Canine-assisted therapy in the inpatient setting.
Canine-assisted therapy (CAT) is widely used in outpatient settings, yet there is little published literature regarding its use, efficacy, and safety in the inpatient setting. The primary objective of this review was to consolidate published information regarding CAT efficacy and safety in the inpatient population. The secondary objective was to review safety concerns associated with CAT. The databases PubMed, Ovid MEDLINE, and Web of Knowledge were searched using the dates April 2003-April 2013 with the terms "animal assisted therapy" and "pet therapy." Articles were reviewed for the relevance of CAT in the inpatient setting, and those meeting our criteria were included in the study. The references of selected articles also were reviewed and included if study criteria were met. The review of the literature resulted in 429 total articles using the search terms. Of the 429 articles, 177 were duplicates and 218 pertained to the outpatient setting or involved animal therapies other than canine, leaving 34 articles that met the search criteria. The bibliography review of the 34 articles yielded an additional 10 articles. Our review of the literature showed that in the inpatient setting, CAT is an effective therapy among patients of all ages and with various medical problems and is safe, with no transmitted infections reported.


Identification and characterization of the water gap in physically dormant seeds of Geraniaceae, with special reference to Geranium carolinianum.
Physical dormancy in seeds of species of Geraniaceae is caused by a water-impermeable palisade layer in the outer integument of the seed coat and a closed chalaza. The chalazal cleft has been reported to be the water gap (i.e. location of initial water entry) in innately permeable seeds of Geraniaceae. The primary aim of this study was to re-evaluate the location of the water gap and to characterize its morphology and anatomy in physically dormant seeds of Geraniaceae, with particular reference to G. carolinianum. Length, width, mass, anatomy and germination of two seed types (light brown and dark brown) of G. carolinianum were compared. Location, anatomy and morphology of the water gap were characterized using free-hand and microtome tissue sectioning, light microscopy, scanning electron microscopy, dye tracking, blocking and seed-burial experiments. Treatment with dry heat caused a colour change in the palisade cells adjacent to the micropyle. When placed in water, the 'hinged valve' (blister) erupted at the site of the colour change, exposing the water gap. The morphology and anatomy in the water-gap region differs from those of the rest of the seed coat. the morphology of the seed coat of the water-gap region is similar in G. carolinianum, G. columbinum, G. molle and G. pusillum and differs from that of the closely related species Erodium cicutarium. Dislodgment of swollen 'hinged valve' palisade cells adjacent to the micropyle caused the water gap to open in physically dormant seeds of G. carolinianum, and it was clear that initial water uptake takes place through this gap and not via the chalazal opening as previously reported. This water gap ('hinged valve gap') differs from water gaps previously described for other families in morphology, anatomy and location in the seed coat.


Growth performance and gastrointestinal responses of broiler chickens fed corn-soybean meal diet without or with exogenous epidermal growth factor upon challenge with Eimeria.
Epidermal growth factor (EGF), a protein known for its mitogenic and anti-apoptotic effects was fed to broiler chickens to evaluate growth performance, gastrointestinal measurements, and apparent retention (AR) of components upon challenge with Eimeria. A total of 216, d old male broiler chicks (Ross 708) were placed in cages (6 birds/cage) and allocated to treatments. The treatments were: 1) control (Lactotobacilli lactis fermentation supernatant without EGF), 2) 80 μg of EGF/kg BW/d, and 3) 160 μg of EGF/kg BW/d. A basal antibiotic-free corn-soybean diet containing TiO2 was used. Birds were offered fresh feed with respective treatments on daily basis and had free access to drinking water for 14 d. On d 5, birds (6 replicates per treatment) were challenged with 1 mL of E. acervulina and E. maxima mixture via oral gavage and the other 6 replicates were given sham. Growth performance was measured in pre- (d 0 to 5) and post- (d 6 to 14) challenge periods. Two birds per cage were necropsied on d 10 for intestinal lesion scores and tissue samples for histomorphology and expression of select intestinal genes. Excreta samples for AR of components and oocyst shedding were taken d 10 to 13 and all birds were necropsied on d 14 for gastrointestinal weight. The EGF linearly (P < 0.05) increased BWG before challenge. There was no EGF and Eimeria interaction (P > 0.05) on growth performance, AR of GE, and intestinal histomorphology; the main effects were such that Eimeria depressed (P < 0.01) BWG, FCR, AR of DM, crude fat, and GE, and villi height to crypt depth ratio. An interaction between EGF and Eimeria (P < 0.05) on indices of gut function was such that EGF improved expression of genes for nutrient transporters and tight junction proteins in Eimeria challenged birds whilst no effect in non-challenged control. In conclusion, Eimeria challenge reduced growth performance and impaired gut function; EGF showed beneficial effects on growth pre-challenge and improved indices of gut function upon Eimeria challenge.


Modulation of Attentional Bias to Drug and Affective Cues by Therapeutic and Neuropsychological Factors in Patients With Opioid Use Disorder on Methadone Maintenance Therapy.
Objective: Abnormal selective attention to drug cues and negative affect is observed in patients with substance dependence, and it is closely associated with drug addiction and relapse. Methadone maintenance is an effective replacement therapy to treat heroin addiction, which significantly reduces the relapse rate. The present study examines whether the patients with opioid use disorder on chronic methadone maintenance therapy exhibit abnormal attentional bias to drug cues and negative-affective cues. Moreover, its relation to therapeutic and neuropsychological factors is also examined. Methods: Seventy-nine patients with opioid use disorder under chronic methadone maintenance therapy and 73 age-, sex-, and education-matched healthy controls were recruited and assessed for attentional bias to drug cues and negative affect using a dot-probe detection task. Correlational analysis was used to examine the relationships between the attentional bias and the demographic, therapeutic, and neuropsychological factors. Results: No significant overall patient-control group difference is observed in drug-related or negative-affective-related attentional bias scores. In the patient group, however, a significant negative correlation is found between the attentional bias scores to negative-affective cues and the duration of methadone treatment (p = 0.027), with the patients receiving longer methadone treatment showing less attentional avoidance to negative-affective cues. A significant positive correlation is found between the negative affect-induced bias and the impulsivity score (p = 0.006), with more impulsive patients showing higher attentional avoidance to negative affective cues than less impulsive patients. Additionally, the patients detect a smaller percentage of probe stimuli following the drug (p = 0.029) or negative-affective pictures (p = 0.009) than the healthy controls. Conclusion: The results of the present study indicate that the patients under chronic methadone maintenance therapy show normalized attentional bias to drug and negative-affective cues, confirming the involuntary attention of the patients is not abnormally captured by external drug or negative-affective clues. Our findings also highlight that the attentional avoidance of negative-affective cues is modulated by the duration of methadone treatment and the impulsivity level in the patients.


A methodology for multivariate phenotype-based genome-wide association studies to mine pleiotropic genes.
Current Genome-Wide Association Studies (GWAS) are performed in a single trait framework without considering genetic correlations between important disease traits. Hence, the GWAS have limitations in discovering genetic risk factors affecting pleiotropic effects. This work reports a novel data mining approach to discover patterns of multiple phenotypic associations over 52 anthropometric and biochemical traits in KARE and a new analytical scheme for GWAS of multivariate phenotypes defined by the discovered patterns. This methodology applied to the GWAS for multivariate phenotype highLDLhighTG derived from the predicted patterns of the phenotypic associations. The patterns of the phenotypic associations were informative to draw relations between plasma lipid levels with bone mineral density and a cluster of common traits (Obesity, hypertension, insulin resistance) related to Metabolic Syndrome (MS). A total of 15 SNPs in six genes (PAK7, C20orf103, NRIP1, BCL2, TRPM3, and NAV1) were identified for significant associations with highLDLhighTG. Noteworthy findings were that the significant associations included a mis-sense mutation (PAK7:R335P), a frame shift mutation (C20orf103) and SNPs in splicing sites (TRPM3). The six genes corresponded to rat and mouse quantitative trait loci (QTLs) that had shown associations with the common traits such as the well characterized MS and even tumor susceptibility. Our findings suggest that the six genes may play important roles in the pleiotropic effects on lipid metabolism and the MS, which increase the risk of Type 2 Diabetes and cardiovascular disease. The use of the multivariate phenotypes can be advantageous in identifying genetic risk factors, accounting for the pleiotropic effects when the multivariate phenotypes have a common etiological pathway.


The knowledge and practice towards COVID-19 pandemic prevention among residents of Ethiopia. An online cross-sectional study.
The disease from the novel coronavirus (COVID-19) has been considered as an international concern and a pandemic starting from the declaration of the World Health Organization (WHO) as an outbreak disease. The objective of this study is to assess the prevention of knowledge and practices towards the COVID-19 pandemic among the residents of Ethiopia. An online cross-sectional study was conducted among a sample of Ethiopian residents via social platforms of the author's network with popular social media such as Facebook, Telegram, and email. The snowball sampling was employed to recruit participants. In doing so, we collected the responses of 341 participants successfully from April 15 to 22, 2020. The collected data were analyzed by STATA version 14 software and descriptive statistics were employed to summarize the knowledge and practices of the community towards the COVID-19 pandemic. The majority of respondents 80.5% were male. About 91.2% of the participants heard about the COVID-19 pandemic. Moreover, out of 341 participants 90.0%, 93.8% of them knew that the COVID-19 pandemic was prevented by maintaining social distance and frequent handwashing, respectively. This shows that the prevention knowledge of the participants towards the COVID-19 by maintaining social distance and frequent handwashing was high. However, out of 341 participants only 61%,84% of them practiced social distance and frequent handwashing toward COVID-19, respectively. The majority of the participants knew the ways to protect themselves from the novel coronavirus (COVID-19), but there was a great problem of changing this prevention knowledge to practices. This shows that there is an action gap between having prevention knowledge of the COVID-19 and implementing it into practices to tackle the spread of the COVID-19 among communities. Therefore, the concerned body should be focused on providing awareness and education for the community regarding the implementation of prevention knowledge to practices.


Ornithine-Urea Cycle Enzymes in the African Lungfish, Protopterus aethiopicus.
The presence of all five enzymes of the ornithine-urea cycle has been demonstrated in the liver of the African lungfish Protopterus aethiopicus. Levels of activity of the rate-limiting enzymes, carbamoyl phosphate synthetase and argininosuccinate synthetase, are similar to those in the premetamorphic tadpole of Rana catesbeiana and considerably lower than the levels reported for other ureotelic animals. They are thus consistent with the predominantly ammonotelic metabolism of the lungfish in an aquatic environment.


