Association Between Hypertension and Kidney Function Decline: The Atherosclerosis Risk in Communities (ARIC) Study.
The relationship between hypertension, antihypertension medication use, and change in glomerular filtration rate (GFR) over time among individuals with preserved GFR requires investigation. Observational study. 14,854 participants from the Atherosclerosis Risk in Communities (ARIC) Study. Baseline hypertension status (1987-1989) was categorized according to the 2017 American College of Cardiology/American Heart Association Clinical Practice Guideline as normal blood pressure, elevated blood pressure, stage 1 hypertension, stage 2 hypertension without medication, or stage 2 hypertension with medication. Slope of estimated GFR (eGFR) at 5 study visits over 30 years. Mixed models with random intercepts and random slopes were fit to evaluate the association between baseline hypertension status and slope of eGFR. At baseline, 13.2%, 7.3%, and 19.4% of whites and 15.8%, 14.9%, and 39.9% of African Americans had stage 1 hypertension, stage 2 hypertension without medication, and stage 2 hypertension with medication. Compared with those with normal blood pressure, the annual eGFR decline was greater in people with higher blood pressure (whites: elevated blood pressure, -0.11mL/min/1.73m2; stage 1 hypertension, -0.15mL/min/1.73m2; stage 2 hypertension without medication, -0.36mL/min/1.73m2; stage 2 hypertension with medication, -0.17mL/min/1.73m2; African Americans: elevated blood pressure, -0.21mL/min/1.73m2; stage 1 hypertension, -0.16mL/min/1.73m2; stage 2 hypertension without medication, -0.50mL/min/1.73m2; stage 2 hypertension with medication, -0.16mL/min/1.73m2). The 30-year predicted probabilities of developing chronic kidney disease stage G3a+with normal blood pressure, elevated blood pressure, stage 1 hypertension, stage 2 hypertension without medication, or stage 2 hypertension with medication among whites were 54.4%, 61.6%, 64.7%, 78.1%, and 70.9%, respectively, and 55.4%, 62.8%, 60.9%, 76.1%, and 66.6% among African Americans. Slope estimated using a maximum of 5 eGFR assessments; differential loss to follow-up. Compared to normotension, baseline hypertension status was associated with faster kidney function decline over 30-year follow-up in a general population cohort. This difference was attenuated among people using antihypertensive medications.


Exposure to endocrine disrupters and nuclear receptor gene expression in infertile and fertile women from different Italian areas.
Within the PREVIENI project, infertile and fertile women were enrolled from metropolitan, urban and rural Italian areas. Blood/serum levels of several endocrine disrupters (EDs) (perfluorooctane sulfonate, PFOS; perfluorooctanoic acid, PFOA; di-2-ethylhexyl-phthalate, DEHP; mono-(2-ethylhexyl)-phthalate, MEHP; bisphenol A, BPA) were evaluated concurrently with nuclear receptors (NRs) gene expression levels (ERa, ERb, AR, AhR, PPARg, PXR) in peripheral blood mononuclear cells (PBMCs). Infertile women from the metropolitan area displayed significantly higher levels of: BPA compared to fertile women (14.9 vs. 0.5 ng/mL serum); BPA and MEHP compared to infertile women from urban and rural areas; enhanced expression levels of NRs, except PPARg. Infertile women from urban and rural areas had PFOA levels significantly higher than those from metropolitan areas. Our study indicates the relevance of the living environment when investigating the exposure to EDs and the modulation of the NR panel in PBMC as a suitable biomarker of the effect, to assess the EDs impact on reproductive health.


Effect of known pathological risk factors on the incidence of metastatic lymph nodes and survival in early-stage vulvar cancer: SEER analysis.
The current study was performed to evaluate the incidence of positive lymph nodes (LNs) in relation to known pathological risk factors, specifically among patients with apparent low-grade, small tumors. We used the Surveillance, Epidemiology, and End Results (SEER) database to retrospectively identify patients with vulvar squamous cell carcinoma (SCC) diagnosed between January 1, 2000, and December 31, 2019, with known tumor size and regional LN examined. A comparison between patients who had positive and negative LNs was conducted to identify risk factors for LN metastases in relation to survival. Subgroup analysis was conducted in patients with diagnosed grade 1 vulvar SCC and tumor size up to 2 cm according to the status of LNs. Multivariate analysis found that both grade of disease and tumor size were significant factors in predicting LN status. Among patients with low-grade small tumors up to 2 cm, the odds ratio for positive LNs was 2.5 for those with tumor size larger than 1 cm. In a multivariate survival analysis, older age, larger tumor size, and positive LNs were independently associated with decreased survival. The current study confirms that among small tumors, those larger than 1 cm have a significantly increased risk for positive nodes compared with those smaller than 1 cm, and, among this specific group, patients with positive nodes have decreased survival. Future studies are needed to answer the question of whether, in the era of the sentinel node procedure, it is safe to omit LN evaluation altogether.


[Comment on the perception of risk and its relationship to advancements in health knowledge].
Since World War II, industrialized Western societies have been making significant public investments that have yielded spectacular improvements in the health status of their populations. Yet despite such considerable strides, it is nonetheless evident that lay peoples are expressing both more scepticism than in the past and greater mistrust toward medical science and biomedicine, even as they show increasing concern about health risks. In this article we intend to discuss some of the broader opportunities that the analysis of lay risk perceptions offers for appreciating the concerns of lay peoples about health-related issues as well as to provide new insights in population health.


MM-SFENet: multi-scale multi-task localization and classification of bladder cancer in MRI with spatial feature encoder network.
Bladder cancer is a common malignant urinary carcinoma, with muscle-invasive and non-muscle-invasive as its two major subtypes. This paper aims to achieve automated bladder cancer invasiveness localization and classification based on MRI. Different from previous efforts that segment bladder wall and tumor, we propose a novel end-to-end multi-scale multi-task spatial feature encoder network (MM-SFENet) for locating and classifying bladder cancer, according to the classification criteria of the spatial relationship between the tumor and bladder wall. First, we built a backbone with residual blocks to distinguish bladder wall and tumor; then, a spatial feature encoder is designed to encode the multi-level features of the backbone to learn the criteria. We substitute Smooth-L1 Loss with IoU Loss for multi-task learning, to improve the accuracy of the classification task. By testing a total of 1287 MRIs collected from 98 patients at the hospital, the mAP and IoU are used as the evaluation metrics. The experimental result could reach 93.34\% and 83.16\% on test set. The experimental result demonstrates the effectiveness of the proposed MM-SFENet on the localization and classification of bladder cancer. It may provide an effective supplementary diagnosis method for bladder cancer staging.


Commentary: Predictors of postoperative adverse events after cone reconstruction for Ebstein's anomaly.
Prediction scores and metrics are being increasingly utilized throughout the fields of cardiothoracic and congenital cardiac surgery to identify areas for perioperative optimization or guide therapeutic intent. Here, we review a novel submission by Yang and colleagues to the Journal of Cardiac Surgery identifying preoperative factors that predict adverse postoperative outcomes from cone reconstruction for Ebstein's anomaly.


Development of a Tool to Assess Surgical Resident Competence On-Call: The Western University Call Assessment Tool (WUCAT).
A central tenet of competency-based medical education is the formative assessment of trainees. There are currently no assessments designed to examine resident competence on-call, despite the on-call period being a significant component of residency, characterized by less direct supervision compared to daytime. The purpose of this study was to design a formative on-call assessment tool and collect valid evidence on its application. Nominal group technique was used to identify critical elements of surgical resident competence on-call to inform tool development. The tool was piloted over six months in the Division of Plastic & Reconstructive Surgery at our institution. Quantitative and qualitative evidence was collected to examine tool validity. A ten-item tool was developed based on the consensus group results. Sixty-three assessments were completed by seven staff members on ten residents during the pilot. The tool had a reliability coefficient of 0.67 based on a generalizability study and internal item consistency was 0.92. Scores were significantly associated with years of training. We found the tool improved the quantity and structure of feedback given and that the tool was considered feasible and acceptable by both residents and staff members. The Western University Call Assessment Tool (WUCAT) has multiple sources of evidence supporting its use in assessing resident competence on-call.


A novel [89Zr]-anti-PD-1-PET-CT to assess response to PD-1/PD-L1 blockade in lung cancer.
Harnessing the anti-tumor immune system response by targeting the program cell death protein (PD-1) and program cell death ligand protein (PD-L1) axis has been a major breakthrough in non-small cell lung cancer (NSCLC) therapy. Nonetheless, conventional imaging tools cannot accurately assess response in immunotherapy-treated patients. Using a lung cancer syngeneic mouse model responder to immunotherapy, we aimed to demonstrate that [89Zr]-anti-PD-1 immuno-PET is a safe and feasible imaging modality to assess the response to PD-1/PD-L1 blockade in NSCLC. A syngeneic mouse model responder to anti-PD-1 therapy was used. Tumor growth and response to PD-1 blockade were monitored by conventional 2-deoxy-2-[18F]fluoro-D-glucose ([18F]-FDG) PET scans. Additionally, tumor lymphocyte infiltration was analyzed by the use of an [89Zr]-labeled anti-PD-1 antibody and measured as 89Zr tumor uptake. Conventional [18F]-FDG-PET scans failed to detect the antitumor activity exerted by anti-PD-1 therapy. However, [89Zr]-anti-PD-1 uptake was substantially higher in mice that responded to PD-1 blockade. The analysis of tumor-infiltrating immune cell populations and interleukins demonstrated an increased anti-tumor effect elicited by activation of effector immune cells in PD-1-responder mice. Interestingly, a positive correlation between [89Zr]-anti-PD-1 uptake and the proportion of tumor-infiltrating lymphocytes (TILs) was found (Cor = 0.8; p = 0.001). Our data may support the clinical implementation of immuno-PET as a promising novel imaging tool to predict and assess the response of PD-1/PD-L1 inhibitors in patients with NSCLC.


