Perceived Stress and Elder Abuse: A Population-Based Study of Adult Protective Services Cases in Chicago.
To characterize the relationship between perceived stress and Adult Protective Services (APS) elder abuse cases in a population-based sample. Cross-sectional. Chicago. community-dwelling, older adults (N = 8,558; mean age 74 ± 7, 62% female, 64% African American). Perceived Stress Scale (PSS), APS database linkage. Bivariate and adjusted analyses showed that perceived stress was significantly higher in APS clients than in participants without any APS interaction for various subtypes of abuse (e.g., abuse from a perpetrator and self-neglect). This relationship was strongest for those with a confirmed history of abuse from a perpetrator, with a medium-large effect size (t = -5.8, P < .001, Cohen D = -0.6). Those in the highest stress tertile had a likelihood of having confirmed history of abuse from a perpetrator that was nearly three times as great as that of those in lower stress tertiles (odds ratio = 2.7, 95% confidence interval = 1.2-6.2). Analyses of individual PSS items revealed a robust relationship between distress items and APS involvement. Items reflecting coping were inconsistently associated with elder abuse. Clients of APS have higher levels of perceived stress, and abuse from a perpetrator strengthens this relationship. Therefore, victims of abuse from a perpetrator may be at the highest risk of stress-related consequences and should be targeted for intervention efforts that enhance empowerment and effective coping strategies.


Myogenic and neurogenic mechanisms and arachidonate metabolites in bronchial muscle response to allergen.
We investigated allergen-induced airway hyperresponsiveness (AH) in bronchial tissues obtained from dogs that inhaled Ascaris suum leading to AH (RESP) in vivo or that exhibited no change (NON-RESP) as well as from dogs that inhaled saline (SHAM). RESP tissues were not hyperresponsive to KCl or to carbachol, whereas contractions to electrical field stimulation (EFS) were reduced. This reduction was reversed partially by indomethacin and completely by replacement of the bathing fluid. Radioimmunoassay revealed marked elevation of prostaglandin (PG) E2 generation in RESP tissues compared with SHAM and NON-RESP tissues. EFS-evoked contractions were often followed by a slowly developing secondary contraction in RESP tissues but not in SHAM or NON-RESP tissues. However, indomethacin unmasked such secondary contractions in many SHAM and NON-RESP tissues and markedly enhanced those in RESP tissues, whereas L-655,240 (thromboxane A2/PGD2 receptor antagonist) abolished such contractions in all groups. We were unable to detect thromboxane using radioimmunoassay. We conclude that allergen-induced AH involves altered generation of cyclooxygenase metabolites of arachidonic acid (particularly PGE2) as well as of a nonprostanoid inhibitory factor; as such, the responsiveness of the tissue in vitro is dependent on the relative levels of inhibitory and excitatory metabolites.


The reporting of studies using routinely collected health data was often insufficient.
To assess reporting quality of studies using routinely collected health data (RCD) to inform the REporting of studies Conducted using Observational Routinely collected health Data (RECORD) guideline development. PubMed search for observational studies using RCD on any epidemiologic or clinical topic. Sample of studies published in 2012. Evaluation of five items based on the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) guideline and eight newly developed items for RCD studies. Of 124 included studies, 39 (31.5%) clearly described its design in title or abstract. Complete information to frame a focused research question, that is, on the population, intervention/exposure, and outcome, was provided for 51 studies (41.1%). In 44 studies where definitions of codes or classification algorithms would be necessary to operationalize such a research question, only nine (20.5%) reported all items adequately. In 81 studies describing multivariable analyses, 54 (66.7%) reported all variables used for modeling and 34 (42.0%) reported basic details required for replication. Database linkage was reported adequately in 12 of 41 studies (29.3%). Statements about data sharing/availability were rare (5/124; 4%). Most RCD studies are insufficiently reported. Specific reporting guidelines and more awareness and education on their use are urgently needed.


The Effect of Cochlear Implants on Cognitive Function in Older Adults: Initial Baseline and 18-Month Follow Up Results for a Prospective International Longitudinal Study.
In older adults, hearing loss is independently associated with an increased rate of cognitive decline, and has been identified to be a modifiable risk factor for dementia. The mechanism underlying the cognitive decline associated with hearing loss is not understood, but it is known that the greater the hearing loss, the faster the rate of decline. It is unknown whether remediation of hearing loss with hearing devices can delay cognitive decline. This 5-year international longitudinal study is investigating the impact of cochlear implants on cognitive function in older people with severe-profound hearing loss, and whether remediation of hearing loss could delay the onset of cognitive impairment. This is the first study to examine the major primary risk factors associated with dementia in the same cohort. Participants were assessed before cochlear implantation and 18 months later using an identical battery including a visually presented cognitive assessment tool (Cogstate battery) that is highly sensitive to small changes in cognition and suitable for use with people with hearing loss. Hearing and speech perception ability were assessed in sound-treated conditions by an audiologist, and a range of questionnaire tools was administered to assess self-perceived ease of listening, quality of life, physical activity, diet, social and emotional loneliness, isolation, anxiety, and depression. A detailed medical health history was taken. Pre-operatively, despite the small initial sample size (n = 59), increased hearing loss and age predicted significantly poorer executive function and visual attention, while tertiary education predicted better executive function. Better self-reported quality of life was correlated with better visual learning performance, and engaging in frequent vigorous physical activity was correlated with poorer visual learning performance. At 18 months, for the first 20 participants, significant benefits of cochlear implants were seen in terms of speech perception, communication ability, and quality of life. Multiple linear regression modeling showed executive function improved significantly for non-tertiary educated males, while cognitive function remained stable for other participants. Further follow-up at 18 month intervals with a larger sample will reveal the effects of cochlear implant intervention on all outcomes, and whether this can delay cognitive decline.


Raising the standards of the calf-raise test: a systematic review.
The calf-raise test is used by clinicians and researchers in sports medicine to assess properties of the calf muscle-tendon unit. The test generally involves repetitive concentric-eccentric muscle action of the plantar-flexors in unipedal stance and is quantified by the number of raises performed. Although the calf-raise test appears to have acceptable reliability and face validity, and is commonly used for medical assessment and rehabilitation of injuries, no universally acceptable test parameters have been published to date. A systematic review of the existing literature was conducted to investigate the consistency as well as universal acceptance of the evaluation purposes, test parameters, outcome measurements and psychometric properties of the calf-raise test. Nine electronic databases were searched during the period May 30th to September 21st 2008. Forty-nine articles met the inclusion criteria and were quality assessed. Information on study characteristics and calf-raise test parameters, as well as quantitative data, were extracted; tabulated; and statistically analysed. The average quality score of the reviewed articles was 70.4+/-12.2% (range 44-90%). Articles provided various test parameters; however, a consensus was not ascertained. Key testing parameters varied, were often unstated, and few studies reported reliability or validity values, including sensitivity and specificity. No definitive normative values could be established and the utility of the test in subjects with pathologies remained unclear. Although adapted for use in several disciplines and traditionally recommended for clinical assessment, there is no uniform description of the calf-raise test in the literature. Further investigation is recommended to ensure consistent use and interpretation of the test by researchers and clinicians.


The Role of Hemoglobin Laboratory Test Results for the Detection of Upper Gastrointestinal Bleeding Outcomes Resulting from the Use of Medications in Observational Studies.
The identification of upper gastrointestinal (UGI) bleeding and perforated ulcers in claims data typically relies on inpatient diagnoses. The use of hemoglobin laboratory results might increase the detection of UGI events that do not lead to hospitalization. Our objective was to evaluate whether hemoglobin results increase UGI outcome identification in electronic databases, using non-steroidal anti-inflammatory drugs (NSAIDs) as a test case. From three data partner sites within the Mini-Sentinel Distributed Database, we identified NSAID initiators aged ≥18 years between 2008 and 2013. Numbers of events and risks within 30 days after NSAID initiation were calculated for four mutually exclusive outcomes: (1) inpatient UGI diagnosis of bleeding or gastric ulcer (standard claims-based definition without laboratory results); (2) non-inpatient UGI diagnosis AND ≥3 g/dl hemoglobin decrease; (3) ≥3 g/dl hemoglobin decrease without UGI diagnosis in any clinical setting; (4) non-inpatient UGI diagnosis, without ≥3 g/dl hemoglobin decrease. We identified 2,289,772 NSAID initiators across three sites. Overall, 45.3% had one or more hemoglobin result available within 365 days before or 30 days after NSAID initiation; only 6.8% had results before and after. Of 7637 potential outcomes identified, outcome 1 accounted for 21.7%, outcome 2 for 0.8%, outcome 3 for 34.3%, and outcome 4 for 43.3%. Potential cases identified by outcome 3 were largely not suggestive of UGI events. Outcomes 1, 2, and 4 had similar distributions of specific UGI diagnoses. Using available hemoglobin result values combined with non-inpatient UGI diagnoses identified few additional UGI cases. Non-inpatient UGI diagnostic codes may increase outcome detection but would require validation.