Effectiveness of renal denervation for treatment of resistant hypertension: an evidence-based case report.
To determine whether the renal sympathetic--nerve ablation method is more effective compared to multiple anti--hypertensive drug among patients with resistant hypertension. a search was conducted on PubMed. The selection of title and abstract was conducted using inclusion and exclusion criteria, which led to five relevant articles. The selected studies were critically appraised for its validity, importance and applicability. one of studies showed that renal denervation is not effectively reduced blood pressure in patients with resistant hypertension; nevertheless other studies showed significant results. literature with strongest evidence showed that there is no relationship between renal sympathetic-nerve ablation procedure and reduction of blood pressure. However, as there is still some methodological flaw on the literature, we recommend doing another study that may find the appropriate results.


In Search of the Spherical Femoroplasty: Cam Overresection Leads to Inferior Functional Scores Before and After Revision Hip Arthroscopic Surgery.
Femoroplasty performed for the treatment of cam-type femoroacetabular impingement (FAI) has become a common procedure. Underresection may result in residual FAI. Conversely, overresection may disrupt the labral seal, which is responsible for chondroprotective fluid dynamics of the hip. Hypothesis/Purpose: It was hypothesized that cam overresection negatively affects hip function. The purpose was to examine the effect of the accuracy of previous femoroplasty on hips presenting for revision hip arthroscopic surgery. Cohort study; Level of evidence, 3. Data were prospectively collected for patients presenting for revision hip arthroscopic surgery between June 2010 and August 2014. On the basis of measurements on Dunn view radiographs, cases were divided into 3 groups: overresection (OR group) in which overresection measured over 5% of the diameter of the femoral head, underresection (UR group) in which there was a residual cam lesion (alpha angle >60°), and neutral resection (neutral group). Data collection included the modified Harris Hip Score (mHHS), Nonarthritic Hip Score (NAHS), Hip Outcome Score-Sports-Specific Subscale, and visual analog scale at presentation and at a minimum 2-year follow-up after revision hip arthroscopic surgery and rates of conversion to total hip arthroplasty (THA). One hundred thirty hips (120 patients) were included. Twenty hips (15.4%) were classified as the OR group, 16 (12.3%) as the UR group, and 94 (72.3%) as the neutral group. The mean follow-up was 39.6 ± 15.9 months. The mHHS and NAHS values at presentation were lower in the OR group compared with the UR group (50.2 ± 15.5 vs 64.7 ± 19.4 [ P = .033] and 48.5 ± 18.6 vs 63.0 ± 19.1 [ P = .044], respectively). The mHHS value at a minimum 2-year follow-up after revision was lower for the OR group (66.7 ± 19.8) than for the UR group (81.0 ± 14.5) ( P = .031). Conversion to THA was more common in the OR group than in the UR group (30% vs 0%, respectively; P = .024). Fifty percent of cases in the OR group, 69.9% in the neutral group, and 75% in the UR group met the minimal clinically important difference for the mHHS (Δ). The latest mHHS value reached the patient acceptable symptomatic state (PASS) in 35% of the cases in the OR group, 53.2% in the neutral group, and 75% in the UR group. Hips in the OR group had a significantly lower chance of reaching the PASS than the UR group (odds ratio, 0.1795 [95% CI, 0.0418-0.7711]; P = .0209). Cam overresection of more than 5% of the diameter of the femoral head on the Dunn view predicts inferior clinical outcomes compared with cam underresection in this population. Furthermore, overresection predicts inferior outcomes after revision hip arthroscopic surgery and higher rates of conversion to THA.


What is the Source of Bilingual Cross-Language Activation in Deaf Bilinguals?
When deaf bilinguals are asked to make semantic similarity judgments of two written words, their responses are influenced by the sublexical relationship of the signed language translations of the target words. This study investigated whether the observed effects of American Sign Language (ASL) activation on English print depend on (a) an overlap in syllabic structure of the signed translations or (b) on initialization, an effect of contact between ASL and English that has resulted in a direct representation of English orthographic features in ASL sublexical form. Results demonstrate that neither of these conditions is required or enhances effects of cross-language activation. The experimental outcomes indicate that deaf bilinguals discover the optimal mapping between their two languages in a manner that is not constrained by privileged sublexical associations.


Children's Cancer and Leukaemia Group (CCLG): review and guidelines for the management of meningioma in children, teenagers and young adults.
Primary tumours of the meninges are rare accounting for only 0.4-4.6% of all paediatric tumours of the central nervous system. Due to the rarity of these tumours in children, and the consequent absence of collaborative prospective trials, there is no clear consensus on how the unique characteristics of paediatric meningiomas impact clinical status, management approach, and survival. Much of the evidence and treatment recommendations for paediatric meningiomas are extrapolated from adult data. Translating and adapting adult treatment recommendations into paediatric practice can be challenging and might inadvertently lead to inappropriate management. In 2009, Traunecker et al. published guidelines for the management of intracranial meningioma in children and young people on behalf of UK Children's Cancer and Leukaemia Group (CCLG). Ten years later we have developed the updated guidelines following a comprehensive appraisal of the literature. Complete surgical resection is the treatment of choice for symptomatic meningiomas, while radiotherapy remains the only available adjuvant therapy and may be necessary for those tumours that cannot be completely removed. However, significant advances have been made in the identification of the genetic and molecular alterations of meningioma, which has not only a potential value in the development of therapeutic agents but also in surveillance of childhood meningioma survivors. This guideline builds upon the CCLG 2009 guideline. We summarise recommendations for the diagnosis, treatment, surveillance and long-term follow-up of children and adolescents with meningioma.


Effect of interferon-β on neuroinflammation, brain injury and neurological outcome after experimental subarachnoid hemorrhage.
Aneurysmal subarachnoid hemorrhage (SAH) has a poor outcome, particularly attributed to progressive injury after the initial incident. Several studies suggest a critical role for inflammation in lesion progression after SAH. Our goal was to test whether treatment with anti-inflammatory interferon-β, which has shown promise as a therapeutic agent in experimental ischaemic stroke, can protect the brain after SAH. SAH was induced in adult male Wistar rats by puncturing the intracranial bifurcation of the right internal carotid artery. Treatment effects of daily interferon-β (n = 16) or vehicle (n = 14) injections were serially evaluated with multiparametric MRI and behavioral tests from day 0 to 7, in compliance with recent recommendations for pre-clinical drug testing. Outcome measures included neurological status, brain lesion volume, blood-brain barrier (BBB) leakage, and levels of inflammatory markers. In animals that survived up to 7 days post-SAH, we found no significant differences between vehicle- and interferon-β-treated animals with respect to final neurological score (14.3 ± 1.0 vs. 13.0 ± 2.2), brain lesion size on T(2)-weighted MR images (59 ± 83 vs. 124 ± 99 mm(3)), BBB leakage (0.26 ± 0.05 vs. 0.22 ± 0.08 contrast-induced relative MR signal change), upregulation of brain RNA for cytokines, chemokines and cell adhesion molecules, and increased neutrophil activation. In contrast to previously published findings in experimental ischemic stroke models, interferon-β has no clear efficacy to protect the brain after SAH. In line with recent highlighting of the significance of negative findings, our data currently do not recommend clinical testing of interferon-β to prevent neurological damage in SAH patients.


Community Advisory Board Members' Perspectives Regarding Opportunities and Challenges of Research Collaboration.
This case study examines the perspectives of rural community advisory board (CAB) members regarding the opportunities and challenges of partnering with academic investigators on funded research. We used a sequential exploratory design to evaluate the phenomena. Qualitative and quantitative data from CAB members were integrated to gain better understanding. Results showed that CAB members valued professional networking and gaining new evidence-based knowledge to enhance their professional practices. They identified rurality, the academic research process, and fulfilling research roles as the most significant challenges. CAB members also believed that strong community-based leaders had been essential in promoting and sustaining a shared vision for evidence-based research solutions to their community problem. Self-evaluation is essential for effective CAB research partnerships, and nurse researchers can strengthen these collaborations by (a) providing continuing education on research and evidence-based practices, (b) assuring that perceived benefits of CAB participation outweigh perceived challenges, and (c) supporting community-based leadership.


Guyin decoction in the treatment of immuno-sterility and its effect on humoral immunity.
60 cases of immuno-sterility (treated group) were treated with Guyin Decoction, and were compared with 25 control cases treated by Western medicine. The results showed that in the treated group 19 cases were cured, 32 improved and 9 failed respond, while in the control group 6 were cured, 8 improved and 11 failed. The decoction had significant effect on serum IgA and IgG.


Quantum transport of high-dimensional spatial information with a nonlinear detector.
Information exchange between two distant parties, where information is shared without physically transporting it, is a crucial resource in future quantum networks. Doing so with high-dimensional states offers the promise of higher information capacity and improved resilience to noise, but progress to date has been limited. Here we demonstrate how a nonlinear parametric process allows for arbitrary high-dimensional state projections in the spatial degree of freedom, where a strong coherent field enhances the probability of the process. This allows us to experimentally realise quantum transport of high-dimensional spatial information facilitated by a quantum channel with a single entangled pair and a nonlinear spatial mode detector. Using sum frequency generation we upconvert one of the photons from an entangled pair resulting in high-dimensional spatial information transported to the other. We realise a d = 15 quantum channel for arbitrary photonic spatial modes which we demonstrate by faithfully transferring information encoded into orbital angular momentum, Hermite-Gaussian and arbitrary spatial mode superpositions, without requiring knowledge of the state to be sent. Our demonstration merges the nascent fields of nonlinear control of structured light with quantum processes, offering a new approach to harnessing high-dimensional quantum states, and may be extended to other degrees of freedom too.