Pretransplant serum vitamin D levels and risk of cancer after renal transplantation.
Serum levels of 25-OH-D3 inversely correlate with the incidence of various types of cancers in the general population. Because risk factors and incidence of cancer in renal transplant recipients (RTRs) are different from the general population, this study was designed to determine whether pretransplant 25-OH-D3 levels could be predictive of cancer risk in RTRs. Pretransplant 25-OH-D3 levels were reviewed in 363 consecutive RTRs. The impact of 25-OH-D3 levels on the development of cancer was then analyzed with respect to other known risk factors. One hundred twenty-four patients (34.2%) showed vitamin D deficiency, 185 (51%) vitamin D insufficiency, and 54 (14.8%) with normal vitamin D levels. Thirty-two cancers (8.8%) occurred in 32 patients. A higher incidence of cancer was observed in patients with vitamin D deficiency (13.7% vs. 7% for patients with vitamin D insufficiency [P=0.068] and 3.7% for those with normal vitamin D levels [P=0.007]). 25-OH-D3 levels were lower in patients who developed cancer after transplantation (13.7+/-6 vs. 18.3+/-17.8 ng/mL, P=0.022). Age (hazard ratio, 1.06; 95% confidence interval, 1.02-1.11, for each 1 year increase; P=0.009) and low 25-OH-D3 levels (hazard ratio, 1.12; 95% confidence interval, 1.04-1.23, for every 1 ng/mL decrease; P=0.021) were independent risk factors for development of cancer. Pretransplant level of 25-OH-D3 is an important determinant for subsequent development of cancer after transplantation. Future studies should examine whether 25-OH-D3 supplementation can effectively decrease the incidence of cancer in RTRs.


Sex Steroids and Major Psychoses: Which Role for DHEA-S and Progesterone.
Endocrine pathways seem to play a role in the etiology of major psychoses. The identification of biomarkers associated with psychotic symptoms in schizophrenia (SKZ) and mood disorders would allow the identification of high-risk subjects for delusions and hallucinations. The aim of this study was to evaluate dehydroepiandrosterone sulfate (DHEA-S) and progesterone plasma levels in drug-free patients with major psychoses and their relation with the diagnosis and history of psychotic symptoms. Eighty-nine consecutive drug-free male inpatients with SKZ or mood disorders were recruited, and DHEA-S and progesterone plasma levels were measured. The groups, divided according to pathological/normal-range hormone levels, were compared in terms of clinical variables using x03C7;2 tests with Bonferroni's corrections or multivariate analyses of variance. The same analyses were performed for groups divided according to the presence/absence of lifetime psychotic symptoms. Binary logistic regression analysis was performed using hormone levels as independent variables and history of lifetime psychotic symptoms as a dependent one. A higher number of patients with abnormal DHEA-S levels was found to have a family history of major depressive disorder (p < 0.05). Higher DHEA-S levels (F = 8.31; p = 0.005) were found in patients with a history of psychotic symptoms. In addition, binary logistic regression confirmed that DHEA-S levels were associated with a higher probability of lifetime psychotic symptoms (p = 0.037). Our results confirm previous data about the role of endocrine factors in the etiology of major psychoses. A high DHEA-S level might be a risk factor for psychotic symptoms. Studies with larger samples are needed to confirm these data.


Nucleation-controlled distributed plasticity in penta-twinned silver nanowires.
A unique size-dependent strain hardening mechanism, that achieves both high strength and ductility, is demonstrated for penta-twinned Ag nanowires (NWs) through a combined experimental-computational approach. Thin Ag NWs are found to deform via the surface nucleation of stacking fault decahedrons (SFDs) in multiple plastic zones distributed along the NW. Twin boundaries lead to the formation of SFD chains that locally harden the NW and promote subsequent nucleation of SFDs at other locations. Due to surface undulations, chain reactions of SFD arrays are activated at stress concentrations and terminated as local stress decreases, revealing insensitivity to defects imparted by the twin structures. Thick NWs exhibit lower flow stress and number of distributed plastic zones due to the onset of necking accompanied by more complex dislocation structures.


High-Intensity Interval Cycling Exercise on Wave Reflection and Pulse Wave Velocity.
Kingsley, JD, Tai, YL, Vaughan, J, and Mayo, X. High-intensity interval cycling exercise on wave reflection and pulse wave velocity. J Strength Cond Res 31(5): 1313-1320, 2017-The purpose of this study was to assess the effects of high-intensity exercise on wave reflection and aortic stiffness. Nine young, healthy men (mean ± SD: age: 22 ± 2 years) participated in the study. The high-intensity interval cycling exercise consisted of 3 sets of Wingate Anaerobic Tests (WATs) with 7.5% of bodyweight as resistance and 2 minutes of rest between each set. Measurements were taken at rest and 1 minute after completion of the WATs. Brachial and aortic blood pressures, as well as wave reflection characteristics, were measured through pulse wave analysis. Aortic stiffness was assessed through carotid-femoral pulse wave velocity (cfPWV). A repeated-measures analysis of variance was used to investigate the effects of the WATs on blood pressure and vascular function across time. There was no change in brachial or aortic systolic pressure from rest to recovery. There was a significant (p ≤ 0.05) decrease in brachial diastolic pressure (rest: 73 ± 6 mm Hg; recovery: 67 ± 9 mm Hg) and aortic diastolic pressure (rest: 75 ± 6 mm Hg; recovery: 70 ± 9 mm Hg) from rest to recovery. In addition, there was no significant change in the augmentation index (rest: 111.4 ± 6.5%; recovery: 109.8 ± 5.8%, p = 0.65) from rest to recovery. However, there was a significant (p ≤ 0.05) increase in the augmentation index normalized at 75 b·min (rest: 3.29 ± 9.82; recovery 21.21 ± 10.87) during recovery compared with rest. There was no change in cfPWV (rest: 5.3 ± 0.8 m·s; recovery: 5.7 ± 0.5m·s; p = 0.09) in response to the WAT. These data demonstrate that high-intensity interval cycling exercise with short rest periods has a nonsignificant effect on vascular function.


Growth, renewal, and challenge: an important era for occupational therapy.
Occupational therapy is facing some important decisions as it approaches a changing health care system. By understanding the prospective payment system it is possible to promote occupational therapy services to a changing marketplace while avoiding major problems. Specific opportunities and strategies are defined to promote occupational therapy to new markets.


Protocol: A grounded theory of 'recovery'-perspectives of adolescent users of mental health services.
Policies internationally endorse the recovery paradigm as the appropriate foundation for youth mental health services. However, given that this paradigm is grounded in the views of adults with severe mental illness, applicability to youth services and relevance to young people is uncertain, particularly as little is known about young people's views. A comprehensive understanding of the experiences and expectations of young people is critical to developing youth mental health services that are acceptable, accessible, effective and relevant. To inform development of policy and youth services, the study described in this protocol aims to develop a comprehensive account of the experiences and expectations of 12-17 year olds as they encounter mental disorders and transition through specialist mental health services. Data will be analysed to model recovery from the adolescents' perspective. This grounded theory study will use quantitative and qualitative data collected in interviews with 12-17 year olds engaged with specialist Child/Youth Mental Health Service in Queensland, Australia. Interviews will explore adolescents' expectations and experiences of mental disorder, and of services, as they transition through specialist mental health services, including the meaning of their experiences and ideas of 'recovery' and how their experiences and expectations are shaped. Data collection and analysis will use grounded theory methods. Adolescents' experiences will be presented as a mid-range theory. The research will provide tangible recommendations for youth-focused mental health policy and practice. Findings will be disseminated within academic literature and beyond to participants, health professionals, mental health advocacy groups and policy and decision makers via publications, research summaries, conferences and workshops targeting different audiences. Ethical and research governance approvals have been obtained from relevant Human Research Ethics committees and all sites involved.


Local and global Ca2+ signals: physiology and pathophysiology.
The pancreatic acinar unit is a classical example of a polarized tissue. Even in isolation, these cells retain their polarity, and this has made them particularly useful for Ca2+ signaling studies. In 1990, we discovered that this cell has the capability of producing both local cytosolic and global Ca2+ signals. The mechanisms underlying this signal generation have now been established. Furthermore, it has become clear that the local signals are sufficient for the control of both fluid and enzyme secretion, whereas prolonged global signals are dangerous and give rise to acute pancreatitis, a disease where the pancreas digests itself.


Gender difference of geographic distribution of physicians in Japan: three-point analysis of 1994, 2004 and 2014.
Japan's medical education system produces 9,000 graduates annually. Despite the government's implementation of several strategies, including increasing the number of doctors trained, the country still struggles with a shortage of physicians in rural areas. This study examined this issue, focusing on gender and considering years of physician experience, demographic and geographic factors. We analyzed the Physician Census from 1994, 2004, and 2014, examining data on physicians' gender and the number of years since licensure. To correct the impact of municipal mergers, the analysis was aligned with the number of municipalities in 2014 (1741). We examined data from each physician (gender and years of medical experience) and analyzed the demographic and geographic distribution trend using Spearman correlation coefficients. We then used the Gini coefficient to evaluate the distribution change of physicians based on gender and years of experience. The number of physicians increased 1.29-fold over the 20-year observation period (1.23-fold for male physicians and 2.17-fold for female physicians), and the percentage of female physicians increased from 13.4% to 20.4%. We found that 87.7% of physicians were concentrated in the top 1/3 municipalities in terms of population. The number of female physicians was higher at 91.8% compared to 86.8% for male physicians. The Gini coefficients were lower for veteran physicians of both sexes than for younger physicians. The Gini coefficient for all physicians was 0.315-0.298-0.298 (male physicians: 0.311-0.289-0.283, female physicians: 0.394-0.385-0.395) The Gini coefficients for female compared to male physicians were higher in all age groups, showing that The distribution of female physicians is skewed toward urban areas. Female physicians are less distributed in rural areas than male physicians. In addition, despite the fact that the number of female physicians has increased more than male physicians over the past 20 years, the geographic ubiquity of female physicians has not improved. Since the trend of increasing the number of female physicians is expected to continue in the future, it is necessary to take some measures, such as providing a work-life balance suitable for female physicians.


Screening for Park Access during a Primary Care Social Determinants Screen.
While there is evidence that access to nature and parks benefits pediatric health, it is unclear how low-income families living in an urban center acknowledge or prioritize access to parks. We conducted a study about access to parks by pediatric patients in a health system serving low-income families. Adult caregivers of pediatric patients completed a survey to identify and prioritize unmet social and economic needs, including access to parks. Univariate and multivariate analyses were conducted to explore associations between lack of access to parks and sociodemographic variables. We also explored the extent to which access to parks competed with other needs. The survey was completed by 890 caregivers; 151 (17%) identified "access to green spaces/parks/playgrounds" as an unmet need, compared to 397 (45%) who endorsed "running out of food before you had money or food stamps to buy more". Being at or below the poverty line doubled the odds ( Odds ratio 1.96, 95% CI 1.16-3.31) of lacking access to a park (reference group: above the poverty line), and lacking a high school degree nearly doubled the odds. Thirty-three of the 151 (22%) caregivers who identified access to parks as an unmet need prioritized it as one of three top unmet needs. Families who faced competing needs of housing, food, and employment insecurity were less likely to prioritize park access (p < 0.001). Clinical interventions to increase park access would benefit from an understanding of the social and economic adversity faced by patients.


