The relationship between multisensory integration and IQ in children.
It is well accepted that multisensory integration has a facilitative effect on perceptual and motor processes, evolutionarily enhancing the chance of survival of many species, including humans. Yet, there is limited understanding of the relationship between multisensory processes, environmental noise, and children's cognitive abilities. Thus, this study investigated the relationship between multisensory integration, auditory background noise, and the general intellectual abilities of school-age children (N = 88, mean age = 9 years, 7 months) using a simple audiovisual detection paradigm. We provide evidence that children with enhanced multisensory integration in quiet and noisy conditions are likely to score above average on the Full-Scale IQ of the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV). Conversely, approximately 45% of tested children, with relatively low verbal and nonverbal intellectual abilities, showed reduced multisensory integration in either quiet or noise. Interestingly, approximately 20% of children showed improved multisensory integration abilities in the presence of auditory background noise. The findings of the present study suggest that stable and consistent multisensory integration in quiet and noisy environments is associated with the development of optimal general intellectual abilities. Further theoretical implications are discussed.


The development and expression of physical nicotine dependence corresponds to structural and functional alterations in the anterior cingulate-precuneus pathway.
Perturbations in neural function provoked by a drug are thought to induce neural adaptations, which, in the absence of the drug, give rise to withdrawal symptoms. Previously published structural data from this study indicated that the progressive development of physical dependence is associated with increasing density of white matter tracts between the anterior cingulum bundle and the precuneus. Using functional magnetic resonance imaging, we compared 11 smokers after 11 h of abstinence from nicotine and after satiation, with 10 nonsmoking controls, using independent component analysis for brain network comparisons as well as a whole brain resting-state functional connectivity analysis using the anterior cingulate cortex as a seed. Independent component analysis demonstrated increased functional connectivity in brain networks such as the default mode network associated with the withdrawal state in multiple brain regions. In seed-based analysis, smokers in the withdrawal state showed stronger functional connectivity than nonsmoking controls between the anterior cingulate cortex and the precuneus, caudate, putamen, and frontal cortex (P < 0.05). Among smokers, compared to the satiated state, nicotine withdrawal was associated with increased connectivity between the anterior cingulate cortex and the precuneus, insula, orbital frontal gyrus, superior frontal gyrus, posterior cingulate cortex, superior temporal, and inferior temporal lobe (P < 0.02). The intensity of withdrawal-induced craving correlated with the strength of connectivity between the anterior cingulate cortex and the precuneus, insula, caudate, putamen, middle cingulate gyrus, and precentral gyrus (r = 0.60-0.76; P < 0.05). In concordance with our previous report that structural neural connectivity between the anterior cingulate area and the precuneus increased in proportion to the progression of physical dependence, resting-state functional connectivity in this pathway increases during nicotine withdrawal in correlation with the intensity of withdrawal-induced craving. These findings suggest that smoking triggers structural and functional neural adaptations in the brain that support withdrawal-induced craving.


Zipf's law and criticality in multivariate data without fine-tuning.
The joint probability distribution of states of many degrees of freedom in biological systems, such as firing patterns in neural networks or antibody sequence compositions, often follows Zipf's law, where a power law is observed on a rank-frequency plot. This behavior has been shown to imply that these systems reside near a unique critical point where the extensive parts of the entropy and energy are exactly equal. Here, we show analytically, and via numerical simulations, that Zipf-like probability distributions arise naturally if there is a fluctuating unobserved variable (or variables) that affects the system, such as a common input stimulus that causes individual neurons to fire at time-varying rates. In statistics and machine learning, these are called latent-variable or mixture models. We show that Zipf's law arises generically for large systems, without fine-tuning parameters to a point. Our work gives insight into the ubiquity of Zipf's law in a wide range of systems.


[Association of COVID-19 dissemination with symptoms of anxiety and depression among university students].
Evidence about the impact of the COVID-19 pandemic on the mental health of specific subpopulations- such as university students-is needed as communities prepare for future waves. To study the association of proximity of COVID-19 with symptoms of anxiety and depression in university students. This trend study analyzed weekly cross-sectional surveys of probabilistic samples of students from the University of British Columbia for 13 weeks through the first wave of COVID-19. The main variable assessed was propinquity of COVID-19, defined as "knowing someone who tested positive for COVID-19", which was specified at different levels: knowing someone anywhere globally, in Canada, in Vancouver, in their course, or at home. Proximity was included in multivariable linear regressions to assess its association with primary outcomes, including 30-day symptoms of anxiety and/or depression. Of 1,388 respondents (adjusted response rate=50%), 5.6% knew someone with COVID-19 in Vancouver, 0.8% in their course, and 0.3% at home. Ten percent were overwhelmed and unable to access help. Knowing someone in Vancouver was associated with an 11 percentage-point increase in the probability of 30-day anxiety symptoms (SE=0,05; p≤0,05), moderated by gender, with a significant interaction of the exposure and being female (coefficient= 20(SE=0,09), p≤0,05). No association was found with depressive symptoms. Propinquity of COVID-19 cases may increase the likelihood of anxiety symptoms in students, particularly amongst men. Most students report coping well, but additional supports are needed for an emotionally overwhelmed minority who report being unable to access help.


PTEN/MMAC1/TEP1 suppresses the tumorigenicity and induces G1 cell cycle arrest in human glioblastoma cells.
PTEN/MMAC1/TEP1 is a tumor suppressor that possesses intrinsic phosphatase activity. Deletions or mutations of its encoding gene are associated with a variety of human cancers. However, very little is known about the molecular mechanisms by which this important tumor suppressor regulates cell growth. Here, we show that PTEN expression potently suppressed the growth and tumorigenicity of human glioblastoma U87MG cells. The growth suppression activity of PTEN was mediated by its ability to block cell cycle progression in the G1 phase. Such an arrest correlated with a significant increase of the cell cycle kinase inhibitor p27(KIP1) and a concomitant decrease in the activities of the G1 cyclin-dependent kinases. PTEN expression also led to the inhibition of Akt/protein kinase B, a serine-threonine kinase activated by the phosphatidylinositol 3-kinase (PI 3-kinase) signaling pathway. In addition, the effect of PTEN on p27(KIP1) and the cell cycle can be mimicked by treatment of U87MG cells with LY294002, a selective inhibitor of PI 3-kinase. Taken together, our studies suggest that the PTEN tumor suppressor modulates G1 cell cycle progression through negatively regulating the PI 3-kinase/Akt signaling pathway, and one critical target of this signaling process is the cyclin-dependent kinase inhibitor p27(KIP1).


A novel fungal effector from Puccinia graminis suppressing RNA silencing and plant defense responses.
Fungal plant pathogens, like rust-causing biotrophic fungi, secrete hundreds of effectors into plant cells to subvert host immunity and promote pathogenicity on their host plants by manipulating specific physiological processes or signal pathways, but the actual function has been demonstrated for very few of these proteins. Here, we show that the PgtSR1 effector proteins, encoded by two allelic genes (PgtSR1-a and PgtSR1-b), from the wheat stem rust pathogen Puccinia graminis f. sp. tritici (Pgt), suppress RNA silencing in plants and impede plant defenses by altering the abundance of small RNAs that serve as defense regulators. Expression of the PgtSR1s in plants revealed that the PgtSR1s promote susceptibility to multiple pathogens and partially suppress cell death triggered by multiple R proteins. Overall, our study provides the first evidence that the filamentous fungus P. graminis has evolved to produce fungal suppressors of RNA silencing and indicates that PgtSR1s suppress both basal defenses and effector triggered immunity.


Detection of Chlamydia trachomatis mRNA using digital PCR as a more accurate marker of viable organism.
Spontaneous resolution of urogenital Chlamydia trachomatis (CT) without treatment has previously been described, but a limitation of these reports is that DNA or RNA-based amplification tests used do not differentiate between viable infection and non-viable DNA. We modified a previously published CT mRNA detection (omp2) method to differentiate between viable infection and non-viable DNA in a sample of CT DNA PCR positive women. We modified a CT mRNA detection (omp2) method from reverse transcriptase qPCR (RTqPCR) to digital PCR (dPCR) and evaluated it in samples from CT DNA positive women. Firstly, CT infected McCoy B cells treated with azithromycin in vitro identified detectable mRNA levels disappeared <2 days, while DNA persisted up to 6 days. We used 55 self-collected vaginal swabs from a cohort of women diagnosed as DNA positive for chlamydia obtained pre- and 7 days of post-azithromycin treatment. Concordance with DNA results was higher for dPCR than RTqPCR (74.5% versus 65.5%). At visit 1, there was a strong linear relationship between DNA and mRNA (r = 0.9, p < 0.000); 24 samples had both mRNA and DNA detected (82.8%) and 5 had only DNA detected with a potential false positive proportion of 17.2% (95%CI: 5.8, 35.8). At visit 2, there was poor correlation between DNA and mRNA (r = 0.14, p = 0.55); eight specimens had only DNA detected (42.1%; 95%CI: 20.25, 66.50) and one had mRNA detected. DNA detection methods alone may detect non-viable DNA. Consideration should be given to further develop mRNA assays as ancillary tests to improve detection of viable chlamydia.


Patient Mutation Directed shRNA Screen Uncovers Novel Bladder Tumor Growth Suppressors.
Next-generation sequencing (NGS) of human bladder cancer has revealed many gene alterations compared with normal tissue, with most being predicted to be "loss of function." However, given the high number of alterations, evaluating the functional impact of each is impractical. Here, we develop and use a high-throughput, in vivo strategy to determine which alterations are loss of function in tumor growth suppressors. Genes reported as altered by NGS in bladder cancer patients were bioinformatically processed by MutationTaster and MutationAssessor, with 283 predicted as loss of function. An shRNA lentiviral library targeting these genes was transduced into T24 cells, a nontumorigenic human bladder cancer cell line, followed by injection into mice. Tumors that arose were sequenced and the dominant shRNA constructs were found to target IQGAP1, SAMD9L, PCIF1, MED1, and KATNAL1 genes. In vitro validation experiments revealed that shRNA molecules directed at IQGAP1 showed the most profound increase in anchorage-independent growth of T24 cells. The clinical relevance of IQGAP1 as a tumor growth suppressor is supported by the finding that its expression is lower in bladder cancer compared with benign patient urothelium in multiple independent datasets. Lower IQGAP1 protein expression associated with higher tumor grade and decreased patient survival. Finally, depletion of IQGAP1 leads to increased TGFBR2 with TGFβ signaling, explaining in part how reduced IQGAP1 promotes tumor growth. These findings suggest IQGAP1 is a bladder tumor growth suppressor that works via modulating TGFβ signaling and is a potentially clinically useful biomarker. This study used gene mutation information from patient-derived bladder tumor specimens to inform the development of a screen used to identify novel tumor growth suppressors. This included identification of the protein IQGAP1 as a potent bladder cancer growth suppressor.