Varying lymphadenectomies for gastric adenocarcinoma in the East compared with the west: effect on outcomes.
There are notable differences in surgical approaches to gastric adenocarcinoma throughout the world, particularly in terms of the extent of lymphadenectomy (LAD). In high-incidence countries such as Japan and South Korea, more extensive (e.g., D2) lymphadenectomies are standard, and these surgeries are generally done by experienced surgeons with low morbidity and mortality. In countries such as the United States, where the incidence of gastric adenocarcinoma is 10-fold lower, the majority of patients are treated at nonreferral centers with less extensive (e.g., D1 or D0) lymphadenectomy. There is little disagreement among gastric cancer (GC) experts that the minimum lymphadenectomy that should be performed for gastric adenocarcinoma should be at least a D1 lymphadenectomy, and many of these experts recommend a D2 lymphadenectomy. More extensive lymphadenectomies provide better staging of patient disease and likely reduce locoregional recurrence rates. Two large, prospective randomized trials performed in the United Kingdom and the Netherlands in the 1990s failed to demonstrate a survival benefit of D2 over D1 lymphadenectomy, but these trials have been criticized for inadequate surgical training and high surgical morbidity and mortality rates (10% to 13%) in the D2 group. More recent studies have demonstrated that Western surgeons can be trained to perform D2 lymphadenectomies on Western patients with low morbidity and mortality. The 15-year follow-up of the Netherlands trial now demonstrates an improved disease-specific survival and locoregional recurrence in the D2 group. Retrospective analyses and one prospective, randomized trial suggest that there may be a survival benefit to more extensive lymphadenectomies when performed safely, but this assertion requires further validation.


miR-449a: a potential therapeutic agent for cancer.
MicroRNAs (miRNAs) have been reported to be associated with cancer progression and carcinogenesis. They are small, highly conserved, noncoding RNA molecules consisting of 19-25 nucleotides. By binding to complementary binding sites within the 3'-untranslated region of target mRNAs, miRNAs inhibit the translation of mRNAs or promote their degradation. miRNAs play critical roles in cancer initiation and development by functioning either as oncogenes or as tumor suppressors. Similarly, several studies have shown that miRNAs are involved in regulating various biological processes, including apoptosis, proliferation, cellular differentiation, signal transduction, and carcinogenesis. Among miRNAs, one that may be of particular interest in cancer biology is miR-449a, which has been reported to inhibit tumor growth, invasion, and metastasis, and to promote apoptosis and differentiation through the transforming growth factor-β activated kinase 1, NOTCH, nuclear factor-κB/P65/vascular endothelial growth factor, retinoblastoma-E2F, mitogen-activated protein kinase signaling pathways, WNT-β-catenin signaling, tumor protein P53, and androgen receptor signaling pathways. The miR-449 cluster is located in the second intron of CDC20B on chromosome 5q11.2, a region that has been identified as a susceptibility locus in cancer, and the abnormal expression of miR-449a may be related to the occurrence and development of tumors. As one example, miR-449a has been reported to be involved in the development of carcinoma and may be a potential prognostic indicator. On the basis of the putative pathogenetic relationships between cancer and miR-449a, we consider that miR-449a has the potential to serve as a therapeutic agent for the treatment of some types of cancer. In this review, the role of miR-449a in tumorigenesis and its mechanism of action are explored. Furthermore, its potential as a therapeutic agent in cancer treatment is considered.


Untargeted high-resolution plasma metabolomic profiling predicts outcomes in patients with coronary artery disease.
Patients with CAD have substantial residual risk of mortality, and whether hitherto unknown small-molecule metabolites and metabolic pathways contribute to this risk is unclear. We sought to determine the predictive value of plasma metabolomic profiling in patients with CAD. Untargeted high-resolution plasma metabolomic profiling of subjects undergoing coronary angiography was performed using liquid chromatography/mass spectrometry. Metabolic features and pathways associated with mortality were identified in 454 subjects using metabolome-wide association studies and Mummichog, respectively, and validated in 322 subjects. A metabolomic risk score comprising of log-transformed HR estimates of metabolites that associated with mortality and passed LASSO regression was created and its performance validated. In 776 subjects (66.8 years, 64% male, 17% Black), 433 and 357 features associated with mortality (FDR-adjusted q<0.20); and clustered into 21 and 9 metabolic pathways in first and second cohorts, respectively. Six pathways (urea cycle/amino group, tryptophan, aspartate/asparagine, lysine, tyrosine, and carnitine shuttle) were common. A metabolomic risk score comprising of 7 metabolites independently predicted mortality in the second cohort (HR per 1-unit increase 2.14, 95%CI 1.62, 2.83). Adding the score to a model of clinical predictors improved risk discrimination (delta C-statistic 0.039, 95%CI -0.006, 0.086; and Integrated Discrimination Index 0.084, 95%CI 0.030, 0.151) and reclassification (continuous Net Reclassification Index 23.3%, 95%CI 7.9%, 38.2%). Differential regulation of six metabolic pathways involved in myocardial energetics and systemic inflammation is independently associated with mortality in patients with CAD. A novel risk score consisting of representative metabolites is highly predictive of mortality.


Sperm Ion Transporters and Channels in Human Asthenozoospermia: Genetic Etiology, Lessons from Animal Models, and Clinical Perspectives.
In mammals, sperm fertilization potential relies on efficient progression within the female genital tract to reach and fertilize the oocyte. This fundamental property is supported by the flagellum, an evolutionarily conserved organelle that provides the mechanical force for sperm propulsion and motility. Importantly several functional maturation events that occur during the journey of the sperm cells through the genital tracts are necessary for the activation of flagellar beating and the acquisition of fertilization potential. Ion transporters and channels located at the surface of the sperm cells have been demonstrated to be involved in these processes, in particular, through the activation of downstream signaling pathways and the promotion of novel biochemical and electrophysiological properties in the sperm cells. We performed a systematic literature review to describe the currently known genetic alterations in humans that affect sperm ion transporters and channels and result in asthenozoospermia, a pathophysiological condition defined by reduced or absent sperm motility and observed in nearly 80% of infertile men. We also present the physiological relevance and functional mechanisms of additional ion channels identified in the mouse. Finally, considering the state-of-the art, we discuss future perspectives in terms of therapeutics of asthenozoospermia and male contraception.


Acceptability of workplace choice architecture modification for healthy behaviours.
Altering the choice architecture of decision contexts can assist behaviour change, but the acceptability of this approach has sparked debate. Considering hypothetical interventions, people generally welcome the approach for promoting health, but little evidence exists on acceptance in the real world. Furthermore, research has yet to explore the implementers' perspective, acknowledging the multidimensionality of the acceptability construct. Addressing these knowledge gaps, this study evaluated the acceptability of a quasi-experimental implementation-effectiveness trial that modified the worksite choice architecture for healthy eating and daily physical activity. Fifty-three worksites participated in the 12-month intervention and implemented altogether 23 choice architecture strategies (Mdn 3/site), including point-of-choice prompts and changes to choice availability or accessibility. Retrospective acceptability evaluation built on deductive qualitative content analysis of implementer interviews (n = 65) and quantitative analysis of an employee questionnaire (n = 1124). Qualitative analysis examined implementers' thoughts and observations of the intervention and its implementation, considering six domains of the Theoretical Framework of Acceptability: ethicality, affective attitude, burden, intervention coherence, opportunity costs, and perceived effectiveness. Quantitative analysis examined employees' acceptance (7-point Likert scale) of eight specific intervention strategies using Friedman test and mixed-effects logistic regression. Implementers considered the choice architecture approach ethical for workplace health promotion, reported mostly positive affective attitudes to and little burden because of the intervention. Intervention coherence supported acceptance through increased interest in implementation, whereas low perceived utility and high intensity of implementation reduced cost acceptance. Perceived effectiveness was mixed and varied along factors related to the implementer, social/physical work environment, employer, and employee. Employees showed overall high acceptance of evaluated strategies (Mdn 7, IQR 6.4-7), though strategies replacing unhealthy foods with healthier alternatives appeared less supported than providing information or enhancing healthy option availability or accessibility (p-values < 0.02). Greater proportion of male employees per site predicted lower overall acceptance (OR 4.4, 95% CI 1.2-16.5). Work communities appear to approve workplace choice architecture interventions for healthy eating and physical activity, but numerous factors influence acceptance and warrant consideration in future interventions. The study contributes with a theory-based, multidimensional evaluation that considered the perspectives of implementers and influenced individuals across heterogeneous real-world settings.


Protection against experimental salmonellosis in mice and sheep by immunisation with aromatic-dependent Salmonella typhimurium.
Mice immunised by the oral or intraperitoneal route with a live aromatic-dependent strain of Salmonella typhimurium exhibited significantly less protection against oral challenge with 50 LD50 of an ovine isolate of S. typhimurium (12313) than when a bovine isolate with the same O antigens and phage-type as strain 12313 was used as the challenge organism. When challenged with 10 LD50, however, protection against both strains was significantly better than that obtained when mice were vaccinated with killed vaccines (heat-killed, acetone-killed or irradiated) even when the antigenic mass of the killed vaccine was increased by up to 500-fold in an attempt to compensate for the expected limited multiplication of the mutant organism. Sheep immunised with the live mutant strain by either the intramuscular or oral route were protected against oral challenge with the virulent ovine isolate of S. typhimurium; unimmunised sheep died of acute enteritis within 7 days, although there was no evidence of systemic invasion by the challenge organism. After challenge, immunised animals ate more food than the unimmunised controls and suffered only transient, mild diarrhoea. Serum antibody titres against O and H antigens measured by direct or antiglobulin tests were significantly higher in sheep immunised by the intramuscular route than in those immunised orally. Sheep in both immunised groups developed skin swellings within 30 min after intradermal inoculation with purified homologous lipopolysaccharide indicating development of immediate-type hypersensitivity, but only those immunised by the intramuscular route showed significant indurated skin swellings characteristic of delayed-type hypersensitivity 48 and 72 h post-inoculation.(ABSTRACT TRUNCATED AT 250 WORDS)


Consideration of species-specific diatom indicators of anthropogenic stress in the Great Lakes.
Robust inferences of environmental condition come from bioindicators that have strong relationships with stressors and are minimally confounded by extraneous environmental variables. These indicator properties are generally assumed for assemblage-based indicators such as diatom transfer functions that use species abundance data to infer environmental variables. However, failure of assemblage approaches necessitates the interpretation of individual dominant taxa when making environmental inferences. To determine whether diatom species from Laurentian Great Lakes sediment cores have the potential to provide unambiguous inferences of anthropogenic stress, we evaluated fossil diatom abundance against a suite of historical environmental gradients: human population, agriculture, mining, atmospheric nutrient deposition, atmospheric temperature and ice cover. Several diatom species, such as Stephanodiscus parvus, had reliable relationships with anthropogenic stress such as human population. However, many species had little or no indicator value or had confusing relationships with multiple environmental variables, suggesting one should be careful when using those species to infer stress in the Great Lakes. Recommendations for future approaches to refining diatom indicators are discussed, including accounting for the effects of broad species geographic distributions to minimize region-specific responses that can weaken indicator power.


STI571: a gene product-targeted therapy for leukemia.
Chronic myelogenous leukemia (CML) is a clonal hematopoietic stem-cell disorder characterized by the (9:22) translocation and resultant production of the constitutively activated bcr-abl tyrosine kinase. Characterized clinically by marked myeloid proliferation, it invariably terminates in an acute leukemia. Conventional therapeutic options include interferon-based regimens and stem-cell transplantation, with stem-cell transplantation being the only curative therapy. Through rational drug development, STI571, a bcr-abl tyrosine kinase inhibitor, has emerged as a paradigm for gene product-targeted therapy, offering new hope for expanded treatment options for patients with CML.