The mercury emergency and Hamilton school children: a follow-up analysis.
In September 1993, children broke into a laboratory in an abandoned scrap metal recycling plant in Hamilton and removed mercury and other materials from the site. They began distribution of the mercury to their peers but this activity was halted once an emergency response was established. This paper focuses on the identification and assessment of children exposed to mercury and the use of Epi Info 6 in the analysis. Approximately 6,000 children were screened and 269 children identified as being exposed or at risk of exposure. We found that distribution of mercury within the school system was swift. Children exhibited a number of risky behaviours with mercury. There were no significant gender differences in these behaviours. The majority of children involved were 10 to 13 years of age. No child exhibited health effects from exposure.


Significance of humidity and temperature on skin and upper airway symptoms.
The objective of the present study was to assess the effect of absolute and relative humidity, temperature and humidification on workers' skin and upper airway symptoms, and perceptions in the office environment. Associations between physical factors, and symptoms and perceptions were assessed in logistic regression models. At temperatures between 18 and 26 degrees C, relative humidity of 17-40%, and absolute humidity of 3.3-5.6 g H2O/kg air, skin symptoms and nasal dryness and congestion were alleviated by both kinds of humidity. Pharyngeal dryness increased when temperatures rose and was alleviated with a rise in relative humidity. Eye symptoms showed no dependence on humidity. Any kind of humidity increased odor sensation. Stuffiness increased when the air was humidified. In non-humidified conditions (21.3-22.7 degrees C, 20.0-31.7%, 3.3-5.6 g H2O/kg air), skin and nasal symptoms showed no association with humidity or temperature. Pharyngeal dryness diminished when humidity rose. In addition, the association between humidity and odor disappeared. In humidified conditions (21.5-23.7 degrees C, 26.6-41.2%, 4.2-7.0 g H2O/kg air), nasal dryness and congestion were alleviated by both absolute and relative humidity, and odor perception increased. Skin dryness and rash, pharyngeal dryness, and nasal dryness and congestion are alleviated in higher humidity. Steam humidification results in a risk for increased perception of odor and stuffiness.


Multicenter Controlled Study of Intracorporeal Mechanical Side-to-Side Isoperistaltic Anastomosis versus Extracorporeal Anastomosis in Laparoscopic Right Hemicolectomy: HEMI-D-TREND-Study.
Colorectal cancer is the second most frequent cancer in the Western world. A third of colorectal tumors are located in the right colon, and right hemicolectomy is the treatment in nondisseminated right colon cancer. The most serious complication of this procedure is anastomotic leak, which occurs in 8.4% of cases. At present, there is no standardized technique for laparoscopic ileo-colic anastomosis. In previous observational studies, intracorporeal side-to-side ileo-colic laparoscopic anastomosis has shown better results than extracorporeal anastomosis in terms of morbidity and mortality. It is known that randomized studies provide higher levels of evidence, but multicenter randomized controlled studies may imply a learning curve bias due to the differences in technical experience acquired at each hospital. As a result, we propose to carry out a prospective, controlled, nonrandomized TREND-study design (Transparent Reporting of Evaluations with Non-randomized Designs-TREND) in a large sample of 416 patients (208 per group) in order to assess the use of intracorporeal side-to-side ileo-colic laparoscopic anastomosis as the gold standard in right hemicolectomy.


Recent advances in the chemistry of phthalimide analogues and their therapeutic potential.
Phthalimide analogues have been extensively used in medicinal chemistry owing to their wide range of applications as anti-convulsant, anti-inflammatory, analgesic, hypolipidimic and immunomodulatory activities. Number of anti-inflammatory phthalimide analogues have been synthesized as tumor necrosis factor-alpha (TNF-alpha) inhibitors. TNF-alpha plays a critical role in certain physiological immune systems and its over-production causes severe damage to the host. It promotes the inflammatory response leading to many of the clinical problems associated with auto-immune disorders like rheumatoid arthritis, Crohn's disease, ankylosing spondylitis, psoriasis and refractory asthma. One of the phthalimide derivatives, LASSBio-468, was recently demonstrated to inhibit TNF-alpha production induced by lipopolysaccharide (LPS), in vivo. Its potential against chronic inflammatory diseases was also witnessed. Another derivative, DIMP, showed good anti-androgenic activity. These analogues have also been employed for the synthesis of several kinds of important therapeutic synthones. However extensive research on the chemistry and biological activities of phthalimide analogues have been carried out and number of reports appeared, a compilation focusing on chemistry and biological activity is still needed. This review, concisely describes the chemical and therapeutic aspects of phthalimide derivatives.


Influence of mydriatics on choroidal thickness measurement using enhanced depth imaging-OCT.
To evaluate the potential influence of mydriatics on choroidal thickness measurement using enhanced depth imaging optical coherence tomography (EDI-OCT). This was a randomized, double-blind, paired-eye study. Fifty-eight healthy eyes of 29 patients were included in this study, and one eye of each subject was designated randomly as experimental and the contralateral eye as control. A single drop of Mydrin-P (tropicamide and phenylephrine; Santen Pharmaceuticals, Japan) or a single drop of unpreserved saline was administered in the respective eyes of patients three times at 5-min intervals. Choroidal thickness (CT) was measured using EDI-OCT, and changes in CT before and after the administration of the eye drops were analyzed at the subfovea and at 0.5 mm intervals (to 3.0 mm) from the fovea at nasal, temporal, superior, and inferior locations. Linear mixed-model analysis showed no significant changes in subfoveal CT after the administration of eye drops in either the mydriatics [from 313.00 ± 90.05 μm (before) to 316.34 ± 96.91 μm (after), p = 0.500] or placebo group [from 311.07 ± 96.26 μm (before) to 313.14 ± 95.46 μm (after), p = 0.248]. CT did not significantly differ within either group at other measured locations, as we moved further from the subfoveal starting point (all p > 0.05, linear mixed model). In evaluating a possible effect of mydriatics, we detected no significant difference in CT changes between the mydriatic test group and the saline placebo group at all intervals from the fovea (all p > 0.05, linear mixed model). This study demonstrates that mydriatics (Mydrin-P) have no significant influence on clinical measurement of CT, as evaluated by EDI-OCT.


ICOSLG acts as an oncogene to promote glycolysis, proliferation, migration, and invasion in gastric cancer cells.
Gastric cancer (GC) has emerged as one of the most common malignancies in gastrointestinal system. Inducible T-cell costimulator ligand (ICOSLG) was found to be highly expressed in various cancers, which contributes to disease progression. This study aims to investigate the role of ICOSLG and its potential mechanism of action in dictating the aggressiveness of GC cell. ICOSLG and miR-331-3p expression patterns in cancerous and para-cancerous tissues from GC patients were examined by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). The miRNAs targeting ICOSLG were predicted by "miRDB", "starBase," and "TargetScan" databases. The interplay of ICOSLG and miR-331-3p in dictating the aggressiveness and glycolysis of GC cells was investigated by CCK-8 proliferation assay and Transwell migration/invasion assays, as well as the detection of glucose uptake, lactate production and ATP levels. The tumorigenesis of GC cells after ICOSLG silencing was examined in the nude mice. ICOSLG was highly expressed in GC tissues, and GC patients with high ICOSLG expression showed a poorer prognosis than the low-expression group. Further, high ICOSLG level was correlated with more advanced TNM stages, more lymph-node metastases, and poorer tumor differentiation. ICOSLG knockdown inhibited the proliferation, migration, invasion and tumor formation of GC cells, which was concomitant with reduced glucose consumption, lactate production, and ATP levels. In contrast, ICOSLG overexpression enhanced the aggressiveness of GC cells, and this effect was abrogated after the treatment with glycolysis inhibitor. We further found that miR-331-3p was a negative regulator of ICOSLG4, and miR-331-3p overexpression reduced ICOSLG4 expression and suppressed the aggressive phenotype induced by ICOSLG4 in GC cells. Together, these findings indicate that ICOSLG4, as an oncogene, is upregulated to promote glycolysis and the malignant phenotype in GC cells. miR-331-3p, which is downregulated in GC tissues, functions as a negative regulator of ICOSLG4. Targeting miR-331-3p/ICOSLG4 axis could potentially suppress GC progression.


Cell envelope composition and organisation in the genus Rhodococcus.
A knowledge of the organisation of the rhodococcal cell envelope is of fundamental importance if the environmental and biotechnological significance of these bacteria are to be understood and successfully exploited. The genus Rhodococcus belongs to a distinctive suprageneric taxon, the mycolata, which includes among others the genera Corynebacterium, Mycobacterium and Nocardia. Members of this taxon exhibit an unusual complexity in their cell envelope composition and organisation compared to other Gram-positive bacteria. Models that describe the architecture of the mycobacterial cell envelope are extrapolated here to provide a model of the rhodococcal cell envelope. The rhodococcal cell envelope is dominated by the presence of an arabinogalactan cell wall polysaccharide and large 2-alkyl 3-hydroxy branched-chain fatty acids, the mycolic acids, which are covalently assembled into a peptidoglycan-arabinogalactan-mycolic acid matrix. This review further emphasises that the mycolic acids in this complex form the basis of an outer lipid permeability barrier. The localisation and roles of other cell envelope components, notably complex free lipids, lipoglycans, proteins and lipoproteins are also considered.


Evaluation of the oral flora in 150 patients suffering from chronic craniofacial pain: a retrospective study.
This study was conducted to determine if microbial infection was a significant factor in patients with undiagnosed craniofacial pain. Of the 150 patients from whom intra-bony cultures were obtained, 23 different groups of isolates were obtained. There were 49 (32.67%) patients whose cultures exhibited growth of microbes other than routine oral flora, mixed skin flora or routine respiratory flora. The most common was of the Streptococcus species (11 or 22.91%) of the 49. Sixty-seven (67) (44.67%) of the total cultures demonstrated the growth of mixed skin flora, nineteen (12.67%) demonstrated the growth of routine respiratory flora and sixteen (10.67%) demonstrated the growth of routine oral flora. No bacterial isolates were found in 16 (10.67%) cultures. The most common histological diagnoses of those who exhibited pathogenic microbial growth were, in order: 1. focal osteoporotic marrow defect; 2. ischemic osteonecrosis; and 3. chronic nonsuppurative osteomyelitis.