ELK3 suppresses angiogenesis by inhibiting the transcriptional activity of ETS-1 on MT1-MMP.
Ets transcription factors play important roles in vasculogenesis and angiogenesis. Knockout of the Ets gene family members in mice resulted in disrupted angiogenesis and malformed vascular systems. In this study, the role and mechanism of ELK3, an Ets factor, in angiogenesis was investigated using ELK3-specific siRNA in human vascular endothelial cells (HUVECs) and in vivo implantation assay. The suppression of ELK3 expression resulted in the reinforcement of VEGF-induced tube formation in HUVECs. The in vivo Matrigel plug assay also showed that ELK3 knockdown resulted in increased angiogenesis. Luciferase activity of the MT1-MMP promoter induced by ETS-1 factor was attenuated ELK3 co-transfection. CHIP assay showed the binding of ELK3 on the MT1-MMP promoter. MT1-MMP knockdown in the ELK3 knockdowned cells resulted in the decrease of tube formation suggesting that MT1-MMP transcriptional repression is required for ELK3-mediated anti-angiogenesis effect. Our data also showed that the suppressive effect of ELK3 on the angiogenesis was partly due to the inhibitory effect of ELK3 to the ETS-1 transcriptional activity on the MT1-MMP promoter rather than direct suppression of ELK3 on the target gene, since the expression level of co-repressor Sin3A is low in endothelial cells. Our results suggest that ELK3 plays a negative role of VEGF-induced angiogenesis through indirectly inhibiting ETS-1 function.


A Comprehensive Profile of Chemokine Gene Expression in the Tissues of the Female Reproductive Tract in Mice.
Homeostatic leukocyte trafficking into and within the female reproductive tract (FRT) contributes to fertility and reproductive health. It is unclear how this process is regulated in the anatomically distinct reproductive tissues, or whether the genes involved are affected by cyclical changes in reproductive hormones. In tissues such as skin and intestine, mouse studies have defined evolutionarily conserved molecular mechanisms for tissue-specific homing, interstitial positioning, and leukocyte egress. Chemokine family members are invariably involved, with the chemokine expression profile of a tissue regulating leukocyte content. Reproductive tissues (ovary, vagina, cervix, uterine horn) of 8 week old virgin female C57BL/6 mice (n = 20) were collected, and expression of mRNA for leukocyte markers and chemokines conducted by qPCR. Lymphocytic and myeloid cell populations within the uterus, cervix, bone marrow and PALN from virgin C57BL/6 mice were determined by flow cytometric analysis. Variation in leukocyte content between reproductive tissues is evident, with the uterus and cervix containing complex mixtures of lymphocytes and myeloid cells. Twenty-six chemokine genes are expressed in the FRT, many by several component tissues, some preferentially by one. Most striking are Xcl1 and Ccl28, which are restricted to the uterus. Ccl20 and genes encoding CXCR2 ligands are primarily transcribed in cervix and vagina. Ovary shows the lowest expression of most chemokine genes, with the notable exception of Ccl21 and Ccl27. We also identify eight chemokines in the vagina whose expression fluctuates substantially across the oestrous cycle. These data reveal complex chemokine networks within the FRT, and provide a framework for future studies of homeostatic leukocyte trafficking into and within these tissues.Abbreviations: BM: bone marrow; DC: dendritic cell; DN: double negative; FRT: female reproductive tract; FSC: forward scatter; NK: natural killer; PALN: para-aortic lymph node; SSC: side scatter; Tregs: regulatory T cells.


Impaired radial artery compliance in normotensive subjects with familial hypercholesterolemia.
Hypercholesterolemia impairs arteriolar dilatation, but whether the vascular abnormalities accompanying this condition include large artery function is unknown. We addressed this issue in 13 normotensive subjects with familial hypercholesterolemia (serum cholesterol 401.6 +/- 16.9 mg/dl, mean +/- S.E., FHC) and no evidence of atherosclerotic lesions, in whom radial artery (RA) diameter and blood pressure (BP) were measured beat to beat by an echotracking and a Finapres device, respectively. RA compliance (RAC) was derived from the diameter/BP relationship and expressed over the systo-diastolic BP range, both at baseline and after a 12-min brachial artery occlusion. RAC was expressed also as the area under the RAC/BP curve divided for pulse BP. Measurements included maximal forearm blood flow (plethysmography) and minimal forearm vascular resistance (FVR) which were obtained from the values following the 12-min brachial arterial occlusion. Data were collected before and after 6- and 24-month lipid lowering treatment (simvastatin 40 mg/day). Ten age-matched normotensive normocholesterolemic healthy subjects (N) served as controls. Compared to N, baseline RAC was strikingly reduced in FHC (-53.5%, P < 0.01). After ischemia RAC increased significantly and markedly in N (+38.7, P < 0.01), while only a modest and non-significant increase was observed in FHC. Minimal FVR was markedly higher in FHC than in N (3.5 +/- 0.9 vs 1.6 +/- 0.1 units, P < 0.01). In FHC (7 subjects) RAC remained unchanged after 6 months of lipid lowering treatment, but increased markedly (+55.2%, p < 0.05) when treatment was prolonged to 24 months. Lipid lowering treatment also reduced minimal FVR, the effect being significant both after 6 and after 24 months. No changes in RAC and minimal FVR were seen after 6 months in controls. Thus, in subjects with a marked increase in serum cholesterol due to FHC, not only arteriolar dilatation, but also RAC and distensibility are markedly impaired. This impairment can be favourably affected by an effective lipid lowering treatment of long duration.


Asymptomatic carotid lesions and silent cerebral infarction.
Few studies have investigated the relationships between asymptomatic carotid lesions and silent infarcts confirmed on magnetic resonance imaging. A consecutive series of 117 subjects (average age, 62 +/- 9.4 years) who were free from neurological deficit but had at least one established risk factor for stroke were investigated by B-mode carotid ultrasonography and magnetic resonance imaging of the brain. Carotid lesions were evaluated by plaque score, maximum percent stenosis, and the existence of ulcerated lesions. The relations between the carotid lesions and the incidence, size, or localization of the brain lesions were investigated. The incidence of silent infarcts was 42% in all subjects and significantly increased with advancing age (P < .05). Most lesions were smaller than 1 cm in diameter and were usually localized in the subcortical white matter or the basal ganglia. The percentage of subjects with infarcts increased significantly as the plaque score increased (P < .05) or when subjects had high-grade stenosis (P < .05) or ulcerated lesions (P < .01). These relationships were also noted in each decade of age. A higher incidence of larger lesions (> 1 cm) was found in the brain hemisphere ipsilateral to the carotid lesion, particularly in subjects with high-grade stenosis or ulcerated lesions (P < .01). Multivariate analysis indicated significant correlations with silent infarcts for age, hypertension, and plaque score. Both the severity and characteristics of asymptomatic carotid lesions estimated by B-mode ultrasonography were closely related to the appearance of silent infarcts. These results demonstrate that noninvasive assessment of carotid lesions can be useful in predicting the existence of silent cerebral infarction even in patients free from neurological deficits.


Olfactory inputs to hypothalamic neurons controlling reproduction and fertility.
In order to gain insight into sensory processing modulating reproductive behavioral and endocrine changes, we have aimed at identifying afferent pathways to neurons synthesizing luteinizing hormone-releasing hormone (LHRH, also known as gonadotropin-releasing hormone [GnRH]), a key neurohormone of reproduction. Injection of conditional pseudorabies virus into the brain of an LHRH::CRE mouse line led to the identification of neuronal networks connected to LHRH neurons. Remarkably, and in contrast to established notions on the nature of LHRH neuronal inputs, our data identify major olfactory projection pathways originating from a discrete population of olfactory sensory neurons but fail to document any synaptic connectivity with the vomeronasal system. Accordingly, chemosensory modulation of LHRH neuronal activity and mating behavior are dramatically impaired in absence of olfactory function, while they appear unaffected in mouse mutants lacking vomeronasal signaling. Further visualization of afferents to LHRH neurons across the brain offers a unique opportunity to uncover complex polysynaptic circuits modulating reproduction and fertility.


Local selection and latitudinal variation in a marine predator-prey interaction.
Although pairs of species often interact over broad geographic ranges, few studies have explored how interactions vary across these large spatial scales. Surveys along 1500 kilometers of the Pacific coast of North America documented marked variation in the frequency of predation by the snail Nucella canaliculata on the intertidal mussel Mytilus californianus. Laboratory rearing experiments suggest that regional differences in drilling behavior have a genetic basis, and mitochondrial sequence variation confirms that gene flow is low among these snail populations. Marine communities separated by hundreds of kilometers may have intrinsically different dynamics, with interactions shaped by restricted gene flow and spatially varying selection.