Association between Physical Activity and Health-Related Quality of Life in Korean: The Korea National Health and Nutrition Examination Survey IV.
Numerous studies have identified that physical activity (PA) has positive influences on quality of life. However, there has been little domestic research about the relation of PA to health-related quality of life (HRQoL) among the general population. The purpose of this study was to evaluate the effect of PA on HRQoL in Korean adults aged 40 years or over. This cross-sectional study was based on data acquired from the Korean National Health and Nutrition Examination Survey IV. Final study subjects were 10,392 adults aged 40 years or over. According to the severity and frequency of PA, the subjects were divided into three PA groups as follows: high-activity, mid-activity, and low-activity group. We compared the HRQoL estimated by the EuroQoL 5-dimension (EQ-5D), the EQ visual analogue scale (EQ-VAS), and EQ-5D index between three PA groups. The odds ratios for mid-activity group and high activity group compared with low activity group were significantly decreased in the dimension of mobility of EQ-5D (mid-activity group, 0.81 [0.69-0.94]; high activity group, 0.81 [0.67-0.99]). EQ-VAS was decreased as PA level was lowered from high activity group and mid-activity to low activity group. EQ-5D index was the highest in mid-activity group and the lowest in low activity group. PA above mid-activity group showed better HRQoL compared than low activity group.


Spatial light modulator based laser microfabrication of volume optics inside solar modules.
Ultrashort pulse laser systems enable new approaches of material processing and manufacturing with enhanced precision and productivity. Time- and cost-effectiveness in the context of the industrialization of ultrashort laser pulse processes require an improvement of processing speed, which is of key importance for strengthening industrial photonics based manufacturing and extending its field of applications. This article presents results on improving the speed of a laser process by parallelization for creating light deflecting volume optics. Diffractive optical elements are fabricated directly inside the encapsulant of solar modules by utilizing a spatial light modulator based parallel laser microfabrication method. The fabricated volume optical elements effectively deflect light away from front side electrodes and significantly reduce the corresponding optical losses.


Kinetics of cisplatin release by in-vitro using poly(D,L-lactide) coated Fe3O4 nanocarriers.
Applications of nanoparticles as drug delivery systems for anticancer therapeutics have great potential to revolutionize the future of cancer therapy. In the present study, Fe3O4 nanoparticles were synthesized by co-precipitation method in the alkaline pH medium. The synthesized nanoparticles were characterized by X-ray diffraction and high resolution scanning electron microscope techniques. These analyses reveal the formation of agglomerated single phase Fe3O4 nanoparticles with average crystallite size of 8 nm. The emulsification solvent evaporation method was employed to prepare anti-cancer drug cisplatin loaded biodegradable poly (D, L-lactide) coated magnetic carriers. Fourier transform infrared spectroscopy shows the presence of cisplatin loaded poly(D,L-lactide) coating on the surface of Fe3O4 nanoparticles. Cisplatin loading efficiency and kinetics of drug release in-vitro were investigated by UV-Vis spectrophotometer. The loading efficiency of the drug was found to be 80% and from that 53% of the drug was released over a period of 70 h in phosphate buffer saline (pH 7.4) at ~ 37°C.


Pediatric risk of mortality (PRISM) score.
The Pediatric Risk of Mortality (PRISM) score was developed from the Physiologic Stability Index (PSI) to reduce the number of physiologic variables required for pediatric ICU (PICU) mortality risk assessment and to obtain an objective weighting of the remaining variables. Univariate and multivariate statistical techniques were applied to admission day PSI data (1,415 patients, 116 deaths) from four PICUs. The resulting PRISM score consists of 14 routinely measured, physiologic variables, and 23 variable ranges. The performance of a logistic function estimating PICU mortality risk from the PRISM score, age, and operative status was tested in a different sample from six PICUs (1,227 patients, 105 deaths), each PICU separately, and in diagnostic groups using chi-square goodness-of-fit tests and receiver operating characteristic (ROC) analysis. In all groups, the number and distribution of survivors and nonsurvivors in adjacent mortality risk intervals were accurately predicted: total validation group (chi 2(5) = 0.80; p greater than .95), each PICU separately (chi 2(5) range 0.83 to 7.38; all p greater than .10), operative patients (chi 2(5) = 2.03; p greater than .75), nonoperative patients (chi 2(5) = 2.80, p greater than .50), cardiovascular disease patients (chi 2(5) = 4.72; p greater than .25), respiratory disease patients (chi 2(5) = 5.82; p greater than .25), and neurologic disease patients (chi 2(5) = 7.15; p greater than .10). ROC analysis also demonstrated excellent predictor performance (area index = 0.92 +/- 0.02).


Suppression of a pituitary-ovarian axis by chronic oral administration of a novel nonpeptide gonadotropin-releasing hormone antagonist, TAK-013, in cynomolgus monkeys.
TAK-013 is a novel nonpeptide and orally active GnRH antagonist. We first examined the effect of TAK-013 on GnRH-stimulated LH release using primary-cultured pituitary cells of cynomolgus monkeys. TAK-013 suppressed LH release to below basal levels at concentrations higher than 100 nM with the IC(50) value of 36 nM. Next, we examined the effect of chronic oral administration of TAK-013 on serum hormone levels in regularly cycling female cynomolgus monkeys. TAK-013 administered at 90 mg/kg x d (30 mg/kg 3 times daily) for approximately 80 d continued to suppress LH, estradiol, and progesterone, but not FSH. The suppressive effect was reversible, in that normal profiles of sex steroids were observed immediately after discontinuation of the TAK-013 treatment. Interestingly, the suppressive effect of TAK-013 was not observed in marmoset monkeys. In summary, TAK-013 by oral administration suppresses a pituitary-ovarian axis continuously and reversibly in cynomolgus monkeys. Considering that TAK-013 has more potent antagonistic properties for human GnRH receptor than for monkey receptor, our data suggest that TAK-013 would be effective for reproductive disorders such as endometriosis and uterine leiomyoma and useful for assisted reproductive technology procedures.


Expression of a squamous cell marker, the spr1 gene, is posttranscriptionally down-regulated by retinol in airway epithelium.
Vitamin A (retinol) is required for the normal mucociliary differentiation of respiratory epithelium. A depletion of vitamin A promotes squamous cell metaplasia. To understand how vitamin A suppresses squamous cell differentiation, the expression of a squamous cell differentiation marker, the small proline-rich protein gene (spr1), was studied in cultured monkey tracheobronchial epithelial (TBE) cells. The expression of the spr1 gene was inhibited about 40 fold by retinol. The mRNA levels of the spr1 gene started to decline within 6 h of retinol treatment and reached a minimum level after 7 days. The inhibition by retinol was concentration dependent and did not require concurrent protein synthesis. The inhibition of the spr1 mRNA by retinol was not due to a decrease in the transcription rate of its gene but due to a decrease in its stability, as determined by nuclear run-on assays and mRNA half-life measurement, respectively. This result was further supported by a DNA transfection study using a chimeric construct containing the spr1 promoter region and the chloramphenicol acetyltransferase (CAT) reporter gene. The CAT activity in transfected cells was not inhibited by retinol. These results suggest that spr1 gene expression is posttranscriptionally down-regulated by retinol.


Post Cardiovascular Surgery Atrial Fibrillation. Biomarkers Determining Prognosis.
New onset of atrial fibrillation (AF) after cardiovascular surgery is associated with increased risk of complications and length of hospital stay. Identification of patients at high risk of post-operative AF (POAF) may help to act with preventive strategies having clinical and economic relevance. The focus of this review is to summarize findings on biomarkers of myocardial fibrosis (PICP and PIIINP), profibrotic mediators (TGF-beta1), extracellular matrix remodeling (MMP-9), myocardial stretch (BNP and NTpro-BNP), inflammation (interleukins, C-reactive protein and sCD40L), and myocardial necrosis (high-sensitivity troponin T), biomarkers, that can be used in clinical practice to stratify patients at risk for POAF. We searched English-language studies on MEDLINE and PubMed. Evidence synthesis was based on cohort studies, clinical trials and meta-analysis data. International clinical practice guidelines were reviewed, as well. Factors such as cardiac remodelling, atrial pressure, surgery trauma, inflammation, oxidative stress, and sympathetic/parasympathetic activation have been implicated in the development of POAF. On the basis of multifactorial mechanism underlying the onset of POAF, several studies have investigated the predictive value of some serum biomarkers. To date, there are promising preliminary data on the clinical utility of PICP, PIINP, TGF-β1 and sCD40L, whereas data on NT-proBNP, BNP, CRP, IL- 6, and hs-cTnT are controversial. Although some studies have shown promising results, there is a need for future larger studies with longer follow-up, before applying biomarkers as tools for POAF risk-stratification into clinical practice.


Feeding jejunostomy in patients with neurologic disorders.
A retrospective study of 54 patients who underwent feeding jejunostomy because of dysphagia on a neurologic basis was performed to determine risk factors affecting a postoperative mortality of 33% and six-month mortality of 67%. Advanced patient age, depressed preoperative level of consciousness, general anesthesia, and the technique of Witzel's jejunostomy were associated with increased postoperative level of consciousness carried an especially poor six month prognosis. It is concluded that a Roux-en-Y jejunostomy should be considered in patients with a hopelessly irreversible neurologic deficit. In all other situations, Stamm's jejunostomy is the feeding procedure of choice.


Concomitant Cushing's Disease and Marked Hyperprolactinemia: Response to a Dopamine Receptor Agonist.
A 38-year-old woman was admitted to our hospital because of amenorrhea, multiple bone fractures, and a Cushingoid appearance. Endocrinological investigations revealed that she had co-existing Cushing's disease and prolactinoma, with a serum level of prolactin (PRL) at 1,480 ng/mL, corticotropin (ACTH) at 81.3 pg/mL, and cortisol at 16.6 μg/dL. Due to the lack of indication for transsphenoidal surgery, cabergoline monotherapy was initiated. A 6-month course of treatment resulted in only subtle amelioration of hypercortisolism, while hyperprolactinemia was dramatically improved. In 5 cases of bihormonal (ACTH/PRL) pituitary macroadenoma reported in the English literature, 2 were initially treated with dopaminergic agonists with substantial effectiveness for both PRL and ACTH. We herein report an extremely rare case of bihormonal macroadenoma in which only PRL was responsive to treatment.