Total hepatectomy, recombinant activated factor VII and rescue liver transplantation.
The aim of this paper was to describe a case of acute liver failure treated with total hepatectomy, recombinant activated factor VII and rescue liver transplantation. We reported our experience with a 51-year-old-woman who developed a massive portal thrombosis after cadaveric liver transplantation for hepatic epithelioid hemangioendothelioma and who then required a total hepatectomy and porto-caval shunt as a bridge procedure while waiting for an urgent new liver transplantation. Subsequently, the patient developed severe hemodynamic instability, massive abdominal and mucosal bleeding and acute renal failure that were managed with infusion of high doses of inotropes, red blood cells and fresh frozen plasma as well as continuous veno-venous hemofiltration. Due to persistent, uncontrolled bleeding, we considered the off-label use of rFVIIa. This caused a correction of the prothrombin times and allowed for sufficient hemostasis. The patient received a new cadaveric liver that was reperfused 38 hours after the first graft was removed. The transplanted liver showed immediate recovery, the hemodynamics ameliorated and the patient was fully awake at day five. In the case of an anhepatic phase complicated by severe bleeding that is unresponsiveness to several transfusions, a single administration of rFVIIa should be considered as a rescue therapy to control massive bleeding.


Long term care financing in four OECD countries: fiscal burden and distributive effects.
This paper compares long term care (LTC) systems in four OECD countries (UK, Japan, Sweden and Germany). In the UK, provision is means tested, so that out of pocket payments depend on levels of income, savings and assets. In Sweden, where the system is wholly tax-financed, provision is essentially free at the point of use. In Germany and Japan, provision is financed from recently introduced compulsory insurance schemes, although the details of how each scheme operates and the distributive consequences differ somewhat. The paper analyses the effects of importing the other three countries' systems for financing LTC into the UK, focussing on both the distributive consequences and the tax burden. It finds that the German system would not be an improvement on the current UK system, because it uses a regressive method of financing. Therefore, the discussion of possible alternatives to the present UK system could be restricted to a general tax-based system as used in Sweden or the compulsory insurance system as used in Japan. The results suggest that all three systems would imply increased taxes in the UK.


The debate over diagnosis related groups.
With the advent of the Prospective Payment System (PPS) using Diagnosis Related Groups (DRGs) as a classification method, the pros and cons of that mechanism have been sharply debated. Grouping the comments into categories related to administration/management, DRG system and quality of care, a review of relevant literature highlights the pertinent attitudes and views of professionals and organizations. Points constantly argued include data utilization, meaningful medical classifications, resource use, gaming, profit centers, patient homogeneity, severity of illness, length of stay, technology limitations and the erosion of standards.


Human listeriosis and paté: a possible association.
To study trends in human listeriosis and determine possible sources of infection. Descriptive analysis of laboratory reports of human listeriosis together with a survey of subtypes of Listeria monocytogenes isolated from patients and foodstuffs and an interview survey of patients to obtain food histories. United Kingdom and Republic of Ireland 1985 to 1990. There was a near doubling in the incidence of human listeriosis in England, Wales, and Northern Ireland between 1985 and mid-1989 followed by a sharp decline. The upsurge in cases was caused largely by two strains of L monocytogenes, which accounted for 30-54% of the annual totals. These strains were less common before 1987 and after July 1989. A survey of paté in England and Wales in July 1989 showed that it frequently contained L monocytogenes. A similar survey in July 1990 showed a reduction in the proportions of samples contaminated. In 1989 patés from a single plant (manufacturer Y) were more likely to be contaminated by L monocytogenes and at higher levels than those from other producers. Most strains of L monocytogenes recovered from manufacturer Y's paté in 1989 were indistinguishable from those responsible for the 1987-9 upsurge in human listeriosis and were uncommon among isolates from patés from other manufacturers and from a wide range of other foodstuffs. Patients infected with the types of L monocytogenes found in paté were significantly more likely to have recently eaten paté than those affected by other strains. The start of the decline in numbers of cases of listeriosis coincided with government health warnings on paté consumption and the suspension of supplies from manufacturer Y. Contamination of paté was a likely contributory cause of the increase in the incidence of listeriosis between 1987 and 1989.


Characterization of glomerular cell phenotypes following repeated cycles of benzo[a]pyrene injury in vitro.
Exposure of cultured glomeruli to benzo[a]pyrene (BaP), a carcinogenic hydrocarbon, modulates mesangial and visceral epithelial cell proliferation in vivo and in vitro. The present studies were conducted to characterize mitogenic signaling profiles of cultured glomeruli following repeated cycles of BaP challenge. Enhanced rates of DNA synthesis were observed by the third passage in randomly cycling cultures after single or repeated carcinogen exposure. This response was characterized by upregulation of mitogenic sensitivity during early cell cycle transit, and increased cell numbers under restrictive growth conditions. The mitogenic response to platelet-derived growth factor (0.5 to 25 ng/mL), acidic fibroblast growth factor (2.5 to 10 ng/mL), basic fibroblast growth factor (0.05 to 5 ng/mL), epidermal growth factor (0.5 to 5 ng/mL), or conditioned medium was not enhanced by hydrocarbon challenge. BaP-treated cultures exhibited anchorage-independent growth and increased expression of hepatocyte growth factor mRNA and E-cadherin protein. Binding of activator protein-1 to DNA was enhanced in BaP-treated cells, but this change did not involve truncation or mutation of the c-jun delta region. Collectively, the data demonstrate that repeated cycles of BaP injury alter mitogenic signaling profiles in cultured glomerular cells. These alterations may contribute to deregulation of proliferative control following carcinogen exposure in vivo.


BMP4 promotes chondrocyte proliferation and hypertrophy in the endochondral cranial base.
Defects in the growth and development of the endochondral bones that comprise the cranial base contribute to several craniofacial dysmorphic syndromes. Since Bone Morphogenetic Protein (BMP) signaling regulates chondrocyte differentiation and endochondral ossification in developing long bones, we have tested the hypothesis that BMP signaling also participates in regulating development of the cranial base. During in vivo developmental progression of the cranial base in mice, a burst of skeletal growth and chondrocyte maturation was identified in the perinatal period. Using a novel serum-free organ culture system, cranial base structures were cultured as explants in the presence of BMP4 or noggin, and analyzed for morphological and molecular changes. Growth of perinatal cranial base explants was inhibited by treatment with noggin, a BMP inhibitor. Exogenous BMP4 promoted cartilage growth, matrix deposition and chondrocyte proliferation in a dose dependent manner. Correspondingly, expression level of the cartilage markers Sox9 and collagen type II were also increased. Alkaline phosphatase and collagen type X expression were up-regulated and expressed in ectopic hypertrophic chondrocytes after treatment of the cultures with 100 ng/ml BMP4 for seven days. This increase in chondrocyte hypertrophy was accompanied by increased indian hedgehog (Ihh) and parathyroid hormone/parathyroid hormone related peptide (PTH/PTHrP) receptor (PPR) expression, but not increased PTHrP expression. We conclude that endogenous BMPs are required to maintain cartilage growth, and exogenous BMP4 can enhance cartilage maturation and induce ectopic chondrocyte hypertrophy in the cranial base. Therefore, appropriate levels of BMP signaling are important for normal cranial base development.


Role of adjunctive thrombectomy and embolic protection devices in acute myocardial infarction: a comprehensive meta-analysis of randomized trials.
Adjunctive thrombectomy and embolic protection devices in acute myocardial infarction have been extensively studied, although outcomes have mainly focused on surrogate markers of reperfusion. Therefore, the effect of adjunctive devices on clinical outcomes is unknown. This study sought to determine whether the use of a thrombectomy or embolic protection device during revascularization for acute myocardial infarction reduces mortality compared with percutaneous coronary intervention (PCI) alone. The Cochrane and Medline databases were searched for clinical trials that randomized patients with ST-elevation acute myocardial infarction to an adjuvant device prior to PCI compared with PCI alone. Devices were grouped into catheter thrombus aspiration, mechanical thrombectomy, and embolic protection. There were a total of 30 studies with 6415 patients who met our selection criteria. Over a weighted mean follow-up of 5.0 months, the incidence of mortality among all studies was 3.2% for the adjunctive device group vs. 3.7% for PCI alone (relative risk, 0.87; 95% confidence interval, 0.67-1.13). Among thrombus aspiration studies, mortality was 2.7% for the adjunctive device group vs. 4.4% for PCI alone (P = 0.018), for mechanical thrombectomy, mortality was 5.3% for the adjunctive device group vs. 2.8% for PCI alone (P = 0.050), and for embolic protection, mortality was 3.1% for the adjunctive device group vs. 3.4% for PCI alone (P = 0.69). Catheter thrombus aspiration during acute myocardial infarction is beneficial in reducing mortality compared with PCI alone. Mechanical thrombectomy appears to increase mortality, whereas embolic protection appears to have a neutral effect.


Protein assembly mediated by sulfonatocalix[4]arene.
A crystal structure of lysozyme in complex with p-sulfonato-calix[4]arene (sclx4) reveals a linear assembly of protein tetramers glued together by protein-calixarene interactions. One interaction involves encapsulation of the highly exposed C-terminal Arg128. The other involves an intricate protein-bound complex of sclx4, Mg(2+) and a fragment of polyethylene glycol.


The large vestibular aqueduct--case report and review of the literature.
Patients with a large vestibular aqueduct (LVA) suffer from a loss of hearing in childhood at an early onset. An acute loss of hearing can be precipitated by minor head trauma. Until now there seems to be no sufficient therapy for stopping the progression of a loss of hearing. It has been shown that a cochlear implantation is a worthwhile procedure if the patient is almost deaf. We report the case of a patient with a bilateral LVA. A loss of hearing was confirmed at the age of 16 months. Exposure to loud noise triggered an acute progression of the hearing loss. At the age of 18 years, LVA was confirmed radiologically, revealing an enlarged endolymphatic duct and sac in MRI scans and an enlarged vestibular aqueduct in the CT scan. We successfully performed a cochlear implant (MED-EL, Combi 40+ flex). Proceeding from this case report, the paper reviews the literature on LVA.


[Isolation and genetic analysis of bacterial mutations gpr blocking the replication of various lambda phages].
Bacterial mutations affecting phi 80 DNA replication have been isolated and designated gpr2, 27. The main difference between gpr2, 27 and groP, grp mutations described earlier is that mutations gpr2, 27 are not essential for lambda replication. The mutations have been mapped between thr and leu loci in the vicinity of mutations groPC756 (dnaK gene) and groPC259 (dnaJ gene), their order being: thr-gpr2-groPC756-groPC259-gpr27. Complementation analysis using transducing phages suggested that mutations gpr2, 27 are localized in genes unknown earlier, outside dnaK and dnaJ genes.


Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention.
Glycoprotein (GP) IIb/IIIa receptor blockers prevent life-threatening cardiac complications in patients with acute coronary syndromes without ST-segment elevation and protect against thrombotic complications associated with percutaneous coronary interventions (PCIs). The question arises as to whether these 2 beneficial effects are independent and additive. We analyzed data from the CAPTURE, PURSUIT, and PRISM-PLUS randomized trials, which studied the effects of the GP IIb/IIIa inhibitors abciximab, eptifibatide, and tirofiban, respectively, in acute coronary syndrome patients without persistent ST-segment elevation, with a period of study drug infusion before a possible PCI. During the period of pharmacological treatment, each trial demonstrated a significant reduction in the rate of death or nonfatal myocardial infarction in patients randomized to the GP IIb/IIIa inhibitor compared with placebo. The 3 trials combined showed a 2.5% event rate in this period in the GP IIb/IIIa inhibitor group (N=6125) versus 3.8% in placebo (N=6171), which implies a 34% relative reduction (P<0.001). During study medication, a PCI was performed in 1358 patients assigned GP IIb/IIIa inhibition and 1396 placebo patients. The event rate during the first 48 hours after PCI was also significantly lower in the GP IIb/IIIa inhibitor group (4. 9% versus 8.0%; 41% reduction; P<0.001). No further benefit or rebound effect was observed beyond 48 hours after the PCI. There is conclusive evidence of an early benefit of GP IIb/IIIa inhibitors during medical treatment in patients with acute coronary syndromes without persistent ST-segment elevation. In addition, in patients subsequently undergoing PCI, GP IIb/IIIa inhibition protects against myocardial damage associated with the intervention.


Reasons for second trimester abortions in England and Wales.
This paper summarises the findings of a study on second trimester abortion in England and Wales in 2005. Second trimester abortions constitute a relatively small proportion of the total number of legal abortions performed in these countries yet attract quite substantial public, and particularly media, attention. Discussion of these abortions has, however, been conducted within a context of little understanding of the factors which explain why they happen. This paper starts with a brief introduction to the policy context for provision of second trimester abortion, and a summary of existing research in the area. It then presents the results of a survey of 883 women on their own reasons why they had abortions in the second trimester. The key concept is that of "delay" and reasons for delay in seeking or obtaining abortion at five stages in the pathway to abortion. No clear, single reason emerges. Amongst the main reasons identified are uncertainty about what to do if they were pregnant, not realising they were pregnant, experiencing bleeding which may have been confused with continuing to have periods, and changes in personal circumstances. The paper ends with a consideration of the implications of the results for education, policy development and service provision.


Regulation of homologous recombination in eukaryotes.
Homologous recombination (HR) is required for accurate chromosome segregation during the first meiotic division and constitutes a key repair and tolerance pathway for complex DNA damage, including DNA double-strand breaks, interstrand crosslinks, and DNA gaps. In addition, recombination and replication are inextricably linked, as recombination recovers stalled and broken replication forks, enabling the evolution of larger genomes/replicons. Defects in recombination lead to genomic instability and elevated cancer predisposition, demonstrating a clear cellular need for recombination. However, recombination can also lead to genome rearrangements. Unrestrained recombination causes undesired endpoints (translocation, deletion, inversion) and the accumulation of toxic recombination intermediates. Evidently, HR must be carefully regulated to match specific cellular needs. Here, we review the factors and mechanistic stages of recombination that are subject to regulation and suggest that recombination achieves flexibility and robustness by proceeding through metastable, reversible intermediates.


Brain-derived neurotrophic factor mediates an excitoprotective effect of dietary restriction in mice.
Dietary restriction (DR; reduced calorie intake) increases the lifespan of rodents and increases their resistance to cancer, diabetes and other age-related diseases. DR also exerts beneficial effects on the brain including enhanced learning and memory and increased resistance of neurons to excitotoxic, oxidative and metabolic insults. The mechanisms underlying the effects of DR on neuronal plasticity and survival are unknown. In the present study we show that levels of brain-derived neurotrophic factor (BDNF) are significantly increased in the hippocampus, cerebral cortex and striatum of mice maintained on an alternate day feeding DR regimen compared to animals fed ad libitum. Damage to hippocampal neurons induced by the excitotoxin kainic acid was significantly reduced in mice maintained on DR, and this neuroprotective effect was attenuated by intraventricular administration of a BDNF-blocking antibody. Our findings show that simply reducing food intake results in increased levels of BDNF in brain cells, and suggest that the resulting activation of BDNF signaling pathways plays a key role in the neuroprotective effect of DR. These results bolster accumulating evidence that DR may be an effective approach for increasing the resistance of the brain to damage and enhancing brain neuronal plasticity.


Gray and White Matter Abnormalities in Treated Human Immunodeficiency Virus Disease and Their Relationship to Cognitive Function.
Long-term comorbidities such as cognitive impairment remain prevalent in otherwise effectively treated people living with human immunodeficiency virus (HIV). We investigate the relationship between cognitive impairment and brain structure in successfully treated patients using multimodal neuroimaging from the Comorbidity in Relation to AIDS (COBRA) cohort. Cognitive function, brain tissue volumes, and white matter microstructure were assessed in 134 HIV-infected patients and 79 controls. All patients had suppressed plasma HIV RNA at cohort entry. In addition to comprehensive voxelwise analyses of volumetric and diffusion tensor imaging, we used an unsupervised machine learning approach to combine cognitive, diffusion, and volumetric data, taking advantage of the complementary information they provide. Compared to the highly comparable control group, cognitive function was impaired in 4 of the 6 cognitive domains tested (median global T-scores: 50.8 vs 54.2; P < .001). Patients had lower gray but not white matter volumes, observed principally in regions where structure generally did not correlate with cognitive function. Widespread abnormalities in white matter microstructure were also seen, including reduced fractional anisotropy with increased mean and radial diffusivity. In contrast to the gray matter, these diffusion abnormalities correlated with cognitive function. Multivariate neuroimaging analysis identified a neuroimaging phenotype associated with poorer cognitive function, HIV infection, and systemic immune activation. Cognitive impairment, lower gray matter volume, and white matter microstructural abnormalities were evident in HIV-infected individuals despite fully suppressive antiretroviral therapy. White matter abnormalities appear to be a particularly important determinant of cognitive dysfunction seen in well-treated HIV-infected individuals.


Unintended specificity of an engineered ligand-binding protein facilitated by unpredicted plasticity of the protein fold.
Attempts to create novel ligand-binding proteins often focus on formation of a binding pocket with shape complementarity against the desired ligand (particularly for compounds that lack distinct polar moieties). Although designed proteins often exhibit binding of the desired ligand, in some cases they display unintended recognition behavior. One such designed protein, that was originally intended to bind tetrahydrocannabinol (THC), was found instead to display binding of 25-hydroxy-cholecalciferol (25-D3) and was subjected to biochemical characterization, further selections for enhanced 25-D3 binding affinity and crystallographic analyses. The deviation in specificity is due in part to unexpected altertion of its conformation, corresponding to a significant change of the orientation of an α-helix and an equally large movement of a loop, both of which flank the designed ligand-binding pocket. Those changes led to engineered protein constructs that exhibit significantly more contacts and complementarity towards the 25-D3 ligand than the initial designed protein had been predicted to form towards its intended THC ligand. Molecular dynamics simulations imply that the initial computationally designed mutations may contribute to the movement of the helix. These analyses collectively indicate that accurate prediction and control of backbone dynamics conformation, through a combination of improved conformational sampling and/or de novo structure design, represents a key area of further development for the design and optimization of engineered ligand-binding proteins.


Delineation of the Pasteurellaceae-specific GbpA-family of glutathione-binding proteins.
The Gram-negative bacterium Haemophilus influenzae is a glutathione auxotroph and acquires the redox-active tripeptide by import. The dedicated glutathione transporter belongs to the ATP-binding cassette (ABC)-transporter superfamily and displays more than 60% overall sequence identity with the well-studied dipeptide (Dpp) permease of Escherichia coli. The solute binding protein (SBP) that mediates glutathione transport in H. influenzae is a lipoprotein termed GbpA and is 54% identical to E. coli DppA, a well-studied member of family 5 SBP's. The discovery linking GbpA to glutathione import came rather unexpectedly as this import-priming SBP was previously annotated as a heme-binding protein (HbpA), and was thought to mediate heme acquisition. Nonetheless, although many SBP's have been implicated in more than one function, a prominent physiological role for GbpA and its partner permease in heme acquisition appears to be very unlikely. Here, we sought to characterize five representative GbpA homologs in an effort to delineate the novel GbpA-family of glutathione-specific family 5 SBPs and to further clarify their functional role in terms of ligand preferences. Lipoprotein and non-lipoprotein GbpA homologs were expressed in soluble form and substrate specificity was evaluated via a number of ligand binding assays. A physiologically insignificant affinity for hemin was observed for all five GbpA homologous test proteins. Three out of five test proteins were found to bind glutathione and some of its physiologically relevant derivatives with low- or submicromolar affinity. None of the tested SBP family 5 allocrites interacted with the remaining two GbpA test proteins. Structure-based sequence alignments and phylogenetic analysis show that the two binding-inert GbpA homologs clearly form a separate phylogenetic cluster. To elucidate a structure-function rationale for this phylogenetic differentiation, we determined the crystal structure of one of the GbpA family outliers from H. parasuis. Comparisons thereof with the previously determined structure of GbpA in complex with oxidized glutathione reveals the structural basis for the lack of allocrite binding capacity, thereby explaining the outlier behavior. Taken together, our studies provide for the first time a collective functional look on a novel, Pasteurellaceae-specific, SBP subfamily of glutathione binding proteins, which we now term GbpA proteins. Our studies strongly implicate GbpA family SBPs in the priming step of ABC-transporter-mediated translocation of useful forms of glutathione across the inner membrane, and rule out a general role for GbpA proteins in heme acquisition.