Systematic comparison of phenome-wide association study of electronic medical record data and genome-wide association study data.
Candidate gene and genome-wide association studies (GWAS) have identified genetic variants that modulate risk for human disease; many of these associations require further study to replicate the results. Here we report the first large-scale application of the phenome-wide association study (PheWAS) paradigm within electronic medical records (EMRs), an unbiased approach to replication and discovery that interrogates relationships between targeted genotypes and multiple phenotypes. We scanned for associations between 3,144 single-nucleotide polymorphisms (previously implicated by GWAS as mediators of human traits) and 1,358 EMR-derived phenotypes in 13,835 individuals of European ancestry. This PheWAS replicated 66% (51/77) of sufficiently powered prior GWAS associations and revealed 63 potentially pleiotropic associations with P < 4.6 × 10⁻⁶ (false discovery rate < 0.1); the strongest of these novel associations were replicated in an independent cohort (n = 7,406). These findings validate PheWAS as a tool to allow unbiased interrogation across multiple phenotypes in EMR-based cohorts and to enhance analysis of the genomic basis of human disease.


Recent incarceration and buprenorphine maintenance treatment outcomes among human immunodeficiency virus-positive patients.
Opioid use disorder is a common cause of morbidity and mortality among people living with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS). Buprenorphine maintenance treatment (BMT) is an effective means of therapy, but patients with recent criminal justice involvement may need more support during BMT than other patients. The authors hypothesized that recently incarcerated BMT patients who initiated treatment in primary care would have poorer treatment outcomes than those who were not recently incarcerated. Investigators analyzed data from a multisite cohort study of BMT integrated into HIV care. Patients were stratified by self-reported incarceration in the 30 days before initiation of BMT. The outcomes of interest were 6- and 12-month treatment retention and self-reported opioid use. Investigators used multivariable logistic regression and hierarchical linear model, respectively, to evaluate the association between recent incarceration and these outcomes while adjusting for potential confounding variables. Among 305 BMT patients living with HIV/AIDS, 39 (13%) reported recent incarceration. Patients with recent incarceration (vs. without) were more likely to be homeless, unemployed, and previously diagnosed with mental illness. Recent incarceration was not significantly associated with differences in 6-month (odds ratio [OR] = 0.95; 95% confidence interval [CI] = 0.46-1.98) and 12-month (OR = 0.57; 95% CI = 0.27-1.18) treatment retention or in self-reported opioid use (OR = 0.99; 95% CI = 0.51-1.92) after adjustment for potential confounding variables. Those with incarceration in the 30 days prior to BMT initiation were more likely to be homeless, unemployed, and previously diagnosed with mental illness than those without recent incarceration. However, no significant difference in self-reported opioid use or 6-month or 12-month retention in treatment was detected between those with and without recent incarceration. Future studies should confirm these findings with larger sample sizes. Encouraging formerly incarcerated individuals with opioid use disorder to initiate evidence-based treatments, including BMT, should be part of efforts to confront the opioid addiction epidemic in the United States.


Ultrastructural clues for glutamate-induced necrosis in parietal and cerebellar neurons.
Glutamate excitotoxicity has been postulated to underlie the neuronal death that occurs after ischemia. The most sensitive tissues to ischemic injury are hippocampus and cerebellum, whereas cerebrum is more resistant. We studied the glutamate-induced ultrastructural alterations in rat parietal and cerebellar neurons comparatively. We observed that glutamate (45 min, 10-7 m) causes considerable nuclear, mitochondrial and cytoplasmic changes in both the neuron types. Mitochondrial and nuclear changes were particularly more severe in cerebellar granular, than the ones in parietal neurons. It has been concluded that glutamate induces necrotic changes in both parietal and cerebellar neurons. But cerebellar cortex was found to be more sensitive to glutamate excitotoxicity than cerebral cortex. We suggest that mitochondrial damage is, probably, an important factor in neuron necrosis, which is mediated by glutamate excitotoxicity.


Landscape-level influences of terrestrial snake occupancy within the southeastern United States.
Habitat loss and degradation are thought to be the primary drivers of species extirpations, but for many species we have little information regarding specific habitats that influence occupancy. Snakes are of conservation concern throughout North America, but effective management and conservation are hindered by a lack of basic natural history information and the small number of large-scale studies designed to assess general population trends. To address this information gap, we compiled detection/nondetection data for 13 large terrestrial species from 449 traps located across the southeastern United States, and we characterized the land cover surrounding each trap at multiple spatial scales (250-, 500-, and 1000-m buffers). We used occupancy modeling, while accounting for heterogeneity in detection probability, to identify habitat variables that were influential in determining the presence of a particular species. We evaluated 12 competing models for each species, representing various hypotheses pertaining to important habitat features for terrestrial snakes. Overall, considerable interspecific variation existed in important habitat variables and relevant spatial scales. For example, kingsnakes (Lampropeltis getula) were negatively associated with evergreen forests, whereas Louisiana pinesnake (Pituophis ruthveni) occupancy increased with increasing coverage of this forest type. Some species were positively associated with grassland and scrub/shrub (e.g., Slowinski's cornsnake, Elaphe slowinskii) whereas others, (e.g., copperhead, Agkistrodon contortrix, and eastern diamond-backed rattlesnake, Crotalus adamanteus) were positively associated with forested habitats. Although the species that we studied may persist in varied landscapes other than those we identified as important, our data were collected in relatively undeveloped areas. Thus, our findings may be relevant when generating conservation plans or restoration goals. Maintaining or restoring landscapes that are most consistent with the ancestral habitat preferences of terrestrial snake assemblages will require a diverse habitat matrix over large spatial scales.


Noninvasive identification of acute myocardial ischemia and reperfusion with contrast ultrasound using intravenous perfluoropropane-exposed sonicated dextrose albumin.
The purpose of this study was to determine whether intravenous dextrose albumin sonicated with a commonly used gas of low blood solubility and diffusivity (perfluoropropane) could identify acute myocardial ischemia and reperfusion. Recently, it has been demonstrated that dextrose albumin sonicated with gases that have low blood solubility and diffusivity results in microbubbles capable of consistently producing myocardial ultrasound contrast after intravenous injection. It remains to be determined, however, whether this contrast agent can visually detect the myocardial blood flow abnormalities seen with acute ischemia or stunned myocardium after reperfusion. We gave intravenous injections (0.06 ml/kg body weight) of perfluoropropane-exposed sonicated dextrose albumin to 10 open chest dogs. The measured degree of myocardial contrast (0+ to 2+) and background-subtracted peak anterior myocardial videointensity produced from each injection were measured at three stages: 1) under baseline conditions, 2) during acute ischemia produced by a proximal left anterior descending coronary artery ligation lasting 10 to 120 min, and 3) after reflow was established. Coronary blood flow was monitored during all injections by using an ultrasound flow probe placed around the left anterior descending artery. Coronary blood flow ranged from 0 to 137 ml/min, and peak myocardial videointensity after intravenous administration of perfluoropropane-exposed sonicated dextrose albumin ranged from 0 to 70 gray scale U. There was consistent visual myocardial opacification in all dogs during baseline conditions and a visually evident decrease in myocardial contrast in the left anterior descending artery distribution after ligation. A relative increase in contrast in this same distribution after intravenous contrast agent administration occurred in 7 of the 10 dogs during reflow. Quantitatively, there was an excellent correlation in individual dogs between peak myocardial videointensity and coronary flow at all stages (mean correlation coefficient 0.95 +/- 0.04, range 0.87 to 0.99). Perfluoropropane-exposed sonicated dextrose albumin is an ultrasound contrast agent that can visually identify myocardial perfusion abnormalities from a peripheral venous injection.


Antibodies to cerebroside sulfate inhibit the effects of morphine and beta-endorphin.
Morphine and beta-endorphin inhibit the shaking response of pentobarbital-anesthetized rats to ice water. Stereotaxically guided administration of antibodies to cerebroside sulfate into the periaqueductal gray region, the most sensitive brain region in which to demonstrate inhibition of this response, antagonizes the effect of morphine and beta-endorphin. These results suggest that cerebroside sulfate may be an integral component of an opiate receptor in rat brain.