Clinical evaluation of carbon-11-phenylephrine: MAO-sensitive marker of cardiac sympathetic neurons.
The sympathomimetic drug phenylephrine recently has been labeled with 11C for use in PET studies of cardiac sympathetic innervation. Previous reports using isolated perfused rat heart models indicate that phenylephrine is metabolized by intraneuronal monoamine oxidase (MAO). This report compares the imaging characteristics, neuronal selectivity and kinetics of (-)-[11C]phenylephrine (PHEN) to the structurally similar but MAO-resistant analog (-)-[11C]-meta-hydroxyephedrine (HED), an established heart neuronal marker. Fourteen healthy volunteers were studied with PET and PHEN. Ten had paired studies with HED; four of the 10 were scanned a second time with each tracer after oral administration of desipramine, a selective neuronal transport blocker. Hemodynamic and electrocardiographic responses were monitored. Blood levels of intact radiotracer and radiolabeled metabolites were determined from venous blood samples taken during the PET study. Myocardial retention indices for both tracers were calculated. No hemodynamic or electrocardiographic effects were observed with either tracer. PHEN showed reduced myocardial retention at 50 min compared to HED; however, image quality and uniformity of distribution were comparable. PHEN cleared from myocardium with a mean half-time of 59 +/- 5 min, while myocardial levels of HED remained constant. PHEN metabolites appeared in the blood approximately three times faster than HED metabolites. Desipramine pretreatment markedly reduced (> 60%) myocardial retention of both PHEN and HED. PHEN provides PET images of human heart comparable in quality and uniformity to HED. Like HED, PHEN localizes in the sympathetic nerves of the heart. However, the more rapid efflux of PHEN, that is likely mediated by MAO, may provide information on the functional status of cardiac sympathetic neurons unobtainable with HED.


miR-34a expands myeloid-derived suppressor cells via apoptosis inhibition.
Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population and show significant expansion under pathological conditions. microRNA plays important roles in many biological processes, whether microRNAs have a function in the expansion of MDSCs is still not very clear. In this study, miR-34a overexpression can induce the expansion of MDSCs in bone marrow chimera and transgenic mice model. The experimental results suggest that miR-34a inhibited the apoptosis of MDSCs but did not affect the proliferation of MDSCs. The distinct mRNA microarray profiles of MDSCs of wild type and miR-34a over-expressing MDSCs combined with the target prediction of miR-34a suggest that miR-34a may target genes such as p2rx7, Tia1, and plekhf1 to inhibit the apoptosis of MDSCs. Taken together, miR-34a contributes to the expansion of MDSCs by inhibiting the apoptosis of MDSCs.


Quality control of regional wall motion analysis in stress Echo 2020.
The trial "Stress Echo (SE) 2020" evaluates novel applications of SE beyond coronary artery disease. The aim of the study was control quality and harmonize reading criteria. One reader from 78 centers of the SE 2020 network asked for credentials to read a set of 20 SE video-clips selected by the core lab. All aspiring centers met the pre-requisite of high-volume and the years of experience in SE ranged from 5 to 31years (mean value 18years). The diagnostic gold standard was a reading by the core lab. The a priori determined pass threshold was 18/20 (≥90%). Of the initial 78 who started, 57 completed the first attempt: individual readers' score on first attempt ranged from 07/20 to 20/20 (accuracy from 35% to 100%, mean 78.7±13%) and 44 readers passed it. There was a very poor correlation between years of experience and the reader's score on first attempt (r=-0.161, p=0.231). Of the 13 readers who failed the first attempt, 12 took it again after the web-based session and their accuracy improved (74% vs. 96%, p<0.001). The kappa inter-observer agreement before and after web-based training was 0.59 on first attempt and rose to 0.91 on the last attempt. In SE reading, the volume of activity or years of experience is not synonymous with diagnostic quality. Qualitative analysis and operator-dependence can become a limiting weakness in clinical practice, in the absence of strict pathways of learning, credentialing and audit.


[NVOG celebrates 125 years].
In light of the 125th anniversary of the Dutch Society of Obstetrics and Gynaecology (NVOG), the Netherlands Journal of Medicine (NTvG) will publish a series of articles over the coming months. The articles will cover various topics from the specialty areas of gynaecology and obstetrics. We hope that these articles will inspire you, so that, in another 25 years, we can report again on positive developments of our specialty for patients, doctors and the community.


Cardiovascular factors are related to dopamine integrity and cognition in aging.
The aging brain undergoes several changes, including reduced vascular, structural, and dopamine (DA) system integrity. Such brain changes have been associated with age-related cognitive deficits. However, their relative importance, interrelations, and links to risk factors remain elusive. The present work used magnetic resonance imaging and positron emission tomography with 11 C-raclopride to jointly examine vascular parameters (white-matter lesions and perfusion), DA D2-receptor availability, brain structure, and cognitive performance in healthy older adults (n = 181, age: 64-68 years) from the Cognition, Brain, and Aging (COBRA) study. Covariance was found among several brain indicators, where top predictors of cognitive performance included caudate and hippocampal integrity (D2DR availability and volumes), and cortical blood flow and regional volumes. White-matter lesion burden was negatively correlated with caudate DA D2-receptor availability and white-matter microstructure. Compared to individuals with smaller lesions, individuals with confluent lesions (exceeding 20 mm in diameter) had reductions in cortical and hippocampal perfusion, striatal and hippocampal D2-receptor availability, white-matter microstructure, and reduced performance on tests of episodic memory, sequence learning, and processing speed. Higher cardiovascular risk as assessed by treatment for hypertension, systolic blood pressure, overweight, and smoking was associated with lower frontal cortical perfusion, lower putaminal D2DR availability, smaller grey-matter volumes, a larger number of white-matter lesions, and lower episodic memory performance. Taken together, these findings suggest that reduced cardiovascular health is associated with poorer status for brain variables that are central to age-sensitive cognitive functions, with emphasis on DA integrity.


The selective phosphodiesterase 4 inhibitor roflumilast and phosphodiesterase 3/4 inhibitor pumafentrine reduce clinical score and TNF expression in experimental colitis in mice.
The specific inhibition of phosphodiesterase (PDE)4 and dual inhibition of PDE3 and PDE4 has been shown to decrease inflammation by suppression of pro-inflammatory cytokine synthesis. We examined the effect of roflumilast, a selective PDE4 inhibitor marketed for severe COPD, and the investigational compound pumafentrine, a dual PDE3/PDE4 inhibitor, in the preventive dextran sodium sulfate (DSS)-induced colitis model. The clinical score, colon length, histologic score and colon cytokine production from mice with DSS-induced colitis (3.5% DSS in drinking water for 11 days) receiving either roflumilast (1 or 5 mg/kg body weight/d p.o.) or pumafentrine (1.5 or 5 mg/kg/d p.o.) were determined and compared to vehicle treated control mice. In the pumafentrine-treated animals, splenocytes were analyzed for interferon-γ (IFNγ) production and CD69 expression. Roflumilast treatment resulted in dose-dependent improvements of clinical score (weight loss, stool consistency and bleeding), colon length, and local tumor necrosis factor-α (TNFα) production in the colonic tissue. These findings, however, were not associated with an improvement of the histologic score. Administration of pumafentrine at 5 mg/kg/d alleviated the clinical score, the colon length shortening, and local TNFα production. In vitro stimulated splenocytes after in vivo treatment with pumafentrine showed a significantly lower state of activation and production of IFNγ compared to no treatment in vivo. These series of experiments document the ameliorating effect of roflumilast and pumafentrine on the clinical score and TNF expression of experimental colitis in mice.


Subcellular localization and clues for the function of the HetN factor influencing heterocyst distribution in Anabaena sp. strain PCC 7120.
In the filamentous cyanobacterium Anabaena sp. strain PCC 7120, heterocysts are formed in the absence of combined nitrogen, following a specific distribution pattern along the filament. The PatS and HetN factors contribute to the heterocyst pattern by inhibiting the formation of consecutive heterocysts. Thus, inactivation of any of these factors produces the multiple contiguous heterocyst (Mch) phenotype. Upon N stepdown, a HetN protein with its C terminus fused to a superfolder version of green fluorescent protein (sf-GFP) or to GFP-mut2 was observed, localized first throughout the whole area of differentiating cells and later specifically on the peripheries and in the polar regions of mature heterocysts, coinciding with the location of the thylakoids. Polar localization required an N-terminal stretch comprising residues 2 to 27 that may represent an unconventional signal peptide. Anabaena strains expressing a version of HetN lacking this fragment from a mutant gene placed at the native hetN locus exhibited a mild Mch phenotype. In agreement with previous results, deletion of an internal ERGSGR sequence, which is identical to the C-terminal sequence of PatS, also led to the Mch phenotype. The subcellular localization in heterocysts of fluorescence resulting from the fusion of GFP to the C terminus of HetN suggests that a full HetN protein is present in these cells. Furthermore, the full HetN protein is more conserved among cyanobacteria than the internal ERGSGR sequence. These observations suggest that HetN anchored to thylakoid membranes in heterocysts may serve a function besides that of generating a regulatory (ERGSGR) peptide.