New vessel formation after surgical brain injury in the rat's cerebral cortex I. Formation of the blood vessels proximally to the surgical injury.
Postnatal neovascularization has been previously considered synonymous with angiogenesis but it was found that circulating endothelial progenitor cells may home into sites of neovascularization and their differentiation into endothelial cells is consistent with vasculogenesis. In this study, we investigated neovascularization of the adult rat's cerebral cortex after surgical brain injury by electron microscopic ultrastructural and immunocytochemical studies. We found places with disrupted brain parenchyma. The blood vessels showed an incomplete endothelial lining. In the brain parenchyma we observed fibrin, likely derived from disrupted blood vessels. In the plasma there were cell aggregates characterized by endothelial-like features with fibrils in the cytoplasm, untypical for endothelial cells. These endothelial-like cells participated in the process of new vessel formation. We used the anti-alpha(v) beta3 integrin antibody to visualize the different morphogenic stages of newly formed blood vessels. We demonstrated the relationship between alpha(v) beta3 integrin localization and different stages of new vessel formation. Our data suggest that growth and development of new blood vessels due to neovascularization following trauma of the adult rat brain are not restricted to angiogenesis but encompass vasculogenesis as well.


Long-term mortality study of oil refinery workers. IV. Exposure to the lubricating-dewaxing process.
A retrospective cohort mortality study of 1,008 male oil refinery workers who ever worked on the lubricating-dewaxing process of the lube oil department and who have been followed for a period of 43 years is presented. These workers were exposed to a number of solvents, primarily methyl ethyl ketone [(MEK) CAS: 78-93-3] and toluene (CAS: 108-88-3), but at levels far below the current Occupational Safety and Health Administration's standard. The standardized mortality ratio (SMR) for all causes (0.70) and the SMR for cancer (0.86) are much lower than unity when they are compared to the mortality experience of the U.S. population. Also observed in this study were 8 prostate cancer deaths (4.4 expected) with an SMR of 1.82, which was not statistically significant (P = .16). Seven of these 8 prostate cancer deaths occurred among nonwhite males, who showed an SMR of 2.47 (P = 0.53). However, only 1 prostate cancer death was seen among workers specifically assigned to the MEK units. The remaining deaths occurred among maintenance workers who had lube oil department-wide assignments. This cancer risk increased with increasing duration of employment in the lube oil department. A latency of 20 years or more was also observed for these prostate cancer deaths. In this study the processing of lubricating oils was found to be at least as important as the MEK solvents, and department-wide maintenance workers were as much at risk as the MEK unit workers. In view of this finding and findings obtained by others, it seems prudent to continue to study lubricating-dewaxing process workers, including the medical monitoring of all such workers for prostate cancer.


LnCeVar: a comprehensive database of genomic variations that disturb ceRNA network regulation.
LnCeVar (http://www.bio-bigdata.net/LnCeVar/) is a comprehensive database that aims to provide genomic variations that disturb lncRNA-associated competing endogenous RNA (ceRNA) network regulation curated from the published literature and high-throughput data sets. LnCeVar curated 119 501 variation-ceRNA events from thousands of samples and cell lines, including: (i) more than 2000 experimentally supported circulating, drug-resistant and prognosis-related lncRNA biomarkers; (ii) 11 418 somatic mutation-ceRNA events from TCGA and COSMIC; (iii) 112 674 CNV-ceRNA events from TCGA; (iv) 67 066 SNP-ceRNA events from the 1000 Genomes Project. LnCeVar provides a user-friendly searching and browsing interface. In addition, as an important supplement of the database, several flexible tools have been developed to aid retrieval and analysis of the data. The LnCeVar-BLAST interface is a convenient way for users to search ceRNAs by interesting sequences. LnCeVar-Function is a tool for performing functional enrichment analysis. LnCeVar-Hallmark identifies dysregulated cancer hallmarks of variation-ceRNA events. LnCeVar-Survival performs COX regression analyses and produces survival curves for variation-ceRNA events. LnCeVar-Network identifies and creates a visualization of dysregulated variation-ceRNA networks. Collectively, LnCeVar will serve as an important resource for investigating the functions and mechanisms of personalized genomic variations that disturb ceRNA network regulation in human diseases.


Differentiated human podocytes endogenously express an inhibitory isoform of vascular endothelial growth factor (VEGF165b) mRNA and protein.
Despite production by podocytes of the proangiogenic molecule vascular endothelial growth factor-A (VEGF), the glomeruli are not sites of angiogenesis. We recently described mRNA expression of an inhibitory splice variant of VEGF (VEGF165b) in normal kidney (Bates DO, Cui TG, Doughty JM, Winkler M, Sugiono M, Shields JD, Peat D, Gillatt D, and Harper SJ. Cancer Res 62: 4123-4131, 2002). Available anti-VEGF antibodies do not distinguish stimulatory from inhibitory VEGF families. To assess the production of VEGF165 (stimulatory) and VEGF165b (inhibitory) isoforms by human podocytes, we examined both primary cultured and conditionally immortalized human podocytes using family- and isoform-specific RT-PCR. In addition, VEGF protein production was analyzed in podocytes, using isoform-specific double-strand small-interference RNAs (siRNA). RT-PCR demonstrated the production of VEGF189 mRNA by podocytes of both phenotypes. In contrast, on differentiation there was a splicing change from VEGF165 to VEGF165b mRNA. In addition, VEGF protein in the supernatant of conditionally immortalized, differentiated podocytes was reduced by VEGF165b siRNA to 20+/-11% of the level of mock-transfected cells (P < 0.01). No reduction was seen with mismatch siRNA. Moreover, there was no reduction in VEGF protein concentration in the supernatant of primary cultured, dedifferentiated human podocytes (109+/-8% of mismatch siRNA, P > 0.1). In conclusion, differentiated but not dedifferentiated human podocytes secrete significant amounts of VEGF165b protein. It is possible that this may explain the paradox of high VEGF production in the glomerulus but no angiogenesis. Furthermore, the existence of this splicing switch in relation to podocyte phenotype suggests that alternative splicing of the VEGF pre-RNA is a regulated process that is open to manipulation and therefore could be a target for novel cancer therapies.


Genetic analysis of the archaeon Methanosarcina barkeri Fusaro reveals a central role for Ech hydrogenase and ferredoxin in methanogenesis and carbon fixation.
Ech hydrogenase (Ech) from the methanogenic archaeon Methanosarcina barkeri catalyzes the reversible reduction of ferredoxin by H(2) and is a member of a distinct group of membrane-bound [NiFe] hydrogenases with sequence similarity to energy-conserving NADH:quinone oxidoreductase (complex I). To elucidate the physiological role(s) of Ech a mutant lacking this enzyme was constructed. The mutant was unable to grow on methanol/H(2)/CO(2), H(2)/CO(2), or acetate as carbon and energy sources but showed wild-type growth rates with methanol as sole substrate. Addition of pyruvate to the growth medium restored growth on methanol/H(2)/CO(2) but not on H(2)/CO(2) or acetate. Results obtained from growth experiments, cell suspension experiments, and enzyme activity measurements in cell extracts provide compelling evidence for essential functions of Ech and a 2[4Fe-4S] ferredoxin in the metabolism of M. barkeri. The following conclusions were made. (i) In acetoclastic methanogenesis, Ech catalyzes H(2) formation from reduced ferredoxin, generated by the oxidation of the carbonyl group of acetate to CO(2). (ii) Under autotrophic growth conditions, the enzyme catalyzes the energetically unfavorable reduction of ferredoxin by H(2), most probably driven by reversed electron transport, and the reduced ferredoxin thus generated functions as low potential electron donor for the synthesis of pyruvate in an anabolic pathway. (iii) Reduced ferredoxin in addition provides the reducing equivalents for the first step of methanogenesis from H(2)/CO(2), the reduction of CO(2) to formylmethanofuran. Thus, in vivo genetic analysis has led to the identification of the electron donor of this key initial step of methanogenesis.


Insulin resistance: lifestyle and nutritional interventions.
Insulin resistance appears to be a common feature and a possible contributing factor to several frequent health problems, including type 2 diabetes mellitus, polycystic ovary disease, dyslipidemia, hypertension, cardiovascular disease, sleep apnea, certain hormone-sensitive cancers, and obesity. Modifiable factors thought to contribute to insulin resistance include diet, exercise, smoking, and stress. Lifestyle intervention to address these factors appears to be a critical component of any therapeutic approach. The role of nutritional and botanical substances in the management of insulin resistance requires further elaboration; however, available information suggests some substances are capable of positively influencing insulin resistance. Minerals such as magnesium, calcium, potassium, zinc, chromium, and vanadium appear to have associations with insulin resistance or its management. Amino acids, including L-carnitine, taurine, and L-arginine, might also play a role in the reversal of insulin resistance. Other nutrients, including glutathione, coenzyme Q10, and lipoic acid, also appear to have therapeutic potential. Research on herbal medicines for the treatment of insulin resistance is limited; however, silymarin produced positive results in diabetic patients with alcoholic cirrhosis, and Inula racemosa potentiated insulin sensitivity in an animal model.


Geographic variations of the bird-borne structural risk of West Nile virus circulation in Europe.
The structural risk of West Nile Disease results from the usual functioning of the socio-ecological system, which may favour the introduction of the pathogen, its circulation and the occurrence of disease cases. Its geographic variations result from the local interactions between three components: (i) reservoir hosts, (ii) vectors, both characterized by their diversity, abundance and competence, (iii) and the socio-economic context that impacts the exposure of human to infectious bites. We developed a model of bird-borne structural risk of West Nile Virus (WNV) circulation in Europe, and analysed the association between the geographic variations of this risk and the occurrence of WND human cases between 2002 and 2014. A meta-analysis of WNV serosurveys conducted in wild bird populations was performed to elaborate a model of WNV seropositivity in European bird species, considered a proxy for bird exposure to WNV. Several eco-ethological traits of bird species were linked to seropositivity and the statistical model adequately fitted species-specific seropositivity data (area under the ROC curve: 0.85). Combined with species distribution maps, this model allowed deriving geographic variations of the bird-borne structural risk of WNV circulation. The association between this risk, and the occurrence of WND human cases across the European Union was assessed. Geographic risk variations of bird-borne structural risk allowed predicting WND case occurrence in administrative districts of the EU with a sensitivity of 86% (95% CI: 0.79-0.92), and a specificity of 68% (95% CI: 0.66-0.71). Disentangling structural and conjectural health risks is important for public health managers as risk mitigation procedures differ according to risk type. The results obtained show promise for the prevention of WND in Europe. Combined with analyses of vector-borne structural risk, they should allow designing efficient and targeted prevention measures.