[Brain activation as endophenotype for investigating genetics of depression].
Many factors are involved in the pathogenesis of depression. This article provides an overview of the results given in the thesis entitled 'Linking Depression', in which some putative underlying neurobiological and genetic mechanisms of depression are examined. To gain more insight in brain activity as endophenotype for depression. As part of the Netherlands Study of Depression and Anxiety (nesda), 301 people, including patients with depression and/or anxiety and healthy volunteers, underwent functional magnetic resonance imaging (fmri) and genotyping. During the processing of negative emotions, patients with depression showed a pattern of heightened limbic activation but less prefrontal activation. The same pattern, but in reverse, was seen during the processing of positive emotions. We showed that the disc1, comt and npy genes were associated with brain activation patterns comparable to those seen in patients with depression. In addition, in cases of depression, there was a different kind of relationship between these genes and brain activation. Depression is characterised by the disturbed processing not only of negative emotions but also of positive emotions. In addition, the studies we describe contribute to our insight into the neurobiology of depression and relevant genetic influences because the results demonstrate that depression alters the relationship between genes and brain activation.


A VIRUS-INDUCED EPIZOOTIC HEMORRHAGIC DISEASE OF THE VIRGINIA WHITE-TAILED DEER (ODOCOILEUS VIRGINIANUS).
A circumscribed natural outbreak of a highly fatal disease of deer, which we have designated epizootic hemorrhagic disease (EHD), has been studied. The disease has proven readily transmissible in deer but not in other experimental or domestic animals tested, nor in embryonating eggs or deer kidney cell cultures. The causative agent is a virus which is readily filterable and is capable of storage, either frozen or in glycerol, for relatively long periods of time. It produces a solid immunity in the few animals that survive and the blood sera of such convalescent animals contain virus-neutralizing antibodies. The disease is one in which large and small hemorrhages occur in both the viscera and skeletal structures of the body, as well as in the subcutaneous tissues. It is probably the same as one known popularly in the southeastern United States as "black tongue" of deer. It is unrelated to epidemic hemorrhagic fever of man or to the disease caused in horses by the equine arteritis virus. At least two serologically different types of EHD virus exist. The New Jersey strain is of greater lethality for experimental deer than the serologically different one obtained from an outbreak that occurred in South Dakota a year after the New Jersey epizootic.


Urine Cotinine for Assessing Tobacco Smoke Exposure in Korean: Analysis of the Korea National Health and Nutrition Examination Survey (KNHANES).
The level of urine cotinine is an indicator of tobacco smoke exposure. The purpose of this study is to investigate urine cotinine for the purpose of assessing the smoking status of Korean smokers and non-smokers exposed to tobacco smoke. The subjects were identified from the 2007-2009 and the 2010 data sets of the Korea National Health and Nutrition Examination Survey (KNHANES). They were assigned as non-smokers, current smokers and ex-smokers. Non-smokers were also divided into three subset groups according to the duration of smoke exposure. Each group was stratified by gender prior to analysis. The median value of urine cotinine in the male current smokers was 1,221.93 ng/mL which was the highest among all groups. The difference between levels of urine cotinine for male and the female groups was statistically significant (p<0.01). In the female group, passive smoke exposure groups reported higher urine cotinine levels than non-exposure groups (p=0.01). The cutoff point for the discrimination of current smokers from non-smokers was 95.6 ng/mL in males and 96.8 ng/mL in females. The sensitivity and specificity were 95.2% and 97.1%, respectively, in males, 96.1% and 96.5% in females. However, the determination of urine cotinine level was not useful in distinguishing between passive smoke exposure groups and non-exposure groups. Urine cotinine concentration is a useful biomarker for discriminating non-smokers from current smokers. However, careful interpretation is necessary for assessing passive smoke exposure by urine cotinine concentration.


Do Dutch doctors communicate differently with immigrant patients than with Dutch patients?
The aim of this study was to gain deeper insight into relational aspects of the medical communication pattern in intercultural consultations at GP practices in the Netherlands. We ask whether there are differences in the verbal interaction of Dutch GPs with immigrant and Dutch patients. Data were drawn from 144 adult patient interviews and video observations of consultations between the patients and 31 Dutch GPs. The patient group consisted of 61 non-Western immigrants (Turkish, Moroccan, Surinamese, Antillean, Cape Verdian) and 83 Dutch participants. Affective and instrumental aspects of verbal communication were assessed using Roter's Interaction Analysis System (RIAS). Patients' cultural background was assessed by ethnicity, language proficiency, level of education, religiosity and cultural views (in terms of being more traditional or more modern). Consultations with the non-Western immigrant patients (especially those from Turkey and Morocco) were well over 2 min shorter, and the power distance between GPs and these patients was greater when compared to the Dutch patients. Major differences in verbal interaction were observed on the affective behavior dimensions, but not on the instrumental dimensions. Doctors invested more in trying to understand the immigrant patients, while in the case of Dutch patients they showed more involvement and empathy. Dutch patients seemed to be more assertive in the medical conversation. The differences are discussed in terms of patients' ethnic background, cultural views (e.g. practicing a religion) and linguistic barriers. It is concluded that attention to cultural diversity does matter, as this leads to different medical communication patterns. A two-way strategy is recommended for improving medical communication, with implications for both doctor and patient behavior.


Pathophysiologic Mechanisms and Current Treatments for Cutaneous Sequelae of Burn Wounds.
Burn injuries are a pervasive clinical problem. Extensive thermal trauma can be life-threatening or result in long-lasting complications, generating a significant impact on quality of life for patients as well as a cost burden to the healthcare system. The importance of addressing global or systemic issues such as resuscitation and management of inhalation injuries is not disputed but is beyond the scope of this review, which focuses on cutaneous pathophysiologic mechanisms for current treatments, both in the acute and long-term settings. Pathophysiological mechanisms of burn progression and wound healing are mediated by highly complex cascades of cellular and biochemical events, which become dysregulated in slow-healing wounds such as burns. Burns can result in fibroproliferative scarring, skin contractures, or chronic wounds that take weeks or months to heal. Burn injuries are highly individualized owing to wound-specific differences such as burn depth and surface area, in addition to patient-specific factors including genetics, immune competency, and age. Other extrinsic complications such as microbial infection can complicate wound healing, resulting in prolonged inflammation and delayed re-epithelialization. Although mortality is decreasing with advancements in burn care, morbidity from postburn deformities continues to be a challenge. Optimizing specialized acute care and late burn outcome intervention on a patient-by-patient basis is critical for successful management of burn wounds and the associated pathological scar outcome. Understanding the fundamentals of integument physiology and the cellular processes involved in wound healing is essential for designing effective treatment strategies for burn wound care as well as development of future therapies. Published 2018. Compr Physiol 8:371-405, 2018.


Navigating HIV citizenship: identities, risks and biological citizenship in the treatment as prevention era.
The use of HIV Treatment as Prevention (TasP) has radically changed our understandings of HIV risk and revolutionised global HIV prevention policy to focus on the use of pharmaceuticals. Yet, there has been little engagement with the very people expected to comply with a daily pharmaceutical regime. We employ the concept of HIV citizenship to explore responses by people living with HIV in the UK to TasP. We consider how a treatment-based public health strategy has the potential to reshape identities, self-governance and forms of citizenship, domains which play a critical role not only in compliance with new TasP policies, but in how HIV prevention, serodiscordant relationships and (sexual) health are negotiated and enacted. Our findings disrupt the biomedical narrative which claims an end to HIV through scaling up access to treatment. Responses to TasP were framed through shifting negotiations of identity, linked to biomarkers, cure and managing treatment. Toxicity of drugs - and bodies - were seen as something to manage and linked to the shifting possibilities in serodiscordant environments. Finally, a sense of being healthy and responsible, including appropriate use of resources, meant conflicting relationships with if and when to start treatment. Our research highlights how HIV citizenship in the TasP era is negotiated and influenced by intersectional experiences of community, health systems, illness and treatment. Our findings show that the complexities of HIV citizenship and ongoing inequalities, and their biopolitical implications, will intimately shape the implementation and sustainability of TasP.


The emerging role of microfluidics in multi-material 3D bioprinting.
To assist the transition of 3D bioprinting technology from simple lab-based tissue fabrication, to fully functional and implantable organs, the technology must not only provide shape control, but also functional control. This can be accomplished by replicating the cellular composition of the native tissue at the microscale, such that cell types interact to provide the desired function. There is therefore a need for precise, controllable, multi-material printing that could allow for high, possibly even single cell, resolution. This paper aims to draw attention to technological advancements made in 3D bioprinting that target the lack of multi-material, and/or multi cell-type, printing capabilities of most current devices. Unlike other reviews in the field, which largely focus on variations in single-material 3D bioprinting involving the standard methods of extrusion-based, droplet-based, laser-based, or stereolithographic methods; this review concentrates on sophisticated multi-material 3D bioprinting using multi-cartridge printheads, co-axial nozzles and microfluidic-enhanced printing nozzles.