Impact of Media-Based Negative and Positive Age Stereotypes on Older Individuals' Mental Health.
During the COVID-19 pandemic, stigmatization of older persons increased in traditional and social media. It was unknown whether this negative messaging could be detrimental to the mental health of older individuals, and whether the relatively uncommon positive messaging about older individuals could benefit their mental health. To address these gaps, we designed age-stereotype interventions based on actual news stories that appeared during the pandemic, and divided them into negative and positive versions of what we term personified (i.e., individual-based) and enumerative (i.e., number-based) age-stereotype messaging. The negative versions of the 2 types of messaging reflected the age stereotype of decline, whereas the positive versions of the 2 types of messaging reflected the age stereotype of resilience. As expected, the exposure of older individuals to the negative-age-stereotype-messaging interventions led to significantly worse mental health (i.e., more anxiety and less peacefulness), compared to a neutral condition; in contrast, the positive-age-stereotype-messaging interventions led to significantly better mental health (i.e., less anxiety and more peacefulness), compared to a neutral condition. The findings were equally strong for the personified and enumerative conditions. Also as expected, the interventions, which were self-irrelevant to the younger participants, did not significantly impact their mental health. This is the first-known study to experimentally demonstrate that institutional ageism, and statistics that reflect stereotypes about older individuals, can impact mental health. The results demonstrate the need for media messaging aimed at empowering older individuals during the pandemic and beyond.


ACR Appropriateness Criteria® Cranial Neuropathy.
Evaluation of cranial neuropathy can be complex given the different pathway of each cranial nerve as well as the associated anatomic landmarks. Radiological evaluation requires imaging of the entire course of the nerve from its nucleus to the end organ. MRI is the modality of choice with CT playing a complementary role, particularly in the evaluation of the bone anatomy. Since neoplastic and inflammatory lesions are prevalent on the differential diagnosis, contrast enhanced studies are preferred when possible. The American College of Radiology Appropriateness Criteria are evidencebased guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.


Diverse modes of action of progesterone and its metabolites.
Progesterone and its metabolites have a variety of diverse effects in the brain, uterus, smooth muscle, sperm and the oocyte. The effects include changes in electrophysiological excitability, induction of anesthesia, regulation of gonadotropin secretion, regulation of estrogen receptors, modulation of uterine contractility and induction of acrosome reaction and oocyte maturation. The latency of the effects vary from several seconds to several hours. Thus, it is not surprising that multiple mechanisms of action are involved. The classical mechanism of steroid hormone action of intracellular receptor binding has been supplemented by the possibility of the steroid acting as a transcription factor after the binding of the receptor protein to DNA. Other mechanisms include influence of the steroids on membrane fluidity and acting through other cell signalling systems, membrane receptors and GABA(A) receptors. Of particular interest are multiple mechanisms for the same types of action. For example the effect of progesterone on gonadotropin release is largely exerted via the classical intracellular receptor as well as membrane receptors, whereas 3(alpha),5(alpha)-tetrahydroprogesterone-induced LH release occurs via the GABA(A) receptor system. The inhibition of uterine contractility by progesterone is regulated by progesterone receptors while the action of 3(alpha),5(alpha)-tetrahydroprogesterone on uterine contractility is regulated by GABA(A) receptors. The regulation of the differences in the pattern of progesterone effects on estrogen receptor dynamics in the anterior pituitary and the uterus in the same animal are also of considerable interest.


Recombinant human erythropoietin reduces epithelial cell apoptosis and attenuates bleomycin-induced pneumonitis in mice.
Erythropoietin (EPO) has recently been demonstrated to have a tissue protective role by acting as an anti-apoptotic agent in various tissues, such as brain, spinal cord, heart and kidney. The purpose of this study was to determine whether human recombinant EPO reduces epithelial cell apoptosis and attenuates bleomycin-induced pneumonitis in mice. Bleomycin was instilled intratracheally into C57BL/6 mice. Recombinant human EPO or saline was injected intraperitoneally, daily from day 5 to day 13 after bleomycin instillation. EPO receptor was expressed in bronchiolar and alveolar type II cells. At 14 days after instillation, the number of terminal uridine deoxynucleotidyl transferase nick end-labelled positive cells in the lung was decreased, and the histological degree of inflammation and fibrosis was attenuated in mice injected with EPO compared with controls. Expression of phosphorylated Akt and Erk, which are thought to mediate the survival signalling pathway induced by EPO, tended to be increased in lung tissues from mice treated with EPO compared with those from mice treated with saline after bleomycin instillation. As it is likely that EPO protects epithelial cells from injury and apoptosis, EPO administration could be a potential therapeutic strategy for the prevention of lung injury.


Influence of the textile structure on the degradation of explanted aortic endoprostheses.
To investigate mechanisms of textile failure in explanted human aortic endoprostheses. Endoprostheses (n31) underwent optical and scanning electron microscopy, filament dynamometry, and saturation index measurement. The macroscopic lesions observed in the Stentor and Vanguard devices were holes at the extremities of the stents and slipping of the warp yarns at the level of sutures or of the longitudinal seams. The macroscopic lesions observed in AneurX endoprostheses were holes, slipping of the warp yarns and ruptures of the ligatures. The macroscopic lesions observed in the two Talent endoprostheses were sections of fibers at the level of the suture holes and few areas lesions of wear, with sometimes holes at the contact of the stent extremities. Stentor, Vanguard and AneurX all demonstrated low saturation indexes of the fabric (44-59%) with an important anisotropy. Whereas the Talent endograft demonstrated a high index of saturation (124-131%) with a low anisotropy. We did not demonstrate significant polymer degradation in any of the endoprostheses. It is essential to take into account the saturation index to optimally choose a woven textile for the construction of an endoprosthesis since this property of the textile may contribute to explain the macroscopic lesions observed. We did not observe significant polymer degradation by filament dynamometry but further studies are needed to confirm these data.


Use of prothrombin complex concentrates: 4-year experience of a national aeromedical retrieval service servicing remote and rural areas.
Prothrombin complex concentrates (PCCs) are recommended as first-line treatment for acquired or congenital factor II, VII, IX and X deficiencies in situations of major haemorrhage. The Emergency Medical Retrieval Service (EMRS) provides critical care and aeromedical retrieval to patients in remote and rural Scotland. It has an important role in the care of these patients. We sought to determine the incidence of haemorrhage requiring PCC administration in our cohort of patients, and to assess compliance with current national guidelines regarding their storage and use. We searched our database for all patients that received PCCs, or met current guidelines for their administration, and followed them through to hospital discharge. We also conducted a telephone survey of all hospitals served by the EMRS to determine compliance with national standards. During the 42-month study period, 1170 retrieval missions were conducted. Twenty-six retrieved patients had a congenital or acquired clotting factor deficiency and seven met criteria for PCC administration. Of these, only three received PCCs prior to transfer to definitive care. Telephone survey revealed that all the rural general hospitals were served by the EMRS stock PCCs, but only one out of 15 GP-led community hospitals had access to PCCs. In the remote and rural setting where access to definitive care may be limited or delayed, timely administration of PCCs in appropriate patients may improve outcomes. As many rural hospitals do not have access to PCCs, the ability of the EMRS to provide this treatment may improve patient care.


Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study.
The long-term safety and tolerability of sildenafil treatment of pulmonary arterial hypertension (PAH) were assessed. Two hundred fifty-nine of 277 randomized and treated patients completed a 12-week, double-blind, placebo-controlled trial (SUPER-1 [Sildenafil Use in Pulmonary Arterial Hypertension]) of oral sildenafil in treatment-naive patients with PAH (96% functional class II/III) and entered an open-label uncontrolled extension study (SUPER-2) that continued until the last patient completed 3 years of sildenafil treatment. Patients titrated to sildenafil 80 mg tid; one dose reduction for tolerability was allowed during the titration phase. The median duration of sildenafil treatment across SUPER-1 and SUPER-2 was 1,242 days (range, 1-1,523 days); 170 patients (61%) completed both studies, and 89 patients discontinued from SUPER-2. After 3 years, 87% of 183 patients on treatment were receiving sildenafil 80 mg tid. Of patients remaining under follow-up, 3%, 10%, and 18% were receiving a second approved PAH therapy at 1, 2, and 3 years, respectively. At 3 years post-SUPER-1 baseline, 127 patients had an increased 6-min walk distance (6MWD); 81 improved and 86 maintained functional class. Most adverse events were of mild or moderate severity. At 3 years, 53 patients had died (censored, n = 37). Three-year estimated survival rate was 79%; if all censored patients were assumed to have died, 3-year survival rate was 68%. No deaths were considered to be treatment related. Long-term treatment of PAH initiated as sildenafil monotherapy was generally well tolerated. After 3 years, the majority of patients (60%) who entered the SUPER-1 trial improved or maintained their functional status, and 46% maintained or improved 6MWD.


A sex-specified effect of obstetrical complications in symptoms of schizophrenia.
Research on obstetrical complications (OCs) reports a connection with the development of more severe (negative) schizophrenic symptoms. To date, no study has tested to see if this association varies by sex. A large sample (n=786) of patients from a state hospital population in the United States was screened for study variables. Statistical tests employed were crosstabular analysis and analysis of variance. The central finding is a significant connection between OCs and negative symptoms for females but not for males. The authors speculate that there may be differences in the ways by which male and female fetuses respond to OCs or a distinction between the sexes in genetic predisposition toward severe schizophrenia.


Effect of mandibular third molars on crowding of mandibular teeth in patients with or without previous orthodontic treatment: a systematic review and meta-analysis.
To assess the scientific evidence related to the role of the mandibular third molars on the late crowding of the lower anterior teeth in patients with or without previous orthodontic treatment. The secondary outcomes included changes in mandibular arch width and arch length. The databases PubMed, Scopus, ProQuest, and Google Scholar were searched from inception until April 2022. The included papers were studies evaluating the role of mandibular third molars on crowding of mandibular anterior teeth in patients of any age and gender, with mandibular third molars impacted or semi-impacted or erupted. Predetermined and prepiloted data collection forms were used to record the necessary information. Thirteen observational studies were included in the present systematic review. Most of them were assigned an overall risk of bias of moderate risk while the rest of them were at high risk. Four studies found an association between the presence of mandibular third molar and mandibular incisor crowding. Finally, seven studies were included in the quantitative analysis. Three different meta-analyses were conducted: for patients (a) with or (b) without previous orthodontic treatment and (c) in combination for patients with and without previous orthodontic treatment. According to the pooled results of all three meta-analyses, random effects model yielded a significant benefit for those without third molars compared to those with third molars regarding crowding, mean Little's irregularity index and mean arch length. Lower third molars may contribute to mandibular crowding and lower arch constriction. Further prospective research of high quality is needed to clarify the impact of third molars on anterior mandibular crowding.