Insulin family polymorphisms in pregnancies complicated by small for gestational age infants.
Being born small for gestational age (SGA) increases the risk for adverse perinatal outcomes and later life vascular and metabolic disorders. The insulin family plays a vital role in intrauterine growth. We investigated the association of functional SNPs in insulin (INS), insulin receptor (INSR) and insulin receptor substrate 2 (IRS2) with small for gestational age (SGA) pregnancies, uterine and umbilical artery Doppler and plasma insulin level. We conducted a nested case-control study of 1401 nulliparous Caucasian women, their partners and babies (216 SGA and 1185 uncomplicated). SGA was defined as a birthweight less than the 10th customized birthweight percentile adjusted for maternal height, weight, parity, ethnicity, gestational age at delivery and infant sex. Uterine and umbilical artery Doppler was performed at 20 ± 1 week gestation. The SNPs in the parent infant trios were genotyped using Sequenom MassARRAY. Plasma insulin was measured by double antibody RIA in 188 healthy non-pregnant adults to assess correlations between SNP genotypes and circulating insulin. Paternal [odds ratio (OR) (95% CI) = 2.2 (1.3-3.9), P = 0.005] and infant [OR (95% CI) = 3.3 (1.7-6.2), P = 0.0001] INSR rs2059806 AA genotype was associated with SGA. Infant INSR rs2059806 A allele was associated with abnormal umbilical artery Doppler [OR (95% CI) = 1.3(1.0-1.7), P = 0.04]. INSR rs2059806 AA homozygous individuals had lower plasma insulin compared with heterozygotes (P = 0.03) and GG homozygotes (P = 0.03). The INSR rs2059806 SNP previously associated with adult vascular and metabolic diseases is also associated with SGA pregnancies. This polymorphism may associate with the risk of vascular and metabolic disorders across the life course.


HIV-related social intolerance and risky sexual behavior in a high HIV prevalence environment.
Although most countries state that fighting social intolerance against persons with HIV is part of their national HIV strategy, the impact of reducing intolerance on risky sexual behavior is largely unknown. In this paper, we estimate the effect of social intolerance against HIV+ persons on risky sexual behavior in rural Malawi using data from roughly 2000 respondents from the 2004 and 2006 waves of the Malawi Longitudinal Study of Families and Health (MLSFH). The effect of social intolerance on risky behavior is a priori ambiguous. On the one hand, higher social intolerance or stigma can lead people to disassociate from the stigmatized group and hence promote risky behavior. On the other hand, intolerance can be viewed as a social tax on being HIV+ and thus higher intolerance may reduce risky behavior. We find that a decrease in social intolerance is associated with a decrease in risky behavior, including fewer partners and a lower likelihood of having extra-marital relations. This effect is mainly driven by the impact of social intolerance on men. Overall the results suggests that reducing social intolerance might not only benefit the HIV positive but might also forestall the spread of HIV.


Assessing depression in primary medical and psychiatric practices.
A two-stage assessment of newly admitted outpatients at community mental health centers and primary medical care centers found the Center for Epidemiological Studies Depression Scale to be highly sensitive but relatively nonspecific when compared with assessments of depression by the Diagnostic Interview Schedule. Considerably higher than usual screening scores are recommended with both patient populations to improve the efficiency of the Center for Epidemiological Studies Depression Scale. The reasons for our finding that primary care clinicians underdiagnose depressive disorder while psychiatric clinicians overdiagnose it relative to the Diagnostic Interview Schedule include varied presentations by each sector's patients, differing clinical acumen, and factors affecting third-party reimbursement.


Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure.
Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Although several studies have suggested that intermittent hypoxia in obstructive sleep apnea may induce abnormalities in glucose homeostasis, it remains to be determined whether these abnormalities improve after discontinuation of the exposure. The objective of this study was to delineate the effects of intermittent hypoxia on glucose homeostasis, beta cell function, and liver glucose metabolism and to investigate whether the impairments improve after the hypoxic exposure is discontinued. C57BL6/J mice were exposed to 14 days of intermittent hypoxia, 14 days of intermittent air, or 7 days of intermittent hypoxia followed by 7 days of intermittent air (recovery paradigm). Glucose and insulin tolerance tests were performed to estimate whole-body insulin sensitivity and calculate measures of beta cell function. Oxidative stress in pancreatic tissue and glucose output from isolated hepatocytes were also assessed. Intermittent hypoxia increased fasting glucose levels and worsened glucose tolerance by 67% and 27%, respectively. Furthermore, intermittent hypoxia exposure was associated with impairments in insulin sensitivity and beta cell function, an increase in liver glycogen, higher hepatocyte glucose output, and an increase in oxidative stress in the pancreas. While fasting glucose levels and hepatic glucose output normalized after discontinuation of the hypoxic exposure, glucose intolerance, insulin resistance, and impairments in beta cell function persisted. Intermittent hypoxia induces insulin resistance, impairs beta cell function, enhances hepatocyte glucose output, and increases oxidative stress in the pancreas. Cessation of the hypoxic exposure does not fully reverse the observed changes in glucose metabolism.


Treatment of giant cell arteritis: interleukin-6 as a biologic marker of disease activity.
To determine the value of the erythrocyte sedimentation rate (ESR) and plasma interleukin-6 (IL-6) as biologic markers for monitoring disease activity in giant cell arteritis (GCA). Twenty-five patients with biopsy-proven GCA were enrolled into a prospective treatment study. Therapy was initiated with prednisone, 60 mg/day, followed by a predetermined tapering schedule. Patients were monitored monthly for clinical signs of active vasculitis and laboratory parameters indicative of inflammation, including elevated ESR (>30 mm/hour) and elevated plasma IL-6 concentrations (>6.1 pg/ml). Upon initiation of corticosteroid treatment, clinical signs of GCA disappeared in all patients; however, 60% of the patients developed symptoms of recurrent disease, on 1 or more occasions, while the prednisone dosage was being reduced. These 31 disease flares diagnosed over 550 days were associated with symptoms of systemic inflammation but did not result in vascular complications. The ESR was elevated in 76% of the patients prior to initiation of treatment (median 65 mm/hour) and normalized by day 28 of therapy (median 6 mm/hour). The median ESR remained in the normal range during the followup period. Plasma IL-6 levels, which were abnormal in 92% of untreated patients (median 16 pg/ml), were partially responsive to the initial high doses of corticosteroids by day 28 (median 6 pg/ml), but levels did not completely normalize with continued therapy. Elevation of the ESR was seen during only 58% of all disease flares, but 89% of disease recurrences were associated with increased plasma IL-6 levels (P = 0.03). Plasma IL-6 is more sensitive than ESR for indicating disease activity in untreated and treated GCA patients. Standard corticosteroid regimens only partially suppress vascular inflammation. Smoldering disease activity may expose GCA patients to the risk of progressive vascular disease (e.g., formation of aortic aneurysms) and chronic systemic complications such as IL-6-mediated osteopenia.


The medial prefrontal cortex during flexible decisions: Evidence for its role in distinct working memory processes.
During decisions that involve working memory, task-related information must be encoded, maintained across delays, and retrieved. Few studies have attempted to causally disambiguate how different brain structures contribute to each of these components of working memory. In the present study, we used transient optogenetic disruptions of rat medial prefrontal cortex (mPFC) during a serial spatial reversal learning (SSRL) task to test its role in these specific working memory processes. By analyzing numerous performance metrics, we found: (1) mPFC disruption impaired performance during only the choice epoch of initial discrimination learning of the SSRL task; (2) mPFC disruption impaired performance in dissociable ways across all task epochs (delay, choice, return) during flexible decision-making; (3) mPFC disruption resulted in a reduction of the typical vicarious-trial-and-error rate modulation that was related to changes in task demands. Taken together, these findings suggest that the mPFC plays an outsized role in working memory retrieval, becomes involved in encoding and maintenance when recent memories conflict with task demands, and enables animals to flexibly utilize working memory to update behavior as environments change.


[Comparative characteristics of tRNA-methyltransferases from rabbit liver and myocardium under normal conditions and in experimental ischemia].
Comparative studies of the state of aggregation and activity of tRNA-methyltransferases in cytosol (105,000 X g supernatant) from normal and ischemic rabbit liver and myocardium were carried out. The optimal conditions (pH, protein concentration, ionic composition of incubation mixture) for the determination of activity of tRNA-methyltransferases were elaborated. The protein fraction precipitated at 55% saturation of ammonium sulfate was shown to inherit the highest activity of tRNA-methyltransferases. In rabbit liver cytosol, the bulk of the tRNA-methyltransferase activity (approximately 50%) was found to be associated with high molecular weight complexes containing aminoacyl-tRNA-synthetases. The tRNA-methyltransferase activity was increased almost 1.4-fold both in the myocardium cytosol under total ischemia of isolated heart (30 min, 37 degrees C) and in liver cytosol under experimental myocardial infarction (EMI, occlusion of anterior coronary artery for 12 hours). Moreover, the labilization of high molecular weight complexes was observed: up to 80% of the tRNA-methyltransferase activity was localized in the fraction of lower molecular weight complexes and free enzyme fraction. In the total set of eight methylated nucleotides (products of submethylated tRNA methylation by liver enzymes), the decreased m1A content and the increased m7G and m1G contents were observed at EMI. It was assumed that the observed changes in the state of aggregation of tRNA-methyltransferases, in particular, their dissociation from the high molecular weight amino-acyl-tRNA-synthetase complexes are prerequisites for the suppression of protein biosynthesis under ischemic conditions.


Gibberellins and auxin regulate soybean hypocotyl elongation under low light and high-temperature interaction.
Soybean is an important oilseed crop grown globally. However, two examples of environmental stresses that drastically regulate soybean growth are low light and high-temperature. Emerging evidence suggests a possible interconnection between these two environmental stimuli. Low light and high-temperature as individual factors have been reported to regulate plant hypocotyl elongation. However, their interactive signal effect on soybean growth and development remains largely unclear. Here, we report that gibberellins (GAs) and auxin are required for soybean hypocotyl elongation under low light and high-temperature interaction. Our analysis indicated that low light and high-temperature interaction enhanced the regulation of soybean hypocotyl elongation and that the endogenous GA3 , GA7 , indole-3-acetic acid (IAA), and indole-3-pyruvate (IPA) contents significantly increased. Again, analysis of the effect of exogenous phytohormones and biosynthesis inhibitors treatments showed that exogenous GA, IAA, and paclobutrazol (PAC), 2, 3, 5,-triiodobenzoic acid (TIBA) treatments significantly regulated soybean seedlings growth under low light and high-temperature interaction. Further qRT-PCR analysis showed that the expression level of GA biosynthesis pathway genes (GmGA3ox1, GmGA3ox2 and GmGA3) and auxin biosynthesis pathway genes (GmYUCCA3, GmYUCCA5 and GmYUCCA7) significantly increased under (i) low light and high-temperature interaction and (ii) exogenous GA and IAA treatments. Altogether, these observations support the hypothesis that gibberellins and auxin regulate soybean hypocotyl elongation under low light and high-temperature stress interaction.


