4.3; 95% CI: 1.7, 10.6). No association was observed between mortality from causes other than cardiovascular disease (n = 11) and urinary sodium excretion. There was a significant linear trend in proportions of MI by quartile of urinary sodium excretion, with a breakpoint after the lowest quartile. In Cox multivariate analysis, the logarithm of PRA, age, systolic blood pressure, and cholesterol as continuous variables, as well as left ventricular hypertrophy and smoking, had a direct association and urinary sodium excretion an inverse, independent association (P = 0.036) with incidence of MI.

To determine the association of renal function and the course of blood pressure in antihypertensive therapy, we studied the changes in serum creatinine as a measure of renal function and in-treatment blood pressure in black and white hypertensive patients. We measured serum creatinine in 2125 mild and moderately hypertensive men during treatment over an average of 5 years. Both unadjusted mean initial and final serum creatinine of 758 blacks (113 and 117 mumol/L respectively) were significantly higher than those of 1367 whites (108 and 107 mumol/L), with a small increase of 4 mumol/L (p < 0.01) for blacks and a fall of 0.9 mumol/L (p > 0.05) for whites. Less than 2% of all patients attained or remained at a final serum creatinine of 177 mumol/L or more. Of this small group (3% blacks, 1.4% whites), 31% had proteinuria at entry. After stratification by in-treatment diastolic blood pressure (< 95 and > or = 95 mm Hg) in each race, mean slopes of reciprocal serum creatinine were estimated, adjusting for age at entry, initial serum creatinine, diastolic pressure, and body-mass index by analysis of covariance. The two adjusted mean slopes did not differ significantly within each race. Multiple regression analysis confirmed that in-treatment diastolic pressure was not independently associated with final serum creatinine. The change in renal function was most likely a reflection of regression towards the mean, and does not support the view that antihypertensive treatment is an important determinant of renal function in mild-to-moderate hypertensive patients. Patients with substantial renal insufficiency may have pre-existing intrinsic renal disease.

High blood pressure (BP) defines a prognostically heterogeneous group. Because BP varies according to time, setting and means of observation, it has been postulated that BP reactivity might better predict cardiovascular disease (CVD) than does unidimensional measurements. To assess BP reactivity, the difference between pretreatment nurse (RN) and physician (MD) diastolic BP (DBP)--systematically recorded in that order--or MD-RN DBP, was obtained in 1737 previously untreated patients with sustained, RN BP greater than or equal to 160 and/or 95 mmHg. Patients stratified by tertiles of MD-RN DBP [(I) less than or equal to - 3, (II) -2 to 3 and (III) greater than or equal to 4 mmHg] were similar by sex, race, age, body mass index, cholesterol, electrocardiography, prior CVD, smoking and pretreatment or attained in-treatment BPs. During 14 years of followup, myocardial infarction (MI) incidence per 1000/year were, tertile I (3.2), II (3.7), III (7.6) (relative risk = 2.4, III vs I + II, p less than 0.05), whereas stroke incidence and non-CVD mortality were evenly distributed. By Cox survival analysis, controlling for other entry characteristics only age, sex and DBP reactivity remained predictive (p less than or equal to 0.03) of MI or total CVD. Thus, BP reactivity, probably a centrally-mediated phenomenon, identifies a subgroup of hypertensives with an increased propensity for MI despite successful BP control.

Lead in soil has been recognized as a public health problem, particularly among children. In recent years, attention has been directed to cumulative adverse effects of lead at low levels of intake. Lead-contaminated soil and dust have been identified as important contributors to blood lead levels. Based on available data on blood lead and lead in soil, an approach has been developed to suggest a permissible level of lead in soil, below which there will be reasonable certainty that adverse health effects will not occur. An acceptable level of 600 ppm of lead in soil suggested as a "safe" level would contribute no more than 5 micrograms/dl to total blood lead of children under 12 years of age. Maximum permissible levels of lead in soil have been recommended based on the dose-response relationship of lead in soil and blood lead in children.