A Sphingosine-type cerebroside in Clavicorona pyxidata induce fruit body formation.
Clavicorona pyxidata is a wild edible and medicinal mushroom that is rich in bioactive natural products and has thus been extensively used as traditional medicine in China. The present study has determined that the organic crude extract prepared from a fermented culture of C. pyxidata imparted auto-inhibitory effects on mycelial growth and then induced the formation of fruiting bodies. By monitoring bioactivity, one compound was isolated via successive chromatography over silica gel, Sephadex LH-20, and Cl8-reversed phase silica gel and was identified as a known sphingosine-type cerebroside by nuclear magnetic resonance (NMR) and physicochemical data, namely, (4E, 8E)-N-D-2'-hydroxypalmitoyl-1-O-β-D-glucopyranosyl-9-methyl-4,8-sphingadienine. The application of this cerebroside at a concentration of 200 μg/disc paper resulted in the inhibition of aerial hyphal growth of C. pyxidata. The findings of the present study indicated that this C. pyxidata cerebroside is a fruiting body-inducing substance (FIS).


Flower color polymorphism of a wild Iris on the Qinghai-Tibet plateau.
Flower color plays a crucial role in attracting pollinators and facilitating environmental adaptation. Investigating the causes of flower color polymorphism and understanding their potential effects on both ecology and genetics can enhance our understanding of flower color polymorphism in wild plant. In this study, we examined the differences of potential male and female fitness between purple- and yellow- flower individuals in Iris potaninii on the Qinghai-Tibet Plateau, and screened key genes and positively selective genes involved in flower color change. Our results showed that yellow flower exhibited a higher pollen-to-ovule ratio. Yellow flowers were derived from purple flowers due to the loss of anthocyanins, and F3H could be an essential gene affecting flower color variation though expression regulation and sequence polymorphism in this species. Furthermore, our findings suggest that genes positively selected in yellow-flowered I. potaninii might be involved in nucleotide excision repair and plant-pathogen interactions. These results suggest that F3H induces the flower color variation of Iris potaninii, and the subsequent ecological and additive positive selection on yellow flowers may further enhance plant adaptations to alpine environments.


The urban homeless: estimating composition and size.
Although homelessness has been recognized as a serious and growing urban social problem, scientifically acceptable methods for estimating the composition and size of the homeless population have been lacking. A new research approach to estimating the size and composition of undomiciled urban populations is presented, and its utility is illustrated through a description of the literal homeless of Chicago. The homeless in the Chicago sample are unaffiliated persons living in extreme poverty, with high levels of physical and mental disability. Homelessness is interpreted as a manifestation of extreme poverty among persons without families in housing markets with declining stocks of inexpensive dwelling units suitable for single persons.


Ceftaroline fosamil: a review of its use in the treatment of complicated skin and soft tissue infections and community-acquired pneumonia.
Ceftaroline, the active metabolite of the prodrug ceftaroline fosamil (Zinforo, Teflaro), is an advanced-generation, parenteral cephalosporin with broad-spectrum antibacterial activity in vitro against Gram-positive bacteria, including methicillin-resistant Staphylococcus aureus (MRSA) and multidrug resistant Streptococcus pneumoniae and Gram-negative bacteria, including Haemophilus influenzae and Moraxella catarrhalis, but not Pseudomonas aeruginosa. Ceftaroline has demonstrated a low potential for the selection of resistance in vitro for drug-resistant Gram-positive organisms, including MRSA, as well as for Gram-negative respiratory pathogens. In pivotal phase III studies, intravenous ceftaroline fosamil demonstrated noninferiority to intravenous vancomycin plus aztreonam in patients hospitalized with complicated skin and soft tissue infections (cSSTIs) and intravenous ceftriaxone in patients hospitalized with community-acquired pneumonia (CAP) [Pneumonia Outcomes Research Team (PORT) risk class III or IV]; however, patients with CAP admitted to the intensive care unit were not evaluated. Ceftaroline fosamil was generally well tolerated in these trials, with an adverse event profile similar to that of other cephalosporins. Diarrhoea was the most commonly reported adverse event; however, the risk of Clostridium difficile-associated diarrhoea with ceftaroline fosamil appeared to be low. Potential limitations of the drug include the lack of an oral formulation and the requirement for twice-daily administration. Nonetheless, ceftaroline fosamil represents an attractive option (either alone or in combination with other agents) for the initial empirical treatment of patients hospitalized with cSSTIs (including those with suspected MRSA infection) or CAP (PORT risk class III or IV) who require intravenous antimicrobial therapy. As with all antibacterial agents, ceftaroline fosamil should be used in accordance with good antimicrobial stewardship.


Self and identity in advanced old age: validation of theory through longitudinal case analysis.
Case studies drawn from a 20-year longitudinal study of aging were examined for the support they provide to two theoretical viewpoints on the self in later life: one focusing on management of self-esteem, the other on development of identity as story. The five cases selected for scrutiny represented diverse trajectories of self-esteem. They furnished ample illustrations of certain key aspects of both theories, including assimilative processes of coping, depression related to absence of accommodation, maintenance of life story themes, and life review processes. They did not, however, give strong support to the dichotomy, drawn within both theoretical models, between younger and older old age. Examples of accommodation, disengagement, and self-transcendence, hypothesized to typify advanced old age, were relatively few in number and emerged only toward the very end of life. It is argued that examination of prototypical cases provides a useful approach to validating and developing theory. A conclusion drawn from this study is that more analysis should be carried out on the lives of persons who exemplify the theoretically ideal characteristics of advanced old age.


The burden of chronic diseases in a rural North Florida sample.
The degree of health disparities present in rural communities is of growing concern and is considered "urgent" since rural residents lag behind their urban counterparts in health status. Understanding the prevalence and type of chronic diseases in rural communities is often difficult since Americans living in rural areas are reportedly less likely to have access to quality health care, although there are some exceptions. Data suggest that rural residents are more likely to engage in higher levels of behavioral and health risk-taking than urban residents, and newer evidence suggests that there are differences in health risk behavior within rural subgroups. The objective of this report is to characterize the prevalence of four major and costly chronic diseases (diabetes, cardiovascular disease, cancer, and arthritis) and putative risk factors including depressive symptoms within an understudied rural region of the United States. These four chronic conditions remain among the most common and preventable of health problems across the United States. Using survey data (N = 2526), logistic regression models were used to assess the association of the outcome and risk factors adjusting for age, gender, and race. Key findings are (1) Lower financial security was associated with higher prevalence of cardiovascular disease, arthritis, and diabetes, but not cancer. (2) Higher levels of depressive symptoms were associated with higher prevalence of cardiovascular disease, arthritis, and diabetes. (3) Former or current smoking was associated with higher prevalence of cardiovascular disease and cancer. (4) Blacks reported higher prevalence of diabetes than Whites; Black women were more likely to report diabetes than all other groups; prevalence of diabetes was greater among women with lower education than among women with higher education. (5) Overall, the prevalence of diabetes and arthritis was higher than that reported by Florida and national data. The findings presented in this paper are derived from one of only a few studies examining patterns of chronic disease among residents of both a rural and lower income geographic region. Overall, the prevalence of these conditions compared to the state and nation as a whole is elevated and calls for increased attention and tailored public health interventions.


Dose-related decrease of serum coenzyme Q10 during treatment with HMG-CoA reductase inhibitors.
Coenzyme Q10 (ubiquinone) the essential mitochondrial redox-component and endogenous antioxidant, packaged into the LDL + VLDL fractions of cholesterol, has been suggested as an important anti-risk factor for the development of atherosclerosis as explained by the oxidative theory. Forty-five hypercholesterolemic patients were randomized in a double-blind trial in order to be treated with increasing dosages of either lovastatin (20-80 mg/day) or pravastatin (10-40 mg/day) over a period of 18 weeks. Serum levels of coenzyme Q10 were measured parallel to the levels of cholesterol at baseline on placebo and diet and during active treatment. A dose-related significant decline of the total serum level of coenzyme Q10 was found in the pravastatin group from 1.27 +/- 0.34 at baseline to 1.02 +/- 0.31 mmol/l at the end of the study period (mean +/- S.D.), P < 0.01. After lovastatin therapy the decrease was significant as well and more pronounced, from 1.18 +/- 0.36 to 0.84 +/- 0.17 mmol/l, P < 0.001. Although HMG-CoA reductase inhibitors are safe and effective within a limited time horizon, continued vigilance of a possible adverse consequence from coenzyme Q10 lowering seems important during long-term therapy.


[Antagonists of platelet P2 receptors: achievements, problems, and prospects].
This review is focused on the participation of P2 receptors in platelet aggregation as a first step of arterial thrombosis. Pharmacological characteristics of three subtypes of P2 receptors and their role in platelet aggregation are described. Advantages and disadvantages of widely used thienopyridine antiplatelet drugs (ticlopidine, clopidogrel)--blockers of platelet P2Y12-receptors--are considered. Characteristics of new promising antiplatelet drugs acting on platelet P2 receptors are presented.


Review of the pharmacological management of hepatitis B viral infection before and after liver transplantation.
The progress in treatment against hepatitis B virus (HBV) with the development of effective and well tolerated nucleotide analogues (NAs) has improved the outcome of patients with HBV decompensated cirrhosis and has prevented post-transplant HBV recurrence. This review summarizes updated issues related to the management of patients with HBV infection before and after liver transplantation (LT). A literature search using the PubMed/Medline databases and consensus documents was performed. Pre-transplant therapy has been initially based on lamivudine, but entecavir and tenofovir represent the currently recommended first-line NAs for the treatment of patients with HBV decompensated cirrhosis. After LT, the combination of HBV immunoglobulin (HBIG) and NA is considered as the standard of care for prophylaxis against HBV recurrence. The combination of HBIG and lamivudine is related to higher rates of HBV recurrence, compared to the HBIG and entecavir or tenofovir combination. In HBIG-free prophylactic regimens, entecavir and tenofovir should be the first-line options. The choice of treatment for HBV recurrence depends on prior prophylactic therapy, but entecavir and tenofovir seem to be the most attractive options. Finally, liver grafts from hepatitis B core antibody (anti-HBc) positive donors can be safely used in hepatitis B surface antigen negative, preferentially anti-HBc/anti-hepatitis B surface antibody positive recipients.