IL-6/STAT3 Signaling Axis Enhances and Prolongs Pdcd1 Expression in Murine CD8 T Cells.
CD8 cytotoxic T cells are a potent line of defense against invading pathogens. To aid in curtailing aberrant immune responses, the activation status of CD8 T cells is highly regulated. One mechanism in which CD8 T cell responses are dampened is via signaling through the immune-inhibitory receptor Programmed Cell Death Protein-1, encoded by Pdcd1. Pdcd1 expression is regulated through engagement of the TCR, as well as by signaling from extracellular cytokines. Understanding such pathways has influenced the development of numerous clinical treatments. In this study, we showed that signals from the cytokine IL-6 enhanced Pdcd1 expression when paired with TCR stimulation in murine CD8 T cells. Mechanistically, signals from IL-6 were propagated through activation of the transcription factor STAT3, resulting in IL-6-dependent binding of STAT3 to Pdcd1 cis-regulatory elements. Intriguingly, IL-6 stimulation overcame B Lymphocyte Maturation Protein 1-mediated epigenetic repression of Pdcd1, which resulted in a transcriptionally permissive landscape marked by heightened histone acetylation. Furthermore, in vivo-activated CD8 T cells derived from lymphocytic choriomeningitis virus infection required STAT3 for optimal Programmed Cell Death Protein-1 surface expression. Importantly, STAT3 was the only member of the STAT family present at Pdcd1 regulatory elements in lymphocytic choriomeningitis virus Ag-specific CD8 T cells. Collectively, these data define mechanisms by which the IL-6/STAT3 signaling axis can enhance and prolong Pdcd1 expression in murine CD8 T cells.


Characterization of a periplasmic nitrate reductase in complex with its biosynthetic chaperone.
Escherichia coli is a Gram-negative bacterium that can use nitrate during anaerobic respiration. The catalytic subunit of the periplasmic nitrate reductase NapA contains two types of redox cofactor and is exported across the cytoplasmic membrane by the twin-arginine protein transport pathway. NapD is a small cytoplasmic protein that is essential for the activity of the periplasmic nitrate reductase and binds tightly to the twin-arginine signal peptide of NapA. Here we show, using spin labelling and EPR, that the isolated twin-arginine signal peptide of NapA is structured in its unbound form and undergoes a small but significant conformational change upon interaction with NapD. In addition, a complex comprising the full-length NapA protein and NapD could be isolated by engineering an affinity tag onto NapD only. Analytical ultracentrifugation demonstrated that the two proteins in the NapDA complex were present in a 1 : 1 molar ratio, and small angle X-ray scattering analysis of the complex indicated that NapA was at least partially folded when bound by its NapD partner. A NapDA complex could not be isolated in the absence of the NapA Tat signal peptide. Taken together, this work indicates that the NapD chaperone binds primarily at the NapA signal peptide in this system and points towards a role for NapD in the insertion of the molybdenum cofactor.


Mechanisms of noise robust representation of speech in primary auditory cortex.
Humans and animals can reliably perceive behaviorally relevant sounds in noisy and reverberant environments, yet the neural mechanisms behind this phenomenon are largely unknown. To understand how neural circuits represent degraded auditory stimuli with additive and reverberant distortions, we compared single-neuron responses in ferret primary auditory cortex to speech and vocalizations in four conditions: clean, additive white and pink (1/f) noise, and reverberation. Despite substantial distortion, responses of neurons to the vocalization signal remained stable, maintaining the same statistical distribution in all conditions. Stimulus spectrograms reconstructed from population responses to the distorted stimuli resembled more the original clean than the distorted signals. To explore mechanisms contributing to this robustness, we simulated neural responses using several spectrotemporal receptive field models that incorporated either a static nonlinearity or subtractive synaptic depression and multiplicative gain normalization. The static model failed to suppress the distortions. A dynamic model incorporating feed-forward synaptic depression could account for the reduction of additive noise, but only the combined model with feedback gain normalization was able to predict the effects across both additive and reverberant conditions. Thus, both mechanisms can contribute to the abilities of humans and animals to extract relevant sounds in diverse noisy environments.


Responses of cultured cardiac myocytes to lysosomotropic compounds and methylated amino acids.
Cardiac myocytes whose lysosomes had been pre-labelled with acridine orange were exposed to either L-amino acid methyl esters (L-leucine or methionine methyl ester) or to 'lysosomotropic' weak bases (chloroquine, methylamine, and NH4Cl) for 1 h. Both types of interventions dilated lysosomes equally and inhibited proteolysis to varying degrees. The weak bases produced no apparent alterations in the acridine orange staining, whereas the methylated amino acids induced a marked redistribution of the fluorescent dye from lysosomes into the myoplasm, suggesting that they may have provoked a change in lysosomal membrane permeability. A brief exposure to weak bases failed to enhance acid proteinase secretion into the culture medium but apparently inactivated cellular cathepsin B activity. In contrast, methylated amino acids induced no alterations in acid proteinase activity or the cellular distribution of the two proteolytic enzymes. Lastly, weak bases markedly elevated intralysosomal pH as measured with fluorescein dextran, while only modest rises were observed after amino acid methyl ester treatment. The present observations imply that amino acid methyl esters represent a new class of reagents with actions distinctly different from those of chloroquine and NH4Cl, and they may provide a unique and valuable means of studying secondary lysosomal function in cell culture.


Risk factors associated with cerebral palsy in preterm infants.
To examine pregnancy outcomes in preterm delivered children with cerebral palsy (CP). A retrospective population-based cohort study of children born in California (January 1, 1991 and December 31, 2001) with CP were identified (State databases) and compared to children without CP. We examined demographic data and pregnancy outcomes by gestational age groups controlling for multiple co-founders. Of 2733 preterm infants (total of 8397, 33% <37 weeks of gestation) with CP, delivery <28 weeks had the largest impact upon the development of CP (Odds ratio (OR) 18.2 95%CI (16.7, 19.9)) with delivery 28-31 6/7 weeks having less impact (OR 8.8 (8.0, 9.7) when compared to term deliveries. Birth asphyxia (OR 5.9 (5.3, 6.6) was associated with the future development of CP as were birth defects (OR 4.3 (4.1. 4.5), cord prolapse (OR 2.0 (1.6, 2.4)) and fetal distress (OR 2.1 (1.9, 2.2)) the latter 2 being less so. Prematurity had the greatest impact upon the future development of CP; however, birth asphyxia, birth defects and adverse labor events contributed significantly to the future development of CP as well, suggesting that the cause of CP in the preterm infant is most likely multifactorial.


A school-based, teacher-mediated prevention program (ERASE-Stress) for reducing terror-related traumatic reactions in Israeli youth: a quasi-randomized controlled trial.
Since September 2000 Israeli children have been exposed to a large number of terrorist attacks. A universal, school-based intervention for dealing with the threat of terrorism as well as with terror-related symptoms, ERASE-Stress (ES), was evaluated in a male religious middle school in southern Israel. The program was administered by the homeroom teachers as part of the school curriculum. It consists of 12 classroom sessions each lasting 90 minutes, and included psycho-educational material, skill training and resiliency strategies delivered to the students by homeroom teachers. One hundred and fourteen 7th and 8th grade students were randomly assigned to the ES intervention or were part of a waiting list (WL). They were assessed on measures of posttraumatic symptomatology, depression, somatic symptoms and functional problems before and 3 months after the intervention or the WL period. Three months after the program ended, students in the experimental group showed significant reduction in all measures compared to the waiting-list control group. The ERASE-Stress program may help students suffering from terror-related posttraumatic symptoms and mitigate the negative effects of future traumatic experiences. Furthermore, a school-based universal program such as the ERASE-Stress may potentially serve as an important and effective component of a community mental health policy for communities affected by terrorism.


Immunity to Friend virus complex: analysis of protection with a sarcoma virus pseudotype.
To specify the mechanism whereby inoculation of sarcoma viruses protects against leukemia development by leukoviruses, several experiments were performed using Friend virus complex (FVC) and MSV-F, a sarcoma virus pseudotype prepared in vitro with FVC as source of the helper component. The sarcomatous lesions induced by MSV-F were self-limited, irrespective of dose and route of inoculation and protected against the progressive, lethal erythroleukemia induced fy FVC. The sera of MSV-F primed mice had high FVC-neutralizing titers, Out of 3 properties titered in FVC, immunogenicity, XC-syncytium-forming activity and lethality, the frmer two were retained at high titers in MSV-F, while lethality was almost entirely lost: the dose-range between lethal immunizing dilutions was 2-3 logs broader for MSV-F than for FVC. It is postulated that the lethal, early erythroleukemia inducing component (Spleen Focus Forrming Virus) is rapidly lost from FVC upon in vitro propagation. The rescued MSV-F would carry a hightitered, immunogenic and Xc-syncytium forming component (Lymphatic Leukemia Virus), thus behaving as an immunogenic virus of limited pathogenicity.


Foreign Bodies in Trachea: A 25-years of Experience.
Tracheobronchial foreign body aspirations may cause cardiopulmonary arrest and sudden death. The incidence in children is higher than in adults. Rapid diagnosis and treatment is live saving. In this paper, we aimed to present our experience in tracheal foreign body aspirations and rigid bronchoscopy for 25-years. From January 1990 to January 2015, 805 patients with suspected tracheobronchial foreign body aspiration were admitted to our department. Hundred and twelve patients with tracheal foreign body were included in this study. We evaluated patients' records, retrospectively. Age, gender, clinical symptoms, physical examination findings, radiological evidences, type of foreign body and intervention types were noted. Sixty-five of the patients were female (58%) and 47 patients were male (42%), and mean age was 8.1 years (8 month-58 years). Coughing was the main symptom (n=112, 100%). Other symptoms and findings included dyspnoea and bilateral decreased lung sounds (n=73, 65.1%), bilateral rhonchi (n=68, 60.7%) and cyanosis (n=41, 36.6%). Rigid bronchoscopy was performed in all patients. The most common foreign body was nuts (n=75, 67%). The main radiologic finding was radiopaque image of the related foreign body in 27 patients (n=27, 24.1%). Cardio-pulmonary arrest occurred in 11 patients and two of them died. Tracheobronchial aspirations of foreign bodies are life-threatening events. If not diagnosed and treated rapidly, distressful results can be seen. Warning people by skilled persons on this topic will reduce the incidence of foreign body aspirations.


Impact of Biological Sex on Radar-Measured Heart Sound Quality.
Radar based contact-free technology has number of potential applications for monitoring the cardiopulmonary functions of patients. However, no study has evaluated the effect of gender on the quality of the recordings. This study makes an attempt to distinguish radar based recording of male and female subjects. The study analysed a publicly available dataset of radar-recorded heart sound signals from both male and female subjects. Here, we exploit the reference signal-to-noise ratio (RSNR) to quantify the signal's quality. The results indicate that there is a significant difference in the signal quality between males and females, with males having a higher RSNR value compared to females. This could be a limitation in the widespread use of the current radar based cardiopulmonary recording techniques and overcoming this should be considered for future research.Clinical relevance- This work has highlighted the gender based difference. By considering this, the radar based cardiopulmonary device has the potential for being used for patients requiring long-term monitoring.