SU-E-I-12: Analysis of Image Noise in 3D Scatter Corrected Cone Beam CT Images as a Function of Object Size.
To characterize the spatial correlation of quantum noise of a cone beam CT (CBCT) system for breast imaging under scatter and non-scatter corrected conditions as a function of object radius. Experiments were conducted using a conical phantom under scatter and non-scatter corrected conditions. The cone phantom filled with 700ml of water was positioned near the isocenter of the quasi-monochromatic CBCT imaging system. 360 projections were acquired and beam-stop measured scatter correction was performed. Both scatter and non-scatter corrected projections were reconstructed with an iterative ordered subsets convex (OSC) algorithm. NPS measurements were made at several cone radii (6-12cm) using 4 overlapping 50×50 pixel ROI's with a 50% overlap between adjacent ROIs. An ensemble average of NPS measurements was taken over 5 slices at each radius. For both scatter and non-scatter corrected data overall noise is higher with increasing object radius. Each 1-D NPS area under the curve was found to be within the standard deviation of the respective ROI variance. The variance of scatter corrected images is higher at each radius. The 1-D NPS indicates a decrease in peak value for both scatter and non-scatter corrected images as radius increases. Scatter corrected NPS shows a slight shift in the peak towards higher spatial frequencies, and a larger spread of noise over all spatial frequencies as radius increases. This work demonstrates that scatter correction increases noise at each spatial frequency at various object radii. owever as radius increases, lower frequency noise decreases and concomitantly higher frequency noise increases. As a Result of this equalization of noise across spatial frequencies, the noise texture appears more uniform at larger radii under scatter corrected conditions. These results and methodology can be used to determine optimal detection of low contrast signals in phantoms of different radii and with clinical breast data.


Natural Anti-Infective Pulmonary Proteins: In Vivo Cooperative Action of Surfactant Protein SP-A and the Lung Antimicrobial Peptide SP-BN.
The anionic antimicrobial peptide SP-B(N), derived from the N-terminal saposin-like domain of the surfactant protein (SP)-B proprotein, and SP-A are lung anti-infective proteins. SP-A-deficient mice are more susceptible than wild-type mice to lung infections, and bacterial killing is enhanced in transgenic mice overexpressing SP-B(N). Despite their potential anti-infective action, in vitro studies indicate that several microorganisms are resistant to SP-A and SP-B(N). In this study, we test the hypothesis that these proteins act synergistically or cooperatively to strengthen each other's microbicidal activity. The results indicate that the proteins acted synergistically in vitro against SP-A- and SP-B(N)-resistant capsulated Klebsiella pneumoniae (serotype K2) at neutral pH. SP-A and SP-B(N) were able to interact in solution (Kd = 0.4 μM), which enabled their binding to bacteria with which SP-A or SP-B(N) alone could not interact. In vivo, we found that treatment of K. pneumoniae-infected mice with SP-A and SP-B(N) conferred more protection against K. pneumoniae infection than each protein individually. SP-A/SP-B(N)-treated infected mice showed significant reduction of bacterial burden, enhanced neutrophil recruitment, and ameliorated lung histopathology with respect to untreated infected mice. In addition, the concentrations of inflammatory mediators in lung homogenates increased early in infection in contrast with the weak inflammatory response of untreated K. pneumoniae-infected mice. Finally, we found that therapeutic treatment with SP-A and SP-B(N) 6 or 24 h after bacterial challenge conferred significant protection against K. pneumoniae infection. These studies show novel anti-infective pathways that could drive development of new strategies against pulmonary infections.


Gp96 is a receptor for a novel Listeria monocytogenes virulence factor, Vip, a surface protein.
By comparative genomics, we have identified a gene of the intracellular pathogen Listeria monocytogenes that encodes an LPXTG surface protein absent from nonpathogenic Listeria species. This gene, vip, is positively regulated by PrfA, the transcriptional activator of the major Listeria virulence factors. Vip is anchored to the Listeria cell wall by sortase A and is required for entry into some mammalian cells. Using a ligand overlay approach, we identified a cellular receptor for Vip, the endoplasmic reticulum (ER) resident chaperone Gp96 recently shown to interact with TLRs. The Vip-Gp96 interaction is critical for bacterial entry into some cells. Comparative infection studies using oral and intravenous inoculation of nontransgenic and transgenic mice expressing human E-cadherin demonstrated a role for Vip in Listeria virulence, not only at the intestine level but also in late stages of the infectious process. Vip thus appears as a new virulence factor exploiting Gp96 as a receptor for cell invasion and/or signalling events that may interfere with the host immune response in the course of the infection.


Anticholinergic versus botulinum toxin A comparison trial for the treatment of bothersome urge urinary incontinence: ABC trial.
This trial compares the change in urgency urinary incontinence episodes over 6 months, tolerability and cost effectiveness between women receiving daily anticholinergic therapy plus a single intra-detrusor injection of saline versus a single intra-detrusor injection of 100 U of botulinum toxin A plus daily oral placebo tablets. We present the rationale and design of a randomized-controlled trial, Anticholinergic versus Botulinum Toxin, Comparison Trial for the Treatment of Bothersome Urge Urinary Incontinence: ABC trial, conducted by the NICHD-funded Pelvic Floor Disorders Network. We discuss the innovative nature of this trial and the challenges related to choice of patient population, maintaining masking, cost effectiveness, ethical considerations, measuring adherence, and placebo development and testing. Enrollment began in April, 2010. 242 participants will be randomized and primary outcome data analysis is anticipated to begin in mid 2012. Several challenges in the trial design are discussed. Randomization to placebo intra-detrusor injections may limit recruitment, potentially impacting generalizability. Other challenges included the heavy marketing of drugs for overactive bladder which could impact recruitment of drug-naïve women. In addition, anticholinergic medications often cause dry mouth, making masking difficult. Finally, adverse reporting of transient urinary retention is challenging as there is no standardized definition; yet this is the most common adverse event following intra-detrusor botulinum toxin injection. The ABC trial will help women with urgency urinary incontinence balance efficacy, side effects and cost of anticholinergic medication versus botulinum toxin intra-detrusor injection. The results have the potential to fundamentally change the therapeutic approach to this condition.


Transmissibility of swine flu at Fort Dix, 1976.
The 1976 outbreak of A/New Jersey/76 influenza in Fort Dix is a rare example of an influenza virus with documented human to human transmission that failed to spread widely. Despite extensive epidemiological investigation, no attempt has been made to quantify the transmissibility of this virus. The World Health Organization and the United States Government view containment of emerging influenza strains as central to combating pandemic influenza. Computational models predict that it may be possible to contain an emergent pandemic influenza if virus transmissibility is low. The A/New Jersey/76 outbreak at the United States Army Training Center at Fort Dix, New Jersey in January 1976 caused 13 hospitalizations, 1 death and an estimated 230 cases. To characterize viral transmission in this epidemic, we estimated the basic reproductive number and serial interval using deterministic epidemic models and stochastic simulations. We estimated the basic reproductive number for this outbreak to be 1.2 (supported interval 1.1-1.4), the serial interval to be 1.9 days (supported interval 1.6-3.8 days), and that the virus had at least six serial human to human transmissions. This places the transmissibility of A/New Jersey/76 virus at the lower end of circulating flu strains, well below the threshold for control.


The cystic fibrosis airway microbiome.
Culture and molecular approaches have established that lower airway infections are polymicrobial. We consider how this new perspective in cystic fibrosis (CF) may affect treatment choices. Standard clinical microbiology of CF infection exacerbations often fails to provide indications of microbial causes that may drive the onset of exacerbation and the anticipated bacteriologic responses to the usual parenteral antibiotics prescribed as treatment. Antimicrobial responses by nonclassical members of the CF airway microbiome may explain why most patients clinically improve. These other organisms contribute to disease either directly as pathogens missed by conventional microbiology or through synergy with conventional pathogens. With these considerations, therapy may best be guided by directed antibiotic therapy to numerically significant isolates. An example is the Streptococcus milleri group, which we now believe to represent new pathogens that profile the exacerbations of infection in the CF lung and that necessitate specific antibiotic therapy to prevent loss of lung function and reduce frequency of exacerbations. A comprehensive understanding of airway infections offers the potential for improved disease management in CF patients. Accurate quantitative microbiology will be a prerequisite for routine intervention based on the polymicrobial perspective of CF infection exacerbations.