Host-produced ADAMTS4 Inhibits Early-Stage Tumor Growth.
Several research groups demonstrated that 'a disintegrin-like and metalloproteinase with thrombospondin type 1 motifs (ADAMTS)'-family proteases play roles in cancer progression. However, the origins and contributions of these proteases are not known. Here, we demonstrate an association between host-produced ADAMTS4 and early-stage tumor growth. Murine Lewis lung carcinoma (LLC) tumors showed marked expressions of Adamts4 and Adamts5. We examined the contributions and distributions of host-derived Adamts4 and Adamts5 on tumor growth, using Adamts4LacZ/LacZ and Adamts5LacZ/LacZ knockout mice. Interestingly, the Adamts4LacZ/LacZ mice showed enhanced tumor growth compared to wild-type mice at 5-, 10- and 12-days post-inoculation, whereas the Adamts5LacZ/LacZ mice did not show significant differences in tumor growth. We next examined LacZ distribution in LLC tumor-bearing Adamts4LacZ/LacZ mice by β-galactosidase (β-gal) staining. We found that the β-gal-positive signals were strictly localized at the interior areas of the tumor at 10 days post-inoculation. Multiple staining demonstrated that most of the β-gal-positive cells were localized at the tumor vasculature in Adamts4LacZ/LacZ mice. Interestingly, β-gal-positive signals were not co-localized with biglycan after 10 days post-inoculation, excluding the biglycan cleavage by host-derived ADAMTS4. Taken together, these findings illustrate that host-derived ADAMTS4 was expressed at the tumor vessels and was associated with early-stage tumor growth.


Electrophysiological effects of ethanol on hippocampal and cerebellar neurons cografted with locus coeruleus in oculo: role of the noradrenergic circuitry.
Nucleus locus coeruleus (LC) was sequentially transplanted with hippocampus or cerebellum from rat fetuses to the anterior eye chamber of adult rat hosts. Histological, electrophysiological and pharmacological studies indicate that the LC neurons survive and functionally innervate neurons in hippocampal and cerebellar cografts. Ethanol, when superfused over the double transplants in urethane-anesthetized hosts, caused excitations of hippocampal neuronal activity at doses between 1 and 30 mM, whereas applications above 30 mM depressed the activity of grafted hippocampal neurons. Similar results were observed in cerebellar Purkinje neurons cografted in oculo, except that cerebellar neurons were more sensitive to both the excitatory and the depressant effects of ethanol. The excitations caused by lower ethanol doses in double grafts were prevented by the cosuperfusion of 0.5 to 1.0 microM clonidine, a treatment which effectively removed the inhibitory influence of the LC neurons from the grafted neuronal circuit by depressing the LC neuronal activity. Ethanol-induced excitations were also not observed in single grafts of hippocampus, which lack a catecholamine innervation. Furthermore, in double grafts, when the noradrenergic inhibition was blocked postsynaptically with the alpha adrenergic antagonist phentolamine, ethanol-induced excitations were prevented, although ethanol did not alter the postsynaptic actions of norepinephrine. Our data suggest that the ethanol-induced excitations in the cerebellar and hippocampal grafts appear to be disinhibitions mediated by an ethanol-induced depression of the inhibitory noradrenergic input to these target tissues from LC cografts. Indeed, the doses of ethanol that induced neuronal excitations in hippocampal transplants also elicited marked depressions of LC neurons.


Studies on sucrose-phosphate synthase from rice leaves.
Sucrose-phosphate synthase (SPS, EC 188.8.131.52) biochemical properties and peptide composition have been analyzed in rice leaf seedlings. SPS was purified using DEAE-Sephacel chromatography, gel filtration on Sepharose 6B and anion exchange chromatography on Mono Q. At this stage two enzyme forms (SPS-I and -II) were separated. SPS-II was purified 90-fold; however, SPS-I presented a lower specific activity regarding the previous purification step and an unstable activity. Both enzyme forms had similar apparent Km values for Fru-6P but the SPS-I Km for UDP-Glc was ca. 10-fold higher than the SPS-II one. In addition, they differentiate in the capacity of being modulated by Glc-6-P and Pi: while SPS-II activity was inhibited by Pi and activated by Glc-6-P, SPS-I was not affected by either effectors. A native molecular mass of ca. 420 kDa was found by gel filtration. In SPS expression analysis using leaf rice and wheat germ SPS antibodies, a 116 kDa polypeptide was revealed in rice leaf extracts and no polypeptide was immunoactive in rice roots.


Transcriptional regulation of aquaporin-2 water channel gene by cAMP.
Aquaporin-2 (AQP-2) water channel is a key molecule for urinary concentration whose expression is augmented by dehydration in vivo. To elucidate the regulatory mechanism of this phenomenon in vitro, mouse collecting duct cell lines were established from a transgenic mouse harboring temperature-sensitive simian virus 40 large T antigen gene and then screened for the AQP-2 expression, using ribonuclease protection assay. In one cell line designated C4, the endogenous AQP-2 mRNA level measured by ribonuclease protection assay increased fourfold after treatment with chlorophenylthio-cAMP (cpt-cAMP) (400 microM). In contrast, phorbol 12-myristate 13-acetate did not affect the AQP-2 mRNA level. To identify the molecular mechanism(s) of cAMP-induced upregulation of AQP-2 mRNA in C4 cells, luciferase assay was performed using various 5'-flanking regions of the human AQP-2 gene. Luciferase activity in C4 cells transfected with constructs containing approximately 2.8-kbp or 224-bp 5'-flanking region showed a 3.5-fold increase by cpt-cAMP treatment, indicating that the 224-bp 5'-flanking region contains the elements necessary for cAMP-induced regulatory mechanisms. This region contains cAMP-responsive element (CRE), and the deletion of the core sequence of CRE (GACGTCA) or introduction of mutation into CRE (GTGGTCA) completely abolished the responsiveness to cpt-cAMP, confirming the key role of CRE in the cAMP-induced transcriptional activation of the AQP-2 gene. Electrophoretic mobility shift assay revealed the existence of proteins binding to CRE in C4 cells and in rat kidney. The binding of CRE proteins to CRE was increased in the nuclear extract from cpt-cAMP-treated C4 cells and dehydrated rat kidney compared with those from controls. These results demonstrated that the CRE in the AQP-2 gene promoter is a key cis-element for cAMP-mediated transcriptional regulation of this gene and may be important for in vivo regulation of AQP-2 expression in a dehydrated state.


Comparative study of alternative Geant4 hadronic ion inelastic physics models for prediction of positron-emitting radionuclide production in carbon and oxygen ion therapy.
The distribution of fragmentation products predicted by Monte Carlo simulations of heavy ion therapy depend on the hadronic physics model chosen in the simulation. This work aims to evaluate three alternative hadronic inelastic fragmentation physics options available in the Geant4 Monte Carlo radiation physics simulation framework to determine which model most accurately predicts the production of positron-emitting fragmentation products observable using in-beam PET imaging. Fragment distributions obtained with the BIC, QMD, and INCL + + physics models in Geant4 version 10.2.p03 are compared to experimental data obtained at the HIMAC heavy-ion treatment facility at NIRS in Chiba, Japan. For both simulations and experiments, monoenergetic beams are applied to three different block phantoms composed of gelatin, poly(methyl methacrylate) and polyethylene. The yields of the positron-emitting nuclei 11C, 10C and 15O obtained from simulations conducted with each model are compared to the experimental yields estimated by fitting a multi-exponential radioactive decay model to dynamic PET images using the normalised mean square error metric in the entrance, build up/Bragg peak and tail regions. Significant differences in positron-emitting fragment yield are observed among the three physics models with the best overall fit to experimental 12C and 16O beam measurements obtained with the BIC physics model.


Serum concentrations of estrogens, sex hormone binding globulin, and androgens and risk of breast hyperplasia in postmenopausal women.
We sought to determine whether serum concentrations of estrogens, androgens, and sex hormone binding globulin in postmenopausal women were related to the presence of mammary hyperplasia, an established breast cancer risk factor. Study participants provided serum before breast biopsy or mastectomy in three hospitals in Grand Rapids, Michigan, between 1977 and 1987. A total of 179 subjects with breast hyperplasia were compared with 152 subjects with nonproliferative breast changes that are not associated with increased breast cancer risk. The odds ratios (OR) associated with the three upper quartiles of estradiol in comparison with the lowest quartile were 2.2 [95% confidence interval (95% CI) 1.1-4.6], 2.5 (95% CI, 1.1-5.3), and 4.1 (95% CI, 2.0-8.5; Ptrend = 0.007). The corresponding ORs for bioavailable estradiol, estrone, and estrone sulfate were of generally similar magnitude (Ptrend = 0.003 for bioavailable estradiol, 0.0004 for estrone, and 0.0009 for estrone sulfate). Relative to women concurrently in the lowest tertile for serum estradiol, estrone, and estrone sulfate, women concurrently in the highest tertile for all three hormones had an OR of 5.8 (95% CI, 2.2-15.2). Serum concentrations of sex hormone binding globulin, testosterone, dehydroepiandrosterone, androstenedione, and androstenediol were not associated with risk of hyperplasia. Serum concentrations of estrogens, but not of androgens or sex hormone binding globulin, were strongly and significantly associated with risk of breast hyperplasia in postmenopausal women, suggesting that estrogens are important early in the pathologic process towards breast cancer.