Loss of heterozygosity at the alpha-inhibin locus on chromosome 2q is not a feature of human granulosa cell tumors.
The alpha-inhibin gene has been shown in knockout mouse models to be a suppressor of granulosa tumorigenesis in the mouse. To determine if alpha-inhibin has the same function in humans, we have assessed the frequency of loss of heterozygosity (LOH) of the alpha-inhibin gene locus on chromosome 2q in 17 human granulosa cell tumors and 36 epithelial ovarian cancers. LOH was detected in 12 of 36 (33.3%) epithelial tumors but in only 1 of 17 (6%) granulosa cell tumors. These data suggest that in contrast to the suggestions from the mouse model alpha-inhibin does not function as a granulosa cell tumor suppressor gene in the human. Furthermore, analysis of the TP53 gene in the granulosa cell tumors failed to detect either LOH or point mutations, indicating that they have a developmental pathway distinct from that of epithelial ovarian tumors.


Induced autologous stem cell transplantation for treatment of rabbit type 1 diabetes.
We have examined the effects of induced autologous stem cells on blood sugar levels in a rabbit model of type 1 diabetes. Rabbit skin fibroblasts were induced to dedifferentiate into multipotent stem cells, and were transplanted into the treatment group via the pancreatic artery. After the fibroblasts had been induced for 72 h, some of them became multipotent stem cells. Four weeks after cell transplantation, blood glucose levels of the induced stem cell treatment group were significantly lower. The plasma insulin and plasma C-peptide levels of the treated group were significantly increased (P < 0.05). The shape and number of islets was different. In the control group, induced cell treatment group and non-induced cell treatment group. In the control group, islet β-cell nucleoli were obvious, and cell volumes were larger with more abundant cytoplasm. The rough endoplasmic reticulum was well-developed and a large number of secretory granules could be seen within the cytoplasm. In the induced cell treatment group, islet β cells were scattered, and their nuclei were oval and slightly irregular in shape. The cytoplasm of these cells contained a nearly normal number of secretory granules. In the non-induced cell treatment group, islet β-cells were atrophied and cell volumes were reduced. Cytoplasmic endocrine granules were significantly reduced or absent. In conclusion, treatment with induced multipotent stem cells can reduce blood sugar levels, improve islet cell function, and repair damaged pancreas in a rabbit model of type 1 diabetes.


Multivariate Analysis of Radiation Responsive Proteins to Predict Radiation Exposure in Total-Body Irradiation and Partial-Body Irradiation Models.
In the event of a radiological or nuclear attack, advanced clinical countermeasures are needed for screening and medical management of the exposed population. In such a scenario, minimally invasive biomarkers that can accurately quantify radiation exposure would be useful for triage management by first responders. In this murine study, we evaluated the efficacy of a novel combination of radiation responsive proteins, Flt3 ligand (FL), serum amyloid A (SAA), matrix metalloproteinase 9 (MMP9), fibrinogen beta (FGB) and pentraxin 3 (PTX3) to predict the received dose after whole- or partial-body irradiation. Ten-week-old female C57BL6 mice received a single whole-body or partial-body dose of 18 Gy from a Pantak X-ray source at a dose rate of 2.28 Gy/min. Plasma was collected by cardiac puncture at 24, 48, 72 h and 1 week postirradiation. Plasma protein levels were determined via commercially available ELISA assay. A multivariate discriminant analysis was utilized to generate best-fit dose prediction models for whole-body exposures using the selected biomarker panel and its potential application to partial-body exposures was examined. The combination of values from FL, SAA, MMP9, FGB and PTX3 between 24 h and 1 week postirradiation yielded novel dose-response relationships. For day 1 postirradiation, the best-fit model yielded a predictive accuracy of 81% utilizing FL alone. The use of additional proteins did not enhance the model accuracy whereas, at day 2 postirradiation, the addition of PTX3 and FGB to FL increased the accuracy to 100%. At day 3 the use of FL and PTX3 yielded a predictive accuracy of 93% and at day 7 use of FL and SAA had an accuracy of 90%. Dose prediction of partial-body exposures based on the TBI model had a higher predictive accuracy when the percentage of the body exposed to radiation increased. Our findings indicate that this novel combination of radiation responsive biomarker proteins are an efficient method for predicting radiation exposure and are more accurate when used in concert compared to using any single biomarker protein alone.


Behavioral and network origins of wealth inequality: insights from a virtual world.
Almost universally, wealth is not distributed uniformly within societies or economies. Even though wealth data have been collected in various forms for centuries, the origins for the observed wealth-disparity and social inequality are not yet fully understood. Especially the impact and connections of human behavior on wealth could so far not be inferred from data. Here we study wealth data from the virtual economy of the massive multiplayer online game (MMOG) Pardus. This data not only contains every player's wealth at every point in time, but also all actions over a timespan of almost a decade. We find that wealth distributions in the virtual world are very similar to those in Western countries. In particular we find an approximate exponential distribution for low wealth levels and a power-law tail for high levels. The Gini index is found to be g = 0.65, which is close to the indices of many Western countries. We find that wealth-increase rates depend on the time when players entered the game. Players that entered the game early on tend to have remarkably higher wealth-increase rates than those who joined later. Studying the players' positions within their social networks, we find that the local position in the trade network is most relevant for wealth. Wealthy people have high in- and out-degrees in the trade network, relatively low nearest-neighbor degrees, and low clustering coefficients. Wealthy players have many mutual friendships and are socially well respected by others, but spend more time on business than on socializing. Wealthy players have few personal enemies, but show animosity towards players that behave as public enemies. We find that players that are not organized within social groups are significantly poorer on average. We observe that "political" status and wealth go hand in hand.


Clinical utility of serial serum dilutions for HLA antibody interpretation.
Luminex single antigen bead (SAB) testing has increased the sensitivity and specificity of accurately identifying HLA antibodies, in support of all organ transplantation. However, as described in manufacturers' recommendation, the output of the assay, using mean fluorescence intensity (MFI) units, is only semi-quantitative. Therefore, the ability to use MFI values to compare between different assays, to accurately guide clinical practice, or be used as an endpoint measure in clinical trials, is limited. To improve potential quantification, one must circumvent inherent limitations of SAB assays such as interference and saturation phenomena. In this review, we discuss how measurement of pre-transplant serum dilutions can be used to determine unacceptable antigens for wait-listing, determine the likelihood for successful HLA antibody reduction with desensitization, and compare degree of HLA (in)compatibility among various living donors. We also discuss how serum dilutions are optimal for measuring and comparing the efficacy of antibody depletion therapies for desensitization or antibody mediated rejection treatment post-transplant. Historically, one of the main criticisms for the use of serum dilutions and titer has been the potential labor and cost associated with additional testing. Here, we show how only one or two dilutions can add major value in most circumstances. In summary, the practical use of serum dilutions and titer determination are important methods that can be used before and after transplantation of all organs to quantify antibody accurately and reliably in routine practice and in clinical trials.


A comparative analysis on the efficacy and safety of intaxel® and taxol® in advanced metastatic breast cancer.
Among the presently available cytotoxic drugs, paclitaxel, in combination with doxorubicin and carboplatin, come under the highly active therapy for metastatic breast cancer. Between the two brands of paclitaxel (Intaxel, which is marketed by Fresenius Kabi and Taxol, the original paclitaxel which is manufactured by BMS) the similarity has not been evaluated in clinical trial settings till date. This prospective, controlled, randomized, multicentre, open-label phase IV study was planned to compare the safety and efficacy of Intaxel with Taxol, when they were used in combination with carboplatin or doxorubicin, as a second line treatment for metastatic breast cancer. Fourty nine eligible patients were randomized to receive Intaxel or Taxol with either doxorubicin or carboplatin. The patients who had received a prior anthracycline based chemotherapy were randomized to the paclitaxel/carboplatin arm. The patients were evaluated in three phases i.e. at baseline, during the treatment and at follow up for the tumour response, the time period till the disease progression and the toxicity. The time till the disease progression was assessed by the Kaplan-Meier method. The continuous and categorical variables were assessed by using the ANOVA test and Fisher's exact test, respectively. After 3 cycles, an objective response rate of 55.56% (CR = 3, PR = 7) was noted in the Intaxel group and that of 59.09% (CR = 1, PR = 12) was noted in the Taxol group. After 6 cycles, an objective response rate of 50% was noted in both the groups. No significant difference was observed in the response rate of the two groups after 3 cycles (p > 0.05) and at the end of the treatment (p > 0.05). The patients who received Intaxel had a lower incidence of thrombocytopaenia (p = 0.0146) and neurosensory loss (p = 0.008) as compared to those who received Taxol. The results of this study demonstrated that the safety and efficacy of Intaxel and Taxol are equivalent when they are used in combination with other cytotoxic agents as the second line of treatment for metastatic stage IV breast cancer.


Icariin protects murine chondrocytes from lipopolysaccharide-induced inflammatory responses and extracellular matrix degradation.
Septic arthritis is an inflammatory arthropathy characterized by degeneration of articular cartilage. Icariin, the main active flavonoid glucoside isolated from Epimedium pubescens, is used as antirheumatics (or antiinflammatory), tonics, and aphrodisiacs in traditional Chinese medicine. In this study, we used lipopolysaccharide (LPS) to simulate the in vitro inflammatory response of chondrocytes during septic arthritis. Our hypothesis is that the icariin can protect chondrocytes from LPS-induced inflammation and extracellular matrix degradation. The inflammation of neonatal mice chondrocytes was induced by LPS and the antiinflammatory effects were examined. The synthesis of nitric oxide was analyzed, whereas the titer of glycosaminoglycan and total collagen were measured and the gene expressions (including inducible nitric oxide synthase [iNOS], matrix metalloproteinase [MMP]-1, MMP-3, and MMP-13) were evaluated. The results showed that the viability of chondrocytes, extracellular matrix synthesis, was significantly decreased, whereas nitric oxide synthesis was significantly increased in the presence of 10(-5) g/mL LPS. Icariin pretreatment can partially reverse these effects. The up-regulated expressions of MMP-1, 3, 13, cyclooxygenase-2 (COX-2), and iNOS genes by LPS treatment were also significantly down-regulated by the pretreatment of icariin to 1.8%, 0.056%, 7.7%, 3.1%, and 5.3% of the LPS-positive control sample, respectively. Our results demonstrate that icariin is a safe anabolic agent of chondrocytes. Icariin may exert its protective effects through inhibition of nitric oxide and MMP synthesis, and may then reduce the extracellular matrix destruction.