Statins decrease expression of the proinflammatory neuropeptides calcitonin gene-related peptide and substance P in sensory neurons.
Clinical and experimental observations suggest that statins may be useful for treating diseases presenting with predominant neurogenic inflammation, but the mechanism(s) mediating this potential therapeutic effect are poorly understood. In this study, we tested the hypothesis that statins act directly on sensory neurons to decrease expression of proinflammatory neuropeptides that trigger neurogenic inflammation, specifically calcitonin gene-related peptide (CGRP) and substance P. Reverse transcriptase-polymerase chain reaction, radioimmunoassay, and immunocytochemistry were used to quantify CGRP and substance P expression in dorsal root ganglia (DRG) harvested from adult male rats and in primary cultures of sensory neurons derived from embryonic rat DRG. Systemic administration of statins at pharmacologically relevant doses significantly reduced CGRP and substance P levels in DRG in vivo. In cultured sensory neurons, statins blocked bone morphogenetic protein (BMP)-induced CGRP and substance P expression and decreased expression of these neuropeptides in sensory neurons pretreated with BMPs. These effects were concentration-dependent and occurred independent of effects on cell survival or axon growth. Statin inhibition of neuropeptide expression was reversed by supplementation with mevalonate and cholesterol, but not isoprenoid precursors. BMPs signal via Smad activation, and cholesterol depletion by statins inhibited Smad1 phosphorylation and nuclear translocation. These findings identify a novel action of statins involving down-regulation of proinflammatory neuropeptide expression in sensory ganglia via cholesterol depletion and decreased Smad1 activation and suggest that statins may be effective in attenuating neurogenic inflammation.


In vitro oxidant effects of D-glucosamine reduce adhesión and biofilm formation of Staphylococcus epidermidis.
Staphylococcus epidermidis is a common pathogen in medical device-associated infections. Its major pathogenic factor is the ability to form adherent biofilms. In this work, three S. epidermidis strains isolated from infected catheters were chosen with the objective of investigating the effect of D-glucosamine (D-Glu) on reactive oxygen species (ROS) production, adhesion and biofilm formation. The chemiluminescence and nitroblue tetrazolium reduction assays were used to determine ROS production by planktonic S. epidermidis and the microtiter plate assay to quantify in vitro biofilm formation. D-Glu generated a dose-dependent increase in ROS in planktonic cells with maximum stimuli at a concentration of 0.05 mM, and reduced adhesion and biofilm formation. On the other hand, glucose showed an antioxidative stress action and promoted biofilm adhesion and growth. This study suggests a potential application of D-Glu against infections associated with indwelling medical devices, since the oxidative stress caused by this hexosamine in planktonic S. epidermidis contributed to reducing biofilm formation.


Chimpanzees and humans mimic pupil-size of conspecifics.
Group-living typically provides benefits to individual group members but also confers costs. To avoid incredulity and betrayal and allow trust and cooperation, individuals must understand the intentions and emotions of their group members. Humans attend to other's eyes and from gaze and pupil-size cues, infer information about the state of mind of the observed. In humans, pupil-size tends to mimic that of the observed. Here we tested whether pupil-mimicry exists in our closest relative, the chimpanzee (P. troglodytes). We conjectured that if pupil-mimicry has adaptive value, e.g. to promote swift communication of inner states and facilitate shared understanding and coordination, pupil-mimicry should emerge within but not across species. Pupillometry data was collected from human and chimpanzee subjects while they observed images of the eyes of both species with dilating/constricting pupils. Both species showed enhanced pupil-mimicry with members of their own species, with effects being strongest in humans and chimpanzee mothers. Pupil-mimicry may be deeply-rooted, but probably gained importance from the point in human evolution where the morphology of our eyes became more prominent. Humans' white sclera surrounding the iris, and the fine muscles around their eyes facilitate non-verbal communication via eye signals.


NEWHINTS cluster randomised trial to evaluate the impact on neonatal mortality in rural Ghana of routine home visits to provide a package of essential newborn care interventions in the third trimester of pregnancy and the first week of life: trial protocol.
Tackling neonatal mortality is essential for the achievement of the child survival millennium development goal. There are just under 4 million neonatal deaths, accounting for 38% of the 10.8 million deaths among children younger than 5 years of age taking place each year; 99% of these occur in low- and middle-income countries where a large proportion of births take place at home, and where postnatal care for mothers and neonates is either not available or is of poor quality. WHO and UNICEF have issued a joint statement calling for governments to implement "Home visits for the newborn child: a strategy to improve survival", following several studies in South Asia which achieved substantial reductions in neonatal mortality through community-based approaches. However, their feasibility and effectiveness have not yet been evaluated in Africa. The Newhints study aims to do this in Ghana and to develop a feasible and sustainable community-based approach to improve newborn care practices, and by so doing improve neonatal survival. Newhints is an integrated intervention package based on extensive formative research, and developed in close collaboration with seven District Health Management Teams (DHMTs) in Brong Ahafo Region. The core component is training the existing community based surveillance volunteers (CBSVs) to identify pregnant women and to conduct two home visits during pregnancy and three in the first week of life to address essential care practices, and to assess and refer very low birth weight and sick babies. CBSVs are supported by a set of materials, regular supervisory visits, incentives, sensitisation activities with TBAs, health facility staff and communities, and providing training for essential newborn care in health facilities.Newhints is being evaluated through a cluster randomised controlled trial, and intention to treat analyses. The clusters are 98 supervisory zones; 49 have been randomised for implementation of the Newhints intervention, with the other 49 acting as controls. Data on neonatal mortality and care practices will be collected from approximately 15,000 babies through surveillance of women of child-bearing age in the 7 districts. Detailed process, cost and cost-effectiveness evaluations are also being carried out. http://www.clinicaltrials.gov (identifier NCT00623337).


Echocardiographic evaluation of ventricular function in mice.
Ventricular dysfunction remains a hallmark of most cardiac disease. The mouse has become an essential model system for cardiovascular biology, and echocardiography an established tool in the study of normal and genetically altered mice. This review describes the measurement of ventricular function, most often left ventricular function, by echocardiographic methods in mice. Technical limitations related to the small size and rapid heart rate in the mouse initially argued for the performance of echocardiography under anesthesia. More recently, higher frame rates and smaller probes operating at higher frequencies have facilitated imaging of conscious mice in some, but not all, experimental protocols and conditions. Ventricular function may be qualitatively and quantitatively evaluated under both conditions. Particular detail is provided for measurement under conscious conditions, and measurement under conscious and sedated or anesthestized conditions are contrasted. Normal values for echocardiographic indices for the common C57BL/6 strain are provided. Diastolic dysfunction is a critical pathophysiologic component of many disease states, and progress in the echocardiographic evaluation of diastolic function is discussed. Finally, echocardiography exists among several competing imaging technologies, and these alternatives are compared.


Evolving polarisation of infiltrating and alveolar macrophages in the lung during metastatic progression of melanoma suggests CCR1 as a therapeutic target.
Metastatic tumour progression is facilitated by tumour associated macrophages (TAMs) that enforce pro-tumour mechanisms and suppress immunity. In pulmonary metastases, it is unclear whether TAMs comprise tissue resident or infiltrating, recruited macrophages; and the different expression patterns of these TAMs are not well established. Using the mouse melanoma B16F10 model of experimental pulmonary metastasis, we show that infiltrating macrophages (IM) change their gene expression from an early pro-inflammatory to a later tumour promoting profile as the lesions grow. In contrast, resident alveolar macrophages (AM) maintain expression of crucial pro-inflammatory/anti-tumour genes with time. During metastatic growth, the pool of macrophages, which initially contains mainly alveolar macrophages, increasingly consists of infiltrating macrophages potentially facilitating metastasis progression. Blocking chemokine receptor mediated macrophage infiltration in the lung revealed a prominent role for CCR2 in Ly6C+ pro-inflammatory monocyte/macrophage recruitment during metastasis progression, while inhibition of CCR2 signalling led to increased metastatic colony burden. CCR1 blockade, in contrast, suppressed late phase pro-tumour MR+Ly6C- monocyte/macrophage infiltration accompanied by expansion of the alveolar macrophage compartment and accumulation of NK cells, leading to reduced metastatic burden. These data indicate that IM has greater plasticity and higher phenotypic responsiveness to tumour challenge than AM. A considerable difference is also confirmed between CCR1 and CCR2 with regard to the recruited IM subsets, with CCR1 presenting a potential therapeutic target in pulmonary metastasis from melanoma.


Maternal and neonatal tetanus.
Maternal and neonatal tetanus is still a substantial but preventable cause of mortality in many developing countries. Case fatality from these diseases remains high and treatment is limited by scarcity of resources and effective drug treatments. The Maternal and Neonatal Tetanus Elimination Initiative, launched by WHO and its partners, has made substantial progress in eliminating maternal and neonatal tetanus. Sustained emphasis on improvement of vaccination coverage, birth hygiene, and surveillance, with specific approaches in high-risk areas, has meant that the incidence of the disease continues to fall. Despite this progress, an estimated 58,000 neonates and an unknown number of mothers die every year from tetanus. As of June, 2014, 24 countries are still to eliminate the disease. Maintenance of elimination needs ongoing vaccination programmes and improved public health infrastructure.