Family history as a risk factor for primary cardiac arrest.
The hypothesis that a family history of myocardial infarction (MI) or primary cardiac arrest (PCA) is an independent risk factor for primary cardiac arrest was examined in a population-based case-control study. In addition, we investigated whether recognized risk factors account for the familial aggregation of these cardiovascular events. PCA cases, 25 to 74 years old, attended by paramedics during the period 1988 to 1994 and population-based control subjects matched for age and sex were identified from the community by random digit dialing. All subjects were free of recognized clinical heart disease and major comorbidity. A detailed history of MI and PCA in first-degree relatives was collected in interviews with the spouses of case and control subjects by trained interviewers using a standardized questionnaire. For each familial relationship, there was a higher rate of MI or primary cardiac arrest (MI/PCA) in relatives of case compared with relatives of control subjects. Overall, the rate of MI/PCA among first-degree relatives of cardiac arrest patients was almost 50% higher than that in first-degree relatives of control subjects (rate ratio [RR]=1.46; 95% CI=1.23 to 1.72). In a multivariate logistic model, family history of MI/PCA was associated with PCA (RR=1.57; 95% CI=1.27 to 1.95) even after adjustment for other common risk factors. Family history of MI or PCA is positively associated with the risk of primary cardiac arrest. This association is mostly independent of familial aggregation of other common risk factors.


Polymerase chain reaction and restriction fragment length polymorphism analysis of varicella-zoster virus isolates from the United States and other parts of the world.
A polymerase chain reaction (PCR) assay that identifies and differentiates wild-type (wt) and vaccine strains of varicella-zoster virus (VZV) was used to determine if VZV strains with restriction fragment length polymorphisms resembling those of the Japanese Oka vaccine strain were present in the wt pool outside of Japan. Virus samples (n = 114) from patients with chickenpox and zoster from various parts of the United States and Australia were analyzed. The assay correctly identified 113 samples as wt strain. The 1 sample identified as Oka vaccine strain came from a child with leukemia who developed a vaccine-associated rash after receiving the live attenuated varicella vaccine. At this point, there is no evidence that wt strains resembling the vaccine are circulating outside of Japan. This indicates that this PCR assay can be utilized to distinguish rashes due to vaccine and wt VZV.


Evidence for a functional renin-angiotensin system in full-term fetoplacental unit.
This investigation was performed to study the renin-angiotensin system in the human fetoplacental circulation. Full-term placentas from uncomplicated pregnancies were studied within 30 min of delivery. The umbilical artery and vein to a single placental cotyledon were cannulated and the artery perfused with RPMI media (0.764 ml/min). Angiotensin II caused a dose-dependent increase in perfusion pressure that was blunted by the administration of the competitive angiotensin II receptor antagonist saralasin. The properties of human placental angiotensin II receptors were further defined in binding studies performed on a crude membrane fraction of placental cotyledons. In experiments performed at 22 degrees C, saturable binding reached steady state at 30 min and was linear with protein concentration. Scatchard analysis of binding data indicated a single class of high-affinity binding sites. The potency order to competitive binding of analogues and antagonists of angiotensin II was [Ile5]angiotensin II = [Sar1, Ala8]-angiotensin II greater than [Val5]angiotensin II greater than angiotensin III greater than angiotensin II-(3-8) hexapeptide. Further evidence for the physiological significance of angiotensin II binding sites was provided by measurements of the circulating components of the renin-angiotensin system in umbilical venous blood (n = 7). Plasma renin activity, angiotensin I, angiotensin-converting enzyme activity, angiotensin II, and aldosterone were each present in elevated amounts. These experiments provide evidence for an active renin-angiotensin system in the human fetal circulation that may modulate placental perfusion and function under physiological conditions.


Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.
Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.


Rationale and Design of the Standard Versus Intensive Statin Therapy for Hypercholesterolemic Patients with Diabetic Retinopathy (EMPATHY) Study: a Randomized Controlled Trial.
Hyperlipidemia and diabetic retinopathy increase the risk of cardiovascular disease (CVD). The standard versus intEnsive statin therapy for hypercholesteroleMic Patients with diAbetic retinopaTHY (EMPATHY) study examines whether intensive lipid-lowering therapy is superior to standard therapy in reducing the incidence of cardiovascular events in patients with hyperlipidemia and diabetic retinopathy, but without a history of coronary artery disease. Patients who had elevated low-density lipoprotein cholesterol (LDL-C) and diabetic retinopathy without a history of coronary artery disease were eligible for the study. Patients were randomly assigned in a 1:1 ratio to receive intensive or standard therapy. Patients are being treated with monotherapy with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor (statin) for a maximum of 5.5 years to achieve the following LDL-C target: <70 mg/dL for the intensive therapy group or ≥100 and <120 mg/dL for the standard therapy group. The primary endpoint is a composite of incidence of CVD and death from CVD. Between May 2010 and October 2013, 5,995 patients were assessed for eligibility, and 5,144 were assigned to the study treatment (2,571 and 2,573 in the intensive and standard therapy groups, respectively), and baseline data were analyzed from 5,107 (2,550 in the intensive therapy group and 2,557 in the standard therapy group). This is the first study assessing the benefits of intensive statin therapy in patients with hypercholesterolemia and diabetic retinopathy in a primary prevention setting. Furthermore, this study evaluates the appropriateness of the treat-to-target approach because all patients are treated to achieve specific LDL-C targets by titrating statin therapy. UMIN000003486.


Establishing policies for the relationship between industry and clinicians: lessons learned from two academic health centers.
The relationship between faculty in academic health centers (AHCs) and commercial entities is critically important to improving the public health, yet it may be prone to conflicts of interest that adversely affect medical education, research, and clinical care. The Association of American Medical Colleges has recently recommended that medical schools and AHCs develop policies that better manage and occasionally prohibit interactions between academic medicine and industry. Because the development of more stringent policies is complex and potentially contentious, the author reports the lessons learned from developing new policies for the interactions between faculty and industry related to medical education and clinical care at Yale School of Medicine and Boston University School of Medicine/Boston Medical Center. The content of the policies was strongly influenced by the tenets of medical professionalism. Faculty support for new policies was strong, an iterative and inclusive process of formulation was critical, compromises in content were necessary, and the views of faculty concerning industry relationships were complex. After implementation of the new policies, the departmental food-related expenses increased, the loss of gifts was not appreciably missed, the faculty assumed more responsibility for educating trainees on the evaluation of new products, a central repository for receiving and evaluating grants from industry was useful, enforcement of the policies has been a lingering challenge, and the new policies generated positive publicity. Several recommendations are proposed. Creating these policies affirmed the importance of an inclusive process, open communication, support of institutional leadership, and focus on professional values.


Bioethics, culture and infanticide in Brazilian indigenous communities: the Zuruahá case.
This article analyzes the practice of infanticide in indigenous communities in Brazil. Taking as a reference point a specific case involving two children of the Zuruahá people, it takes a broader look at the issue and discusses how infanticide is understood among other indigenous peoples. A debate focusing specifically on this topic that took place during a public hearing held in the Brazilian National Congress in December 2005 has also been taken into consideration in this discussion. In view of the positions adopted as a result of the hearing, this paper seeks to identify the ethical problems and moral dilemmas relating to the subject, by putting them into context and analyzing them in the light of respect for cultural pluralism. Seeking to contribute to the debate, the authors analyze the possibilities for intervention in the traditional practices of infanticide, while rejecting those positions that are not anchored in an attitude of profound respect for other people's cultures or that do not create conditions for dialogue between individuals or groups with different moralities.


From inorganic precipitation to organic aggregation: solubility product constant-mediated specific metal-ion lighting-up using a triazolium iodide organic fluorescence tag.
Innovation in sensing strategies is a continual goal pursued by analytical chemists. This work reports for the first time a solubility product constant (Ksp)-mediated specific aggregation phenomenon, which is well applicable for selective metal-ion sensing, where the conventional inorganic ion binding is replaced by the anion-induced aggregation of organic molecules. A fluorescent triazolium iodide with aggregation-induced emission (AIETOI) was synthesized via click decorating a triazole onto the tetraphenylethylene backbone followed with cationization of the triazole ring. The novel probe afforded excellent specific lighting-up capability of mercury or silver ions at the ppm level followed by fluorescence quenching with excess Hg2+ or Ag+. The extremely low Ksp of HgI2 or AgI was proven to be responsible for the specific recognition ability. Hg2+/Ag+ can coordinate with the semi-dissociated iodide causing the aggregation and fluorescence lighting-up of the AIETOI, and the subsequent fluorescence quenching can be ascribed to the "peeling" of AIETOI molecules from the aggregates. The sensing process was relatively inert to pH, ionic strength and other ion interferences, providing an interesting perspective for sensing platform design.


Association between thermal responses, medical events, performance, heat acclimation and health status in male and female elite athletes during the 2019 Doha World Athletics Championships.
To determine associations between thermal responses, medical events, performance, heat acclimation and health status during a World Athletics Championships in hot-humid conditions. From 305 marathon and race-walk starters, 83 completed a preparticipation questionnaire on health and acclimation. Core (Tcore; ingestible pill) and skin (Tskin; thermal camera) temperatures were measured in-competition in 56 and 107 athletes, respectively. 70 in-race medical events were analysed retrospectively. Performance (% personal best) and did not finish (DNF) were extracted from official results. Peak Tcore during competition reached 39.6°C±0.6°C (maximum 41.1°C). Tskin decreased from 32.2°C±1.3°C to 31.0°C±1.4°C during the races (p<0.001). Tcore was not related to DNF (25% of starters) or medical events (p≥0.150), whereas Tskin, Tskin rate of decrease and Tcore-to-Tskin gradient were (p≤0.029). A third of the athletes reported symptoms in the 10 days preceding the event, mainly insomnia, diarrhoea and stomach pain, with diarrhoea (9% of athletes) increasing the risk of in-race medical events (71% vs 17%, p<0.001). Athletes (63%) who performed 5-30 days heat acclimation before the competition: ranked better (18±13 vs 28±13, p=0.009), displayed a lower peak Tcore (39.4°C±0.4°C vs 39.8°C±0.7°C, p=0.044) and larger in-race decrease in Tskin (-1.4°C±1.0°C vs -0.9°C±1.2°C, p=0.060), than non-acclimated athletes. Although not significant, they also showed lower DNF (19% vs 30%, p=0.273) and medical events (19% vs 32%, p=0.179). Tskin, Tskin rate of decrease and Tcore-to-Tskin gradient were important indicators of heat tolerance. While heat-acclimated athletes ranked better, recent diarrhoea represented a significant risk factor for DNF and in-race medical events.