Ice sheets as a missing source of silica to the polar oceans.
Ice sheets play a more important role in the global silicon cycle than previously appreciated. Input of dissolved and amorphous particulate silica into natural waters stimulates the growth of diatoms. Here we measure dissolved and amorphous silica in Greenland Ice Sheet meltwaters and icebergs, demonstrating the potential for high ice sheet export. Our dissolved and amorphous silica flux is 0.20 (0.06-0.79) Tmol year-1, ∼50% of the input from Arctic rivers. Amorphous silica comprises >95% of this flux and is highly soluble in sea water, as indicated by a significant increase in dissolved silica across a fjord salinity gradient. Retreating palaeo ice sheets were therefore likely responsible for high dissolved and amorphous silica fluxes into the ocean during the last deglaciation, reaching values of ∼5.5 Tmol year-1, similar to the estimated export from palaeo rivers. These elevated silica fluxes may explain high diatom productivity observed during the last glacial-interglacial period.


Effects of unidirectional flow shear stresses on the formation, fractal microstructure and rigidity of incipient whole blood clots and fibrin gels.
Incipient clot formation in whole blood and fibrin gels was studied by the rheometric techniques of controlled stress parallel superposition (CSPS) and small amplitude oscillatory shear (SAOS). The effects of unidirectional shear stress on incipient clot microstructure, formation kinetics and elasticity are reported in terms of the fractal dimension (df) of the fibrin network, the gel network formation time (TGP) and the shear elastic modulus, respectively. The results of this first haemorheological application of CSPS reveal the marked sensitivity of incipient clot microstructure to physiologically relevant levels of shear stress, these being an order of magnitude lower than have previously been studied by SAOS. CSPS tests revealed that exposure of forming clots to increasing levels of shear stress produces a corresponding elevation in df, consistent with the formation of tighter, more compact clot microstructures under unidirectional flow. A corresponding increase in shear elasticity was recorded. The scaling relationship established between shear elasticity and df for fibrin clots and whole blood confirms the fibrin network as the dominant microstructural component of the incipient clot in terms of its response to imposed stress. Supplementary studies of fibrin clot formation by rheometry and microscopy revealed the substantial additional network mass required to increase df and provide evidence to support the hypothesis that microstructural changes in blood clotted under unidirectional shear may be attributed to flow enhanced thrombin generation and activation. CSPS also identified a threshold value of unidirectional shear stress above which no incipient clot formation could be detected. CSPS was shown to be a valuable haemorheological tool for the study of the effects of physiological and pathological levels of shear on clot properties.


White lupin cluster root acclimation to phosphorus deficiency and root hair development involve unique glycerophosphodiester phosphodiesterases.
White lupin (Lupinus albus) is a legume that is very efficient in accessing unavailable phosphorus (Pi). It develops short, densely clustered tertiary lateral roots (cluster/proteoid roots) in response to Pi limitation. In this report, we characterize two glycerophosphodiester phosphodiesterase (GPX-PDE) genes (GPX-PDE1 and GPX-PDE2) from white lupin and propose a role for these two GPX-PDEs in root hair growth and development and in a Pi stress-induced phospholipid degradation pathway in cluster roots. Both GPX-PDE1 and GPX-PDE2 are highly expressed in Pi-deficient cluster roots, particularly in root hairs, epidermal cells, and vascular bundles. Expression of both genes is a function of both Pi availability and photosynthate. GPX-PDE1 Pi deficiency-induced expression is attenuated as photosynthate is deprived, while that of GPX-PDE2 is strikingly enhanced. Yeast complementation assays and in vitro enzyme assays revealed that GPX-PDE1 shows catalytic activity with glycerophosphocholine while GPX-PDE2 shows highest activity with glycerophosphoinositol. Cell-free protein extracts from Pi-deficient cluster roots display GPX-PDE enzyme activity for both glycerophosphocholine and glycerophosphoinositol. Knockdown of expression of GPX-PDE through RNA interference resulted in impaired root hair development and density. We propose that white lupin GPX-PDE1 and GPX-PDE2 are involved in the acclimation to Pi limitation by enhancing glycerophosphodiester degradation and mediating root hair development.


Transhepatic arterial chemoembolization with oxaliplatin-eluting microspheres (OEM-TACE) for unresectable hepatic tumors.
While conventional transhepatic arterial chemoembolization (TACE) is accepted worldwide as an effective treatment for patients with unresectable hepatocellular carcinoma (HCC), its use in other hepatic tumors is not supported by randomized studies. Preliminary results have shown that new drug-eluting microspheres (DEM) seem to optimize TACE procedures. The aim of this study was to evaluate the capability of HepaSphere to load oxaliplatin and their pharmacokinetic outcome. The feasibility and safety of treatment with oxaliplatin-eluting microspheres (OEM-TACE) was also evaluated in patients with unresectable liver metastasis of colorectal cancer and unresectable intrahepatic cholangiocarcinoma. An inductively coupled plasma mass spectrometer (ICP-MS) was used to quantify the oxaliplatin bound to microspheres and the oxaliplatin in liver biopsies. Fifteen patients (8 with colorectal carcinoma liver metastases, 7 with intrahepatic cholangiocarcinoma) were treated with 27 sessions of OEM-TACE. The data suggested that the microspheres can bind oxaliplatin entirely. The pharmacokinetic parameters were significantly different between the OEM-TACE patients and a control group of patients treated with oxaliplatin chemotherapy. The mean oxaliplatin concentration within the tumor was twenty-times higher than the extratumoral liver concentration in the OEM-TACE patients. According to response evaluating criteria in solid tumors (RECIST), stable disease was observed in 8 out of the 15 patients (53.3%), a partial response in 2 (13.3%) and intrahepatic or extrahepatic tumor progression in 5 out of the 15 patients (33.3%). No major adverse event (AE G3/4) occurred. TACE with oxaliplatin-loaded microspheres is a safe and feasible treatment without major adverse events and with a favorable pharmacokinetic profile.


Use of prolonged hypothermia to treat ischemic and hemorrhagic stroke.
Therapeutic (induced) hypothermia (TH) has been extensively studied as a means to reduce brain injury following global and focal cerebral ischemia, intracerebral hemorrhage (ICH), and subarachnoid hemorrhage (SAH). Here, we briefly review the clinical and experimental evidence supporting the use of TH in each condition. We emphasize the importance of systematically evaluating treatment parameters, especially the duration of cooling, in each condition. We contend that TH provides considerable protection after global and focal cerebral ischemia, especially when cooling is prolonged (e.g., >24 h). However, there is presently insufficient evidence to support the clinical use of TH for ICH and SAH. In any case, further animal work is needed to develop optimized protocols for treating cardiac arrest (global ischemia), and to maximize the likelihood of successful clinical translation in focal cerebral ischemia.


Pituitary changes involved in prolactin secretion induced by mifepristone and naloxone during late pregnancy.
The antiprogesterone mifepristone facilitates prolactin release, an effect enhanced by administration of the opioid antagonist naloxone. The present study explores ultrastructural changes in lactotropes after mifepristone and naloxone administration, correlating them with the expression of pituitary prolactin. Rats were sacrificed at 18:00 h on day 19 of pregnancy. Prolactin immunoelectron microscopy of lactotropes from control rats showed characteristics of quiescent cells with numerous small and spherical secretory granules. Naloxone administration did not modify lactotrope morphology or prolactin expression in terms of mRNA or protein abundances. Mifepristone treatment induced lactotrope activation with development of the rough endoplasmic reticulum and Golgi complex with prolactin immunoreactive small newly formed and large mature secretory granules. Mifepristone increased prolactin mRNA and protein expression. Naloxone administration to mifepristone-treated rats potentiated lactotrope activation compared with mifepristone alone showing exocytotic images of prolactin granules and some cells with evident signs of involution. (1) Blockade of progesterone action by mifepristone activated the lactotrope, increased significantly prolactin mRNA and protein expression and prepared the pituitary for naloxone action. (2) The high serum prolactin levels induced by mifepristone and naloxone may regulate negatively lactotrope activity as suggested by the presence of regressing cells neighboring the actively secreting cells.


Computational and In-Vitro Validation of Natural Molecules as Potential Acetylcholinesterase Inhibitors and Neuroprotective Agents.
Cholinesterase inhibitors are the first line of therapy for the management of Alzheimer's disease (AD), however, it is now established that they provide only temporary and symptomatic relief, besides, having several inherited side-effects. Therefore, an alternative drug discovery method is used to identify new and safer 'disease-modifying drugs'. Herein, we screened 646 small molecules of natural origin having reported pharmacological and functional values through in-silico docking studies to predict safer neuromodulatory molecules with potential to modulate acetylcholine metabolism. Further, the potential of the predicted molecules to inhibit acetylcholinesterase (AChE) activity and their ability to protect neurons from degeneration was determined through in-vitro assays. Based on in-silico AChE interaction studies, we predicted quercetin, caffeine, ascorbic acid and gallic acid to be potential AChE inhibitors. We confirmed the AChE inhibitory potential of these molecules through in-vitro AChE inhibition assay and compared results with donepezil and begacestat. Herbal molecules significantly inhibited enzyme activity and inhibition for quercetin and caffeine did not show any significant difference from donepezil. Further, the tested molecules did not show any neurotoxicity against primary (E18) hippocampal neurons. We observed that quercetin and caffeine significantly improved neuronal survival and efficiently protected hippocampal neurons from HgCl2 induced neurodegeneration, which other molecules, including donepezil and begacestat, failed to do. Quercetin and caffeine have the potential as "disease-modifying drugs" and may find application in the management of neurological disorders such as AD.


How psychoactive drugs shape human culture: A multi-disciplinary perspective.
Psychoactive drug use occurs in essentially all human societies. A range of disciplines contribute to our understanding of the influence of drugs upon the human world. For example pharmacology and neuroscience analyse biological responses to drugs, sociology examines social influences upon people's decisions to use drugs, and anthropology provides rich accounts of use across a variety of cultural contexts. This article reviews work from multiple disciplines to illustrate that drugs influence aspects of culture from social life to religion, politics to trade, while acting as enablers of cultural change throughout human history. This broad view is valuable at a time when the influence not only of traditional drugs but a growing armoury of novel drugs is felt and debated.