Evidence of shared bovine viral diarrhea infections between red deer and extensively raised cattle in south-central Spain.
Bovine viral diarrhea virus (BVDV) is a pestivirus that affects cattle production worldwide and that can infect other ungulates such as cervids and even wild boar (Sus scrofa). It is believed that domestic livestock can become infected through contact with wild animals, though it is known that infection can spread among wild animals in the absence of contact with livestock. Little is known about the sharing of BVDV infection between wild and domestic animals in the same habitat, which is important for designing eradication campaigns and preventing outbreaks, especially on hunting estates with high animal densities. We assessed the sharing of BVDV infections among hunted red deer, wild boar and cattle in south-central Spain. Sampled red deer (Cervus elaphus; n = 267) and wild boar (n = 52) were located on 19 hunting estates, and cattle (n = 180) were located on 18 nearby farms. We used ELISA kits for the serological screening, Taqman RT-PCR assay for the virus determination, and subsequent phylogenetic analysis for 17 RT-PCR positive sample amplicons. Fifty-two red deer (19.5%) and 82 cattle (45.6%) samples tested positive by ELISA. A high apparent prevalence (22.47%) was obtained for red deer, while only five cattle farms tested positive by RT-PCR. Conversely, no wild boar tested positive by both ELISA or RT-PCR. Eleven red deer (4.1%) tested positive by both ELISA and RT-PCR; these animals may have been sampled during the last phase of viremia, or they may represent previously exposed individuals infected by a different BVDV strain. The amplicons shared 92.7-100% identity and fell within the BVDV subgroup 1b, although nine of these (from four red deer and five cattle pools) formed a separate branch. This suggests that there might be a common BVDV infecting both cattle and red deer. Higher red deer abundance was significantly associated with greater risk that extensively raised cattle would test positive for BVDV by ELISA. Our findings suggest that BVDV is circulating between cattle and red deer populations in proximity, but further work is required to determine whether they share the same strain(s). These results suggest the potential of BVDV to serve as a surveillance marker in these shared habitats. High seroprevalence of BVDV in red deer from our study area suggests that although BVDV infection is common, animals usually survive the infection. Further research is needed to verify and investigate the role of red deer as a BVDV reservoir.


In vitro characterization of alkylaminophenols-induced cell death.
Alkylaminophenols are synthetic derivatives well known for their anticancer activity. In the previous studies, we described the activity of the series of Alkylaminophenols derivatives and their ability to induce cell death for many cancer cell lines. However, temporal heterogeneity in cell death induced by lead compounds, N-(2-hydroxy-5-nitrophenyl (4'-methylphenyl) methyl) indoline (Compound I) and 2-((3,4-dihydroquinolin-1(2H)-yl) (4-methoxyphenyl) methyl) phenol (Compound II), has never been tested on osteosarcoma cells (U2OS). Here, we address the level of cell-to-cell heterogeneity by examine whether differences in the type of compounds could influence its effects on cell death of U2OS. Here, we applied imaging, computational methods and biochemical methods to study heterogeneity, apoptosis, reactive oxygen species and caspase. Our results demonstrate that the Hill coefficient of dose-response curve of Compound II is greater than compound I in treated U2OS cells. Both Compounds trigger not only apoptotic cell death but also necro-apoptotic and necrotic cell death. The percentage of these sub-populations varies depending on compounds in which greater variance is induced by compound II than Compound I. We also identified the accumulation of compounds-induced reactive oxygen species during the treatment. This resulted in caspase 3/7 activation in turn induced apoptosis. In summary, the screening of Compound I and II molecules for heterogeneity, apoptosis, reactive oxygen species and caspase has identified compound II as promising anti-osteosarcoma cancer agent. Compound II could be a promising lead compound for future antitumor agent development.


Enhancing Mobility With Quasi-Passive Variable Stiffness Exoskeletons.
Shoes were invented to provide user comfort using rubber soles, despite marginal improvement in human mobility. Unlike shoes, current lower-limb exoskeletons use fixed stiffness springs to store and recycle energy to improve mobility. However, the maximum kinetic energy a human can accumulate when augmented with a fixed stiffness spring is limited by the maximum deflection and the ability of the limbs to generate force; tying the advantage of fixed stiffness exoskeletons to biological constraints. Here, we propose a method for improving mobility using quasi-passive variable stiffness spring exoskeletons, where the maximum kinetic energy accumulated by a human is independent of the limb deflection and the ability of the limb to generate force. This is achieved by a variable stiffness augmentation of the human, where the exoskeleton does not provide mechanical work. The theoretical advantage provided by this new augmentation method can be useful in demanding tasks, where humans could benefit from increased speed and reduced energy cost of motion.


The Frenchay Activities Index. Assessment of functional status in stroke patients.
Assessment of functional status in stroke patients is of major importance in both clinical practice and outcome studies. The Frenchay Activities Index has been developed specifically for measuring disability and handicap in stroke patients. The purpose of the study was to evaluate the metric properties of this instrument and to obtain normal values in a group of unselected elderly subjects. The Frenchay Activities Index was tested in a group of stroke patients and a group of unselected subjects aged 65 or older. The functional status of the stroke patients was measured 26 weeks after stroke. Their prestroke status was registered retrospectively. Reliability and validity of the instrument were assessed. The mean scores in the prestroke, poststroke, and control group demonstrated differences in functional status. The reliability of unweighted scores (range of Cronbach's alpha-coefficients, 0.78 to 0.87) was sufficient. The construct validity was supported by meaningful correlations between the Frenchay Activities Index and scores on the Barthel Index and Sickness Impact Profile. Principal-components analysis indicated that the Frenchay Activities Index showed two traits: instrumental disability and some aspects of handicap. The reliability of the instrument could be improved by deleting two items and by creating two subscale scores: domestic and outdoors activities. The Frenchay Activities Index is a useful stroke-specific instrument to assess functional status. Completion of the questionnaire is easy and takes only a few minutes. Currently, the instrument is suitable for use in patient care and cross-sectional, descriptive studies.


Heterogeneous impact of smoking on major salivary gland cancer according to histopathological subtype: A case-control study.
Major salivary gland cancers (M-SGCs) are rare, and have distinct heterogeneous histopathological subtypes. To the authors' knowledge, no consistent evidence of an association between cigarette smoking and the risk of M-SGCs has appeared to date. Furthermore, evidence of potential heterogeneity in the impact of smoking on histopathological subtypes is scarce, despite the fact that the histopathological subtypes of M-SGC exhibit different genetic features. The authors conducted a case-control study to investigate the association between smoking and M-SGC by histopathological subtype. Cases were 81 patients with M-SGCs and the controls were 810 age-matched and sex-matched first-visit outpatients without cancer treated at Aichi Cancer Center Hospital from 1988 to 2005. Odds ratios (OR) and 95% confidence intervals (95% CI) were assessed by conditional logistic regression analysis with adjustment for potential confounders. Smoking was found to be associated with a significantly increased risk of M-SGC overall, with an OR of 3.45 (95% CI, 1.58-7.51; P =.001) for heavy smokers compared with never-smokers. A significant dose-response relationship was observed (P for trend, .001). When stratified by histological subtype, no obvious impact of smoking was observed among patients with mucoepidermoid carcinoma (MEC). In contrast, smoking demonstrated a significantly increased risk of M-SGCs other than MEC, with an OR of 5.15 (95% CI, 2.06-12.87; P<.001) for heavy smokers compared with never-smokers. The authors observed possible heterogeneity with regard to the impact of smoking on risk between MEC and M-SGCs other than MEC (P for heterogeneity, .052). The results of the current study demonstrate a significant positive association between cigarette smoking and the risk of M-SGC overall. However, the impact of smoking appeared to be limited to M-SGCs other than MEC. Cancer 2018;124:118-24. © 2017 American Cancer Society.


Involvement in Special Olympics and its relations to self-concept and actual competency in participants with developmental disabilities.
The current study examined the relations among components of a physical activity program, Special Olympics (SO), and the self-concepts (i.e., perceived physical competence, social acceptance, and general self-worth) and adaptive behaviors of individuals with developmental disabilities. This research can assist in the development of theoretical models of how physical activity programs can be implemented to effect psychological change. Participants consisted of a randomly selected group of 97 individuals with developmental disabilities, between 9 and 43 years of age, and their parents. Participants' self-concepts and adaptive behaviors were measured both by direct interview and parental report. Examined program components consisted of the length of time affiliated to the organization, number of competitions attended, of hours spent in training, of sports, and of medals obtained. Multiple regression analyses suggest relations between specific components of SO and participants' self-concepts and adaptive behaviors. These relations highlight the importance of competition and sport for individuals with developmental disabilities.