Genome-Wide Linkage and Association Mapping of Halo Blight Resistance in Common Bean to Race 6 of the Globally Important Bacterial Pathogen.
Pseudomonas syringae pv. phaseolicola (Psph) Race 6 is a globally prevalent and broadly virulent bacterial pathogen with devastating impact causing halo blight of common bean (Phaseolus vulgaris L.). Common bean lines PI 150414 and CAL 143 are known sources of resistance against this pathogen. We constructed high-resolution linkage maps for three recombinant inbred populations to map resistance to Psph Race 6 derived from the two common bean lines. This was complemented with a genome-wide association study (GWAS) of Race 6 resistance in an Andean Diversity Panel of common bean. Race 6 resistance from PI 150414 maps to a single major-effect quantitative trait locus (QTL; HB4.2) on chromosome Pv04 and confers broad-spectrum resistance to eight other races of the pathogen. Resistance segregating in a Rojo × CAL 143 population maps to five chromosome arms and includes HB4.2. GWAS detected one QTL (HB5.1) on chromosome Pv05 for resistance to Race 6 with significant influence on seed yield. The same HB5.1 QTL, found in both Canadian Wonder × PI 150414 and Rojo × CAL 143 populations, was effective against Race 6 but lacks broad resistance. This study provides evidence for marker-assisted breeding for more durable halo blight control in common bean by combining alleles of race-nonspecific resistance (HB4.2 from PI 150414) and race-specific resistance (HB5.1 from cv. Rojo).


Improvement of Emotional Empathy and Cluster B Personality Disorder Symptoms Associated With Decreased Cocaine Use Severity.
Aims: Chronic cocaine users display impaired social cognitive abilities, reduced prosocial behavior, and pronounced cluster B personality disorder (PD) symptoms all contributing to their social dysfunctions in daily life. These social dysfunctions have been proposed as a major factor for maintenance and relapse of stimulant use disorders in general. However, little is known about the reversibility of social cognitive deficits and socially problematic personality facets when stimulant use is reduced or ceased. Therefore, we examined the relation between changing intensity of cocaine use and the development of sociocognitive functioning and cluster B PD symptomatology over the course of 1 year. Methods: Social cognition, social decision-making, and cluster B PD symptoms were assessed in 38 cocaine users (19 with increased and 19 with decreased use) and 48 stimulant-naive healthy controls at baseline and at 1-year follow-up. Cocaine use severity was objectively determined by quantitative 6-month hair analyses. The categorization of the two cocaine user groups was based on a combination of absolute (± 0.5 ng/mg) and relative (± 10%) changes in the cocaine hair concentration between baseline and the 1-year follow-up. Social cognition was assessed using the Multifaceted Empathy Test (MET) and the Movie for the Assessment of Social Cognition (MASC). A combined Distribution/Dictator Game was applied for assessing social decision-making. Cluster B PD symptoms were measured by a Structured Clinical Interview for DSM-IV Axis II Disorders (SCID-II) PD questionnaire according to Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Results: Increased cocaine use was linked to worsened empathy, while decreased cocaine use went along with improved emotional empathy. Moreover, whereas decreased cocaine use was associated with reduced severity of self-reported cluster B PD symptoms, these symptoms remained largely stable in increasers. In contrast to a significant reduction of prosocial behavior at baseline in the combined cocaine user group, specifically decreasers were not statistically distinguishable from controls at the follow-up. Conclusions: Sociocognitive deficits and cluster B PD symptoms of chronic cocaine users are adaptable over time as they covary with the increase or decrease in cocaine use. Hence, abstinence orientation and training of social cognition and interaction might improve social functioning, and should therefore be important therapeutic elements in cocaine addiction treatment.


Microscale 3-D hydrogel scaffold for biomimetic gastrointestinal (GI) tract model.
Here we describe a simple and efficient method for fabricating natural and synthetic hydrogels into 3-D geometries with high aspect ratio and curvature. Fabricating soft hydrogels into such shapes using conventional techniques has been extremely difficult. Combination of laser ablation and sacrificial molding technique using calcium alginate minimizes the stress associated with separating the mold from the hydrogel structure, and therefore allows fabrication of complex structures without damaging them. As a demonstration of this technique, we have fabricated a microscale collagen structure mimicking the actual density and size of human intestinal villi. Colon carcinoma cell line, Caco-2 cells, was seeded onto the structure and cultured for 3 weeks until the whole structure was covered, forming finger-like structures mimicking the intestinal villi covered with epithelial cells. This method will enable construction of in vitro tissue models with physiologically realistic geometries at microscale resolutions.


Ultrasound of intrinsic wrist ligament and triangular fibrocartilage injuries.
The objective of this study was to evaluate ultrasound as a diagnostic tool for investigating scapholunate and lunatotriquetral ligamentous and triangular fibrocartilage (TFC) tears. Ultrasound findings were compared to conventional arthrogram findings, as the reference gold standard. In total 26 patients, 17 males and 9 females ranging in age from 17 to 35 (mean age, 34), were evaluated on referral for investigation of wrist pain. All patients were examined by high resolution ultrasound, using a 9-13 MHz transducer. All wrist ultrasound examinations were also compared to conventional tricompartmental arthrography, as the diagnostic gold standard reference. All ten scapholunate tears confirmed on arthrography were detected on ultrasound. Two of 8 lunatotriquetral and 7 of 11 TFC tears were correctly diagnosed on ultrasound. Sensitivity of ultrasound diagnosis ranged from 25% for lunatotriquetral tears to 100% for scapholunate tears. No false positive results were recorded for any of the three examined structures. The study results suggest that sonography is accurate for scapholunate tears, but is not accurate for evaluation of lunate-triquetral tears. It has intermediate accuracy for triangular fibrocartilage tears.


Efficient retrieval of a single excitation stored in an atomic ensemble.
We report significant improvements in the retrieval efficiency of a single excitation stored in an atomic ensemble and in the subsequent generation of strongly correlated pairs of photons. A 50% probability of transforming the stored excitation into one photon in a well-defined spatio-temporal mode at the output of the ensemble is demonstrated. These improvements are illustrated by the generation of high-quality heralded single photons with a suppression of the two-photon component below 1% of the value for a coherent state. A broad characterization of our system is performed for different parameters in order to provide input for the future design of realistic quantum networks.


Integrating genome-wide association study summaries and element-gene interaction datasets identified multiple associations between elements and complex diseases.
Chemical elements are closely related to human health. Extensive genomic profile data of complex diseases offer us a good opportunity to systemically investigate the relationships between elements and complex diseases/traits. In this study, we applied gene set enrichment analysis (GSEA) approach to detect the associations between elements and complex diseases/traits though integrating element-gene interaction datasets and genome-wide association study (GWAS) data of complex diseases/traits. To illustrate the performance of GSEA, the element-gene interaction datasets of 24 elements were extracted from the comparative toxicogenomics database (CTD). GWAS summary datasets of 24 complex diseases or traits were downloaded from the dbGaP or GEFOS websites. We observed significant associations between 7 elements and 13 complex diseases or traits (all false discovery rate (FDR) < 0.05), including reported relationships such as aluminum vs. Alzheimer's disease (FDR = 0.042), calcium vs. bone mineral density (FDR = 0.031), magnesium vs. systemic lupus erythematosus (FDR = 0.012) as well as novel associations, such as nickel vs. hypertriglyceridemia (FDR = 0.002) and bipolar disorder (FDR = 0.027). Our study results are consistent with previous biological studies, supporting the good performance of GSEA. Our analyzing results based on GSEA framework provide novel clues for discovering causal relationships between elements and complex diseases.


Vascular localization of soluble epoxide hydrolase in the human kidney.
Epoxyeicosatrienoic acids are cytochrome P-450 metabolites of arachidonic acid with multiple biological functions, including the regulation of vascular tone, renal tubular transport, cellular proliferation, and inflammation. Epoxyeicosatrienoic acids are converted by soluble epoxide hydrolase into the corresponding dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acid hydration is regarded as one mechanism whereby their biological effects are eliminated. Previous animal studies indicate that soluble epoxide hydrolase plays an important role in the regulation of renal eicosanoid levels and systemic blood pressure. To begin to elucidate the mechanism of these effects, we determined the cellular localization of soluble epoxide hydrolase in human kidney by examining biopsies taken from patients with a variety of non-end-stage renal diseases, as well as those without known renal disease. Immunohistochemical staining of acetone-fixed kidney biopsy samples revealed that soluble epoxide hydrolase was preferentially expressed in the renal vasculature with relatively low levels in the surrounding tubules. Expression of soluble epoxide hydrolase was evident in renal arteries of varying diameter and was localized mostly in the smooth muscle layers of the arterial wall. Western blot analysis and functional assays confirmed the expression of soluble epoxide hydrolase in the human kidney. There were no obvious differences in soluble epoxide hydrolase expression between normal and diseased human kidney tissue in the samples examined. Our results indicate that soluble epoxide hydrolase is present in the human kidney, being preferentially expressed in the renal vasculature, and support an essential role for this enzyme in renal hemodynamic regulation and its potential utility as a target for therapeutic intervention.


The development of numerical estimation: evidence against a representational shift.
How do our mental representations of number change over development? The dominant view holds that children (and adults) possess multiple representations of number, and that age and experience lead to a shift from greater reliance upon logarithmically organized number representations to greater reliance upon more accurate, linear representations. Here we present a new theoretically motivated and empirically supported account of the development of numerical estimation, based on the idea that number-line estimation tasks entail judgments of proportion. We extend existing models of perceptual proportion judgment to the case of abstract numerical magnitude. Two experiments provide support for these models; three likely sources of developmental change in children's estimation performance are identified and discussed. This work demonstrates that proportion-judgment models provide a unified account of estimation patterns that have previously been explained in terms of a developmental shift from logarithmic to linear representations of number.