Decreased levels of cytochrome P450 2E1-derived eicosanoids sensitize renal arteries to constrictor agonists in spontaneously hypertensive rats.
We compared renal interlobar arteries of spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) in terms of cytochrome P450 (CYP) 4A and CYP2E1 protein expression; levels of 20-HETE, 19-HETE, and 18-HETE; and responsiveness to phenylephrine in the absence and presence of N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS; 30 mumol/L), a CYP4A inhibitor. Relative to data in WKY, arteries of SHR exhibited diminished (P<0.05) CYP2E1 and levels of 19-HETE (66.7+/-6.0 versus 44.9+/-2.8 pmol/mg) and 18-HETE (13.8+/-1.6 versus 7.9+/-0.5 pmol/mg), whereas CYP4A and 20-HETE levels (99.3+/-9.1 versus 98.9+/-12.8 pmol/mg) were unchanged. Phenylephrine contracted vascular rings of SHR and WKY; the R(max) was similar in both strains, but SHR vessels were more sensitive as denoted by the lower (P<0.05) EC50 (0.28+/-0.07 versus 0.71+/-0.12 mumol/L). DDMS decreased 20-HETE and, to a lesser extent, 19-HETE, while increasing (P<0.05) the EC50 for phenylephrine by 475% and 54% in vessels of SHR and WKY, respectively. The desensitizing effect of DDMS was reversed by 20-HETE. Notably, the minimal concentration of 20-HETE that decreased the EC50 for phenylephrine in DDMS-treated vessels was smaller in SHR (0.1 micromol/L) than WKY (10 micromol/L), and the sensitizing effect of 20-HETE was blunted (P<0.05) by the (R) stereoisomers of 19-HETE and 18-HETE. We conclude that the increased sensitivity to phenylephrine in arteries of SHR is attributable to a vasoregulatory imbalance produced by a deficit in vascular CYP2E1-derived products, most likely 19(R)-HETE and 18(R)-HETE, which condition amplification of the sensitizing action of 20-HETE.


Vaccine uptake in the Irish Travelling community: an audit of general practice records.
Compared to the general population, the Traveller community has substantial health inequalities. Vaccination coverage in Traveller children is estimated to be low and Travellers are at higher risk of vaccine-preventable diseases due to their social circumstances. Audit of vaccination history of Traveller (n = 214) and non-Traveller (n = 776) children registered at a general practice in England. The Green Book childhood immunization schedule was used as a reference standard. There was significantly lower coverage for Traveller children compared to non-Traveller children for all vaccinations in the routine childhood immunization schedule. The percentage of children completing the schedule at all time points was significantly lower in the Traveller community. Traveller communities have significantly lower uptake of vaccinations, and therefore Travellers' children should be targeted by general practitioners for catch-up vaccination to improve outcomes for individuals and local herd immunity.


Discovery and characterization of RecA protein of thermophilic bacterium Thermus thermophilus MAT72 phage Tt72 that increases specificity of a PCR-based DNA amplification.
The recA gene of newly discovered Thermus thermophilus MAT72 phage Tt72 (Myoviridae) was cloned and overexpressed in Escherichia coli. The 1020-bp gene codes for a 339-amino-acid polypeptide with an Mr of 38,155 which shows 38.7% positional identity to the E. coli RecA protein. When expressed in E. coli, the Tt72 recA gene did not confer the ability to complement the ultraviolet light (254nm) sensitivity of an E. coli recA mutant. Tt72 RecA protein has been purified with good yield to catalytic and electrophoretic homogeneity using a three-step chromatography procedure. Biochemical characterization indicated that the protein can pair and promote ATP-dependent strand exchange reaction resulting in formation of a heteroduplex DNA at 60°C under conditions otherwise optimal for E. coli RecA. When the Tt72 RecA protein was included in a standard PCR-based DNA amplification reaction, the specificity of the PCR assays was significantly improved by eliminating non-specific products.


Neural substrates of eyeblink conditioning: acquisition and retention.
Classical conditioning of the eyeblink reflex to a neutral stimulus that predicts an aversive stimulus is a basic form of associative learning. Acquisition and retention of this learned response require the cerebellum and associated sensory and motor pathways and engage several other brain regions including the hippocampus, neocortex, neostriatum, septum, and amygdala. The cerebellum and its associated circuitry form the essential neural system for delay eyeblink conditioning. Trace eyeblink conditioning, a learning paradigm in which the conditioned and unconditioned stimuli are noncontiguous, requires both the cerebellum and the hippocampus and exhibits striking parallels to declarative memory formation in humans. Identification of the neural structures critical to the development and maintenance of the conditioned eyeblink response is an essential precursor to the investigation of the mechanisms responsible for the formation of these associative memories. In this review, we describe the evidence used to identify the neural substrates of classical eyeblink conditioning and potential mechanisms of memory formation in critical regions of the hippocampus and cerebellum. Addressing a central goal of behavioral neuroscience, exploitation of this simple yet robust model of learning and memory has yielded one of the most comprehensive descriptions to date of the physical basis of a learned behavior in mammals.


Laparoscopic treatment of testicular torsion in a puppy.
A 6 mo old male puppy was presented as an emergency for an acute onset of lethargy, ptyalism, and vomiting. On physical examination, the dog was painful on abdominal palpation. A torsed intra-abdominal testis was diagnosed via abdominal ultrasonography and radiography. Laparoscopy was used to identify and remove the torsed testis. The dog recovered uneventfully and was described as doing well by the owners at the 6 mo follow-up telephone contact. This is the first report of an abdominal testicular torsion treated with laparoscopy.


Reduced glomerular filtration rate and prior cardiovascular event entail similar risk for coronary atherosclerotic burden.
Prior cardiovascular event and kidney dysfunction are both strong risk factors for coronary artery disease. The aim of this study is to assess coronary atherosclerotic burden in a large population of patients undergoing coronary angiography, according to prior cardiovascular event or chronic kidney disease. We evaluated 700 consecutive patients who underwent coronary angiography (CA). Serum creatinine to estimate glomerular filtration rate (eGFR) was measured. Clinically significant coronary artery disease (CAD) was defined by the presence of a coronary lesion resulting in a luminal stenosis >50%. For the purpose of the study, the whole population was divided into 4 subgroups according to the presence/absence of eGFR <60 ml/min/1.73 m2 or prior cardiovascular event: eGFR≥60/no event (Group A), eGFR≥60/yes event (Group B), eGFR<60/no event (Group C), eGFR<60/yes event (Group D). As expected, patients in group D had the worst clinical and biochemical profile. These patients also presented the highest values of urinary albumin creatinine ratio (ACR, p<0.001) and the lowest values of eGFR (p<0.01). One-hundred-ninety-six patients had three-vessel disease. Patients who had undergone PCI procedure showed a lower eGFR as compared to patients who had not (p=0.009). Considering group A as reference, the risk of having three-vessel disease was increased in group B (OR= 2.09; 95% CI 1.37-3.19), in group C, (OR= 1.80; 95% CI 1.04-3.14), and finally in group D (OR= 3.35; 95% CI 2.01-5.58). The risk carried by group C was not significantly different from that carried by Group B: OR= 0.86; 95% CI 0.5-1.5. In our study, low eGFR seems to have the same excess risk of prior CV event.


Topical dermatological drug delivery: quo vadis?
Skin disease (dermatological conditions') affects at least one-third of the US population and has been cited as one of the top 15 medical conditions for which prevalence and healthcare spending increased in the last decade. The outcome of topical dermatological drug treatment is significantly influenced by the choice of vehicle or delivery system. Advancements in the life sciences coupled with a growing market for dermatologicals have facilitated the emergence of improved topical formulations and drug delivery systems. The current and emerging approaches of optimizing the topical delivery of dermatological agents (small and large molecules) include the use of chemical enhancers, bio-polymers (e.g. sodium hyaluronate), liposomes, particulate carriers (microspheres and lipid nanoparticles), topical sprays and foams, occlusion (via dressings and patches) topical peels, temperature (heat), iontophoresis, and ultrasound. These delivery approaches (when used solely or in a synergistic manner) are a significant improvement over conventional systems (creams, lotions, ointments and pastes) and have the potential to enhance efficacy and tolerability, improve patient compliance (including dermatology life quality), and also fulfil other unmet needs of the topical dermatological market.


Classifying temporal microarray data by selecting informative genes.
In order to more accurately predict an individual's health status, in clinical applications it is often important to perform analysis of high-dimensional gene expression data that varies with time. A major challenge in predicting from such temporal microarray data is that the number of biomarkers used as features is typically much larger than the number of labeled subjects. One way to address this challenge is to perform feature selection as a preprocessing step and then apply a classification method on selected features. However, traditional feature selection methods cannot handle multivariate temporal data without applying techniques that flatten temporal data into a single matrix in advance. In this study, a feature selection filter that can directly select informative features from temporal gene expression data is proposed. In our approach, we measure the distance between multivariate temporal data from two subjects. Based on this distance, we define the objective function of temporal margin based feature selection to maximize each subject's temporal margin in its own relevant subspace. The experimental results on synthetic and two real flu data sets provide evidence that our method outperforms the alternatives, which flatten the temporal data in advance.


Person-centered profiles of parasympathetic physiology, anxiety symptoms, and depressive symptoms in mothers and fathers of young children.
Respiratory sinus arrhythmia (RSA) is a biomarker of mental health, but RSA-symptom relations in parents of young children are understudied. We examined how anxiety symptoms, depressive symptoms, resting RSA, and RSA reactivity during challenging parent-child interactions clustered in a community sample of mothers (N = 126) and fathers (N = 87) of 3-year-olds and whether profiles predicted child emotional and behavioral dysregulation at age 4. Mothers fit four profiles (Typical, Mild Risk, Moderate Risk/Withdrawal, and Moderate Risk/Augmentation), suggesting that RSA reactivity was distinct by predominant symptom type at higher levels of risk: specifically, heightened RSA withdrawal was associated with a higher probability of anxiety symptoms and RSA augmentation was associated with a higher probability of depressive symptoms. Fathers fit three profiles (Typical, Mild Risk, and Moderate Risk) where Moderate Risk was characterized by RSA augmentation and a higher probability of both anxiety and depressive symptoms. Mild risk profiles showed heightened resting RSA for mothers and fathers but no differences in RSA reactivity. Both mild and moderate risk profiles predicted higher child dysregulation 1 year later compared to typical profiles. Findings offer preliminary evidence that parasympathetic physiology covaries with symptoms differently for mothers and fathers and that parental profiles of physiology and symptoms inform children's developmental psychopathology.