Amputation level and hind limb regeneration in larvae of the Egyptian toad Bufo regularis Reuss: length, volume and rate.
Study of the influence of the amputation level on regeneration length and volume and on the rate of regeneration of the hind limbs of a larval stage of Bufo regularis revealed that, during dedifferentiation and blastema accumulation and growth, the parts regenerating from proximal and distal amputation levels were almost the same length and volume, and grew at the same rate, irrespective of the amputation level. During blastema differentiation and morphogenesis, however, there were significant length, volume and elongation rate differences between parts regenerating from different amputation levels. The results also demonstrated that there was a strong positive correlation between regeneration length and volume, but that the elongation rate was not correlated to regeneration volume.


Laminin isoforms in atherosclerotic arteries from mice and man.
The properties of the arterial vasculature depend to a large extent on the activities of smooth muscle cells, which, in turn, are determined by their extracellular environment. During pathological conditions, such as atherosclerosis, this interaction is altered. In close proximity to medial smooth muscle cells are basement membrane components, such as different isoforms of laminin. These proteins can have great impact on cellular function via interaction with cell surface integrins. However, knowledge of laminins in smooth muscle cell basement membranes during normal and pathological conditions is scarce. Therefore, we have analyzed the presence of laminin isoforms in atherosclerotic lesions of apolipoprotein E (ApoE)-deficient mice. Our study revealed that the laminin chain isotype composition within atherosclerotic plaque tissue was different from the chain composition in the media. In addition, obvious differences in laminin chain composition could be observed in areas of the media, which were or were not associated with plaque tissue. Our major findings demonstrate that laminin gamma3 was exclusively present in media associated with plaque tissue. Laminin alpha2 was also enriched in these medial areas. Plaque tissue was predominantly enriched in laminin alpha5 chains. This general distribution applied to lesions both with and without a fibrous cap-like structure. The differential distribution of laminin chains were partially accompanied by changes in the presence of the integrin alpha subunits 7 and V. The distribution of laminin chains in human atherosclerotic arteries, with different size and morphology, grossly resembled their distribution in mouse arteries.


Potential Mechanism of Platelet-rich Plasma Treatment on Testicular Problems Related to Diabetes Mellitus.
Diabetes mellitus is a condition of continuously increased blood glucose levels that causes hyperglycemia. This condition can result in disorders of various organs including testicular problems. The use of platelet-rich plasma (PRP) which is contained in several growth factors shows its potential in overcoming testicular problems. This literature review study was conducted to identify the potential of PRP in overcoming various testicular problems due to diabetic conditions.


Measurement of perceived health problems as a means of detecting elderly people at risk of malnutrition.
As nutritional preventative measures are more effective in elderly people assessed as non protein-energy malnourished (non-PEM) than such interventions are in those who are malnourished, early detection of those at risk of malnutrition is important. This study tests the hypothesis that health problems measured by the Nottingham Health Profile (NHP) can predict residents at risk of malnutrition. Nutritional status was assessed in 261 residents newly admitted to municipal care using a combination of anthropometry and serum protein measurements. From this sample, 20 non-PEM residents, simultaneously assessed as moderately malnourished according to a subjective method, were consecutively included. Using a paired matched design, 20 other non-PEM residents, who were simultaneously subjectively assessed as well nourished, completed the pairs. Univariate logistic regression analyses showed that the dimensions of emotional reactions, energy, pain, physical mobility and sleep had significant power to predict residents at risk of malnutrition. In the multiple logistic regression analysis, energy had the highest explanatory power. Non-PEM residents, assessed as moderately malnourished according to the Subjective Global Assessment, perceived significantly greater health problems than non-PEM residents subjectively assessed as well nourished. Measurement of health problems adds important information to that used in early detection of residents at risk of malnutrition.


Acetylcholine activation of K+ channels in cell-free membrane of atrial cells.
The activation mechanisms of K+ channels by muscarinic acetylcholine (m-ACh) receptors were examined in isolated atrial cells by use of patch-recording technique. In "cell-attached" patch recordings, ACh, present in the pipette, activated an inwardly rectifying K+ channel. In "inside-out" patches, activation of the K+ channel by ACh diminished with time following excision of the patch, but it resumed when GTP was present in the solution bathing the intracellular side of the membrane. The A protomer of pertussis toxin, together with NAD, inhibited the channel activation in the presence of GTP. Since pertussis toxin specifically ADP-ribosylates GTP-binding proteins Ni and No, which can interact with m-ACh receptors, and inhibits their functions, it was concluded that m-ACh receptors communicate with the K+ channel via GTP-binding proteins, probably Ni and/or No, in atrial cell membrane.


Perinatal morbidity and mortality in early-onset fetal growth restriction: cohort outcomes of the trial of randomized umbilical and fetal flow in Europe (TRUFFLE).
Few data exist for counseling and perinatal management of women after an antenatal diagnosis of early-onset fetal growth restriction. Yet, the consequences of preterm delivery and its attendant morbidity for both mother and baby are far reaching. The objective of this study was to describe perinatal morbidity and mortality following early-onset fetal growth restriction based on time of antenatal diagnosis and delivery. We report cohort outcomes for a prospective multicenter randomized management study of fetal growth restriction (Trial of Randomized Umbilical and Fetal Flow in Europe (TRUFFLE)) performed in 20 European perinatal centers between 2005 and 2010. Women with a singleton fetus at 26-32 weeks of gestation, with abdominal circumference < 10(th) percentile and umbilical artery Doppler pulsatility index > 95(th) percentile, were recruited. The main outcome measure was a composite of fetal or neonatal death or severe morbidity: survival to discharge with severe brain injury, bronchopulmonary dysplasia, proven neonatal sepsis or necrotizing enterocolitis. Five-hundred and three of 542 eligible women formed the study group. Mean ± SD gestational age at diagnosis was 29 ± 1.6 weeks and mean ± SD estimated fetal weight was 881 ± 217 g; 12 (2.4%) babies died in utero. Gestational age at delivery was 30.7 ± 2.3 weeks, and birth weight was 1013 ± 321 g. Overall, 81% of deliveries were indicated by fetal condition and 97% were by Cesarean section. Of 491 liveborn babies, outcomes were available for 490 amongst whom there were 27 (5.5%) deaths and 118 (24%) babies suffered severe morbidity. These babies were smaller at birth (867 ± 251 g) and born earlier (29.6 ± 2.0 weeks). Death and severe morbidity were significantly related to gestational age, both at study entry and delivery and also with the presence of maternal hypertensive morbidity. The median time to delivery was 13 days for women without hypertension, 8 days for those with gestational hypertension, 4 days for pre-eclampsia and 3 days for HELLP syndrome. Fetal outcome in this study was better than expected from contemporary reports: perinatal death was uncommon (8%) and 70% survived without severe neonatal morbidity. The intervals to delivery, death and severe morbidity were related to the presence and severity of maternal hypertensive conditions.


Antarctic timing of surface water changes off Chile and Patagonian ice sheet response.
Marine sediments from the Chilean continental margin are used to infer millennial-scale changes in southeast Pacific surface ocean water properties and Patagonian ice sheet extent since the last glacial period. Our data show a clear "Antarctic" timing of sea surface temperature changes, which appear systematically linked to meridional displacements in sea ice, westerly winds, and the circumpolar current system. Proxy data for ice sheet changes show a similar pattern as oceanographic variations offshore, but reveal a variable glacier-response time of up to approximately 1000 years, which may explain some of the current discrepancies among terrestrial records in southern South America.


Should sand fly taxonomy predict vectorial and ecological traits?
I review species concepts, the taxonomy of phlebotomine sand flies, and some transmission cycles of leishmaniasis in order to illustrate the difficulties of classifying these vectors in a way that will be ideal both for medical parasitologists and sand fly specialists. Choices will have to be made between different classifications, either maintaining a practical one containing few vectorial genera (mostly Phlebotomus for the Old World and Lutzomyia for the Neotropics) or changing the generic names of many vectors so that the classification represents an evolutionary hypothesis. However, sand flies also transmit arboviruses and members of other sand fly genera bite humans, and so vectorial status alone might not provide the criteria for recognizing only a few genera. Vectorial roles are often determined by species-level co-evolution of susceptibility to Leishmania species, with selection being initiated and maintained by ecological contacts. There is only imperfect co-cladogenesis of genus-level groups or subgeneric complexes of sand flies and Leishmania species. Natural hybridization between sand fly species has been recorded in several species complexes, and this highlights the need to focus on gene flow and the distribution of phenotypes of biomedical importance, not on taxa.


Tuberculosis-like respiratory infection in 245-million-year-old marine reptile suggested by bone pathologies.
An absence of ancient archaeological and palaeontological evidence of pneumonia contrasts with its recognition in the more recent archaeological record. We document an apparent infection-mediated periosteal reaction affecting the dorsal ribs in a Middle Triassic eosauropterygian historically referred to as 'Proneusticosaurus' silesiacus. High-resolution X-ray microtomography and histological studies of the pathologically altered ribs revealed the presence of a continuous solid periosteal reaction with multiple superficial blebs (protrusions) on the visceral surfaces of several ribs. Increased vascularization and uneven lines of arrested growth document that the pathology was the result of a multi-seasonal disease. While visceral surface localization of this periosteal reaction represents the earliest identified evidence for pneumonia, the blebs may have an additional implication: they have only been previously recognized in humans with tuberculosis (TB). Along with this diagnosis is the presence of focal vertebral erosions, parsimoniously compared to vertebral manifestation of TB in humans.


Meta-analytic evidence of low convergence between implicit and explicit measures of the needs for achievement, affiliation, and power.
The correlation between implicit and explicit motive measures and potential moderators of this relationship were examined meta-analytically, using Hunter and Schmidt's (2004) approach. Studies from a comprehensive search in PsycINFO, data sets of our research group, a literature list compiled by an expert, and the results of a request for gray literature were examined for relevance and coded. Analyses were based on 49 papers, 56 independent samples, 6151 subjects, and 167 correlations. The correlations (ρ) between implicit and explicit measures were 0.130 (CI: 0.077-0.183) for the overall relationship, 0.116 (CI: 0.050-0.182) for affiliation, 0.139 (CI: 0.080-0.198) for achievement, and 0.038 (CI: -0.055-0.131) for power. Participant age did not moderate the size of these relationships. However, a greater proportion of males in the samples and an earlier publication year were associated with larger effect sizes.