PPARGC1B gene is associated with Kashin-Beck disease in Han Chinese.
Kashin-Beck disease (KBD) is a chronic osteochondropathy. The genetic basis of KBD remains elusive now. To investigate the relationship between PPARGC1B gene polymorphism and KBD, we conducted a two-stage association study using 2743 unrelated Han Chinese subjects. In the first stage, three SNPs rs1078324, rs4705372, and rs11743128 of PPARGC1B gene were genotyped in 559 KBD patients and 467 health controls using Sequenom MassARRAY platform. In the second stage, the association analysis results of PPARGC1B with KBD were replicated using an independent sample of 1717 subjects. SNP association analysis was conducted by PLINK software. Genotype imputation was conducted by IMPUTE 2.0 against the reference panel of the 1000 genome project. Bonferroni multiple testing correction was performed. We observed a significant association signal at rs4705372 (P = 0.0160) and a suggestive association signal at rs11743128 (P = 0.0290). Further replication study confirmed the association signals of rs4705372 (P = 0.0026) and rs11743128 (P = 0.0387) in the independent validation sample. Our study results suggest that PPARGC1B is a novel susceptibility gene of KBD.


Effects of raloxifene hydrochloride on bone mineral density, bone metabolism and serum lipids in postmenopausal women: a randomized clinical trial in Beijing.
To determine the effects of raloxifene hydrochloride (RLX) on bone mineral density (BMD), bone metabolism markers and serum lipids in healthy postmenopausal women in Beijing. A multicenter, randomized, double-blind, placebo-controlled study was conducted in a total of 204 healthy postmenopausal women (age 59.5 +/- 5.0 years and weight 62.8 +/- 8.7 kg) treated with either RLX 60 mg (n = 102) or placebo (n = 102) daily for 12 months. BMD, serum lipids, and bone markers were measured before and after drug administration. Compared with placebo, RLX produced a significant increase in both total lumbar spine and total hip BMD. For the lumbar spine, percentage increase in total BMD was 2.3% with RLX compared with a decrease of 0.1% with placebo (P < 0.001). Corresponding values for total hip BMD were a 2.5% increase for RLX and a 1.1% increase for placebo (P = 0.011). For biochemical markers of bone metabolism, serum osteocalcin and C-telopeptide, percentage decreases were 27.65% and 24.02% in RLX-treated subjects. Corresponding values in placebo were a 10.64% decrease and a 15.75% increase (RLX compared with placebo, both P < 0.001). For total cholesterol and low-density lipoprotein cholesterol levels, percentage decreases were 6.44% and 34.58% in the RLX-treated group. Corresponding values in placebo-treated patients were a 1.44% increase and a 19.07% decrease (RLX compared with placebo, both P < 0.001). No differences were found for high-density lipoprotein cholesterol or triglyceride levels between the two groups. Only 5 subjects discontinued early owing to an adverse event (3 in the RLX group and 2 in the placebo group). This study confirms that RLX exerts positive effects on the skeleton, increasing BMD and decreasing biochemical markers of bone metabolism, and has a positive effect on the overall serum lipid profile in postmenopausal women in China.


Association between changes in air pollution levels during the Beijing Olympics and biomarkers of inflammation and thrombosis in healthy young adults.
Air pollution is a risk factor for cardiovascular diseases (CVD), but the underlying biological mechanisms are not well understood. To determine whether markers related to CVD pathophysiological pathways (biomarkers for systemic inflammation and thrombosis, heart rate, and blood pressure) are sensitive to changes in air pollution. Using a quasi-experimental opportunity offered by greatly restricted air pollution emissions during the Beijing Olympics, we measured pollutants daily and the outcomes listed below in 125 healthy young adults before, during, and after the 2008 Olympics (June 2-October 30). We used linear mixed-effects models to estimate the improvement in outcome levels during the Olympics and the anticipated reversal of outcome levels after pollution controls ended to determine whether changes in outcome levels were associated with changes in pollutant concentrations. C-reactive protein (CRP), fibrinogen, von Willebrand factor, soluble CD40 ligand (sCD40L), soluble P-selectin (sCD62P) concentrations; white blood cell count (WBC); heart rate; and blood pressure. Concentrations of particulate and gaseous pollutants decreased substantially (-13% to -60%) from the pre-Olympic period to the during-Olympic period. Using 2-sided tests conducted at the .003 level, we observed statistically significant improvements in sCD62P levels by -34.0% (95% CI, -38.4% to -29.2%; P < .001) from a pre-Olympic mean of 6.29 ng/mL to a during-Olympic mean of 4.16 ng/mL and von Willebrand factor by -13.1% (95% CI, -18.6% to -7.5%; P < .001) from 106.4% to 92.6%. After adjustments for multiple comparisons, changes in the other outcomes were not statistically significant. In the post-Olympic period when pollutant concentrations increased, most outcomes approximated pre-Olympic levels, but only sCD62P and systolic blood pressure were significantly worsened from the during-Olympic period. The fraction of above-detection-limit values for CRP (percentage ≥ 0.3 mg/L) was reduced from 55% in the pre-Olympic period to 46% in the during-Olympic period and reduced further to 36% in the post-Olympic period. Interquartile range increases in pollutant concentrations were consistently associated with statistically significant increases in fibrinogen, von Willebrand factor, heart rate, sCD62P, and sCD40L concentrations. Changes in air pollution levels during the Beijing Olympics were associated with acute changes in biomarkers of inflammation and thrombosis and measures of cardiovascular physiology in healthy young persons. These findings are of uncertain clinical significance.


A T cell- and natural killer cell-specific, trypsin-like serine protease. Implications of a cytolytic cascade.
A new trypsin-like serine protease was cloned from both a murine cytotoxic T lymphocyte and a human PHA-stimulated peripheral blood lymphocyte cDNA library. In both the mouse and human system, this transcript had a T cell- and NK-specific distribution, being detected in cytotoxic T lymphocytes (CTL), some T-helper clones, and NK, but not in a variety of normal tissues. T-cell activation with Con A plus IL-2 induced mouse spleen cells to express this gene with kinetics correlating with the acquisition of cytolytic capacity. Both the mouse and human nucleotide sequences of this gene encoded an amino acid sequence with 25-40% identity to members of the serine protease family. The active-site "charge-relay" residues (His-57, Asp-102, and Ser-195 of the chymotrypsin numbering system) are conserved, as well as the trypsin-specific Asp (position 189 in trypsin). We reviewed the evidence of this serine protease's role in lymphocyte lysis and proposed a "lytic cascade." We discussed the biological and clinical implications of a cascade, proposing these enzymes as markers for cytolytic cells and as targets for rational drug therapy. Genetic and acquired deficits in the lethal hit-delivery system are considered as a basis for approaching some immunodeficiency states, including severe EBV infections, T-gamma leukemias, and T8+ lymphocytosis syndromes.


Pregnancy-associated osteoporosis.
The clinical features, investigation and outcome in 24 patients with pregnancy-associated osteoporosis, followed for up to 24 years from the first pregnancy are described. Symptoms occurred most often in the first pregnancy (17 patients) at a mean age of 27 years (range 21-36); the most frequent was back pain in late pregnancy or post partum (n = 18); less common was hip (n = 5) or ankle (n = 1) pain. In most, symptoms improved soon after delivery. Four subjects had pre-existing disorders known to reduce bone density (corticosteroid therapy, heparin treatment, mild osteogenesis imperfecta and previous anorexia nervosa). Radiographs showed vertebral collapse or localized osteoporosis of the hip, with MRI evidence of oedema. Forearm bone mineral density (BMD) was sometimes normal, but spinal BMD (measured by DXA) was low. Bone biopsies in eleven patients showed features compatible with osteoblast failure. Except for the patient with mild osteogenesis imperfecta, cultured dermal fibroblasts synthesized and exported normal Type I collagen. In 14 subsequent pregnancies (10 patients) there was no recurrence in ten and mild symptoms in the remainder. Excluding one patient who had repeated osteoporotic fractures and vertebral collapse, the long-term prognosis was good.


Cardiovascular and renal benefits of dry bean and soybean intake.
Dry beans and soybeans are nutrient-dense, fiber-rich, and are high-quality sources of protein. Protective and therapeutic effects of both dry bean and soybean intake have been documented. Studies show that dry bean intake has the potential to decrease serum cholesterol concentrations, improve many aspects of the diabetic state, and provide metabolic benefits that aid in weight control. Soybeans are a unique source of the isoflavones genistein and diadzein, which have numerous biological functions. Soybeans and soyfoods potentially have multifaceted health-promoting effects, including cholesterol reduction, improved vascular health, preserved bone mineral density, and reduction of menopausal symptoms. Soy appears to have salutary effects on renal function, although these effects are not well understood. Whereas populations consuming high intakes of soy have lower prevalences of certain cancers, definitive experimental data are insufficient to clarify a protective role of soy. The availability of legume products and resources is increasing, incorporating dry beans and soyfoods into the diet can be practical and enjoyable. With the shift toward a more plant-based diet, dry beans and soy will be potent tools in the treatment and prevention of chronic disease.


Proteinase-related broad-spectrum inhibitory activity among group-A streptococci.
Some 10% of group-A streptococci have inhibitory activity against all nine strains (eight of them streptococci) in a set of indicators in an inhibitor-production typing (P-typing) scheme. This activity was associated with the concurrent synthesis of cell-associated proteinase by the streptococcal strain. Inhibitor production was prevented either by incubation of the test strain in conditions inimical to proteinase production, e.g., at low temperature and alkaline pH, or by addition to the medium of substances, such as glucose, iodoacetic acid, lincomycin, Congo red or trypan blue, that had an anti-proteinase effect. Inhibitory activity was not detectable in liquid cultures, but freeze-thaw extracts of cultures of group-A streptococcus strain A1013 on Gibco Columbia Agar Base (Gibco Diagnostics, Madison, WI, USA) had some inhibitory activity. The inhibitor was concentrated and partially purified, and the active agent was shown to be a high-mol.-wt cationic protein which was bactericidal for various bacteria in the logarithmic growth phase, including the homologous producer strain.