Impacts of Hypervirulence Determinants on Clinical Features and Outcomes of Bacteremia Caused by Extended-Spectrum β-Lactamase-Producing Klebsiella pneumoniae.
We investigated the implications of hypervirulence determinants on clinical features of 48 adult patients with bacteremia caused by extended-spectrum β-lactamase-producing Klebsiella pneumoniae. Isolates in the hypervirulence group included any of the following virulence determinants: K1/K2 capsule serotypes, hypermucoviscosity phenotype, rmpA gene, or rmpA2 gene. Nonhypervirulence group isolates were negative for all of the above virulence factors. In this study, all isolates used were non-K1/K2 strains. Statistically significant differences were observed in clinical features of patients between the two groups. The hypervirulent isolates (n = 19), including 11 isolates with the hypermucoviscosity phenotype, 15 with the rmpA gene, and 16 with the rmpA2 gene, were more commonly recovered from diabetic patients and mainly manifested as secondary bacteremia (such as pneumonia, urinary tract infections, or other localized infections). The nonhypervirulent isolates (n = 29) were more commonly recovered from patients after prolonged hospital stays (>30 days) and mostly manifested as primary bacteremia. The overall in-hospital mortality was 56.3%. Hazard ratio (HR) analysis revealed the following positive predictors for mortality: nosocomial infection, stay in an intensive care unit, no removal of the central venous catheter, Charlson comorbidity score, and APACHE II score (≧15). The negative predictors were initial appropriate antibiotic therapy (HR 0.42) and urinary tract infection (HR 0.19). Charlson score was an independent confounder based on multivariate analysis (HR 1.43, 95% confidence interval 1.04-1.99). In conclusion, hypervirulence determinants played a role in causing secondary infections in diabetic patients; however, the presence of morbidity cofactors could themselves influence mortality, despite the absence of hypervirulence determinants.


EULAR recommendations for patient education for people with inflammatory arthritis.
The task force aimed to: (1) develop evidence-based recommendations for patient education (PE) for people with inflammatory arthritis, (2) identify the need for further research on PE and (3) determine health professionals' educational needs in order to provide evidence-based PE. A multidisciplinary task force, representing 10 European countries, formulated a definition for PE and 10 research questions that guided a systematic literature review (SLR). The results from the SLR were discussed and used as a basis for developing the recommendations, a research agenda and an educational agenda. The recommendations were categorised according to level and strength of evidence graded from A (highest) to D (lowest). Task force members rated their agreement with each recommendation from 0 (total disagreement) to 10 (total agreement). Based on the SLR and expert opinions, eight recommendations were developed, four with strength A evidence. The recommendations addressed when and by whom PE should be offered, modes and methods of delivery, theoretical framework, outcomes and evaluation. A high level of agreement was achieved for all recommendations (mean range 9.4-9.8). The task force proposed a research agenda and an educational agenda. The eight evidence-based and expert opinion-based recommendations for PE for people with inflammatory arthritis are intended to provide a core framework for the delivery of PE and training for health professionals in delivering PE across Europe.


Global Survey of Antibiotic Resistance Genes in Air.
Despite its emerging significant public health concern, the presence of antibiotic resistance genes (ARGs) in urban air has not received significant attention. Here, we profiled relative abundances (as a fraction, normalized by 16S rRNA gene) of 30 ARG subtypes resistant to seven common classes of antibiotics, which are quinolones, β-lactams, macrolides, tetracyclines, sulfonamides, aminoglycosides, and vancomycins, in ambient total particulate matter (PM) using a novel protocol across 19 world cities. In addition, their longitudinal changes in PM2.5 samples in Xi'an, China as an example were also studied. Geographically, the ARGs were detected to vary by nearly 100-fold in their abundances, for example, from 0.07 (Bandung, Indonesia) to 5.6 (San Francisco, USA). The β-lactam resistance gene blaTEM was found to be most abundant, seconded by quinolone resistance gene qepA; and their corresponding relative abundances have increased by 178% and 26%, respectively, from 2004 to 2014 in Xi'an. Independent of cities, gene network analysis indicates that airborne ARGs were differentially contributed by bacterial taxa. Results here reveal that urban air is being polluted by ARGs, and different cities are challenged with varying health risks associated with airborne ARG exposure. This work highlights the threat of urban airborne transmission of ARGs and the need of redefining our current air quality standards in terms with public health.


No time for drifting: Comparing performance and applicability of signal detrending algorithms for real-time fMRI.
As a consequence of recent technological advances in the field of functional magnetic resonance imaging (fMRI), results can now be made available in real-time. This allows for novel applications such as online quality assurance of the acquisition, intra-operative fMRI, brain-computer-interfaces, and neurofeedback. To that aim, signal processing algorithms for real-time fMRI must reliably correct signal contaminations due to physiological noise, head motion, and scanner drift. The aim of this study was to compare performance of the commonly used online detrending algorithms exponential moving average (EMA), incremental general linear model (iGLM) and sliding window iGLM (iGLMwindow). For comparison, we also included offline detrending algorithms (i.e., MATLAB's and SPM8's native detrending functions). Additionally, we optimized the EMA control parameter, by assessing the algorithm's performance on a simulated data set with an exhaustive set of realistic experimental design parameters. First, we optimized the free parameters of the online and offline detrending algorithms. Next, using simulated data, we systematically compared the performance of the algorithms with respect to varying levels of Gaussian and colored noise, linear and non-linear drifts, spikes, and step function artifacts. Additionally, using in vivo data from an actual rt-fMRI experiment, we validated our results in a post hoc offline comparison of the different detrending algorithms. Quantitative measures show that all algorithms perform well, even though they are differently affected by the different artifact types. The iGLM approach outperforms the other online algorithms and achieves online detrending performance that is as good as that of offline procedures. These results may guide developers and users of real-time fMRI analyses tools to best account for the problem of signal drifts in real-time fMRI.


PRMT1-mediated methylation of the EGF receptor regulates signaling and cetuximab response.
Posttranslational modifications to the intracellular domain of the EGFR are known to regulate EGFR functions; however, modifications to the extracellular domain and their effects remain relatively unexplored. Here, we determined that methylation at R198 and R200 of the EGFR extracellular domain by protein arginine methyltransferase 1 (PRMT1) enhances binding to EGF and subsequent receptor dimerization and signaling activation. In a mouse orthotopic colorectal cancer xenograft model, expression of a methylation-defective EGFR reduced tumor growth. Moreover, increased EGFR methylation sustained signaling activation and cell proliferation in the presence of the therapeutic EGFR monoclonal antibody cetuximab. In colorectal cancer patients, EGFR methylation level also correlated with a higher recurrence rate after cetuximab treatment and reduced overall survival. Together, these data indicate that R198/R200 methylation of the EGFR plays an important role in regulating EGFR functionality and resistance to cetuximab treatment.


Surgical adjuvant therapy of large-bowel carcinoma: an evaluation of levamisole and the combination of levamisole and fluorouracil. The North Central Cancer Treatment Group and the Mayo Clinic.
A total of 401 eligible patients with resected stages B and C colorectal carcinoma were randomly assigned to no-further therapy or to adjuvant treatment with either levamisole alone, 150 mg/d for 3 days every 2 weeks for 1 year, or levamisole plus fluorouracil (5-FU), 450 mg/m2/d intravenously (IV) for 5 days and beginning at 28 days, 450 mg/m2 weekly for 1 year. Levamisole plus 5-FU, and to a lesser extent levamisole alone, reduced cancer recurrence in comparison with no adjuvant therapy. These differences, after correction for imbalances in prognostic variables, were only suggestive for levamisole alone (P = .05) but quite significant for levamisole plus 5-FU (P = .003). Whereas both treatment regimens were associated with overall improvements in survival, these improvements reached borderline significance only for stage C patients treated with levamisole plus 5-FU (P = .03). Therapy was clinically tolerable with either regimen and severe toxicity was uncommon. These promising results have led to a large national intergroup confirmatory trial currently in progress.


Comprehensive Evaluation of Virulence and Resistance Data: A New Analysis Tool.
The functioning and features of the new software package VAT (Virulence Analysis Tool) are introduced. VAT provides a range of methods for the analysis of plant pathosystems. The techniques are applicable to other binary data sets that are organized in large two-way tables, e.g., molecular marker data. The main features are data entry, descriptive tools, and inference statistics by resampling. About 50 well-established or newly developed indices allow a detailed diversity analysis of sexually and asexually reproducing populations. VAT facilitates a comprehensive, effective, and logically consistent evaluation and presentation of virulence and resistance data. A translation option simplifies the comparison of results from differently coded pathotypes. The software package comes with a detailed manual and is freely available on the internet at tau.ac.il/lifesci/departments/plant_s/members/kosman/VAT.html and at va-tipp.de .


Origin of sex for error repair. II. Rarity and extreme environments.
In a previous paper we studied the simultaneous, and at times conflicting, needs of coping with DNA damage, efficient cell replication, and the avoidance of cell mortality. These selective factors operated on sexual and asexual haploid and diploid populations that were reproductively isolated from one another. We concluded, in part, that a sexual type of cell could not expand from extreme rarity in populations dominated by asexual haploid and diploid cells. In the present paper we show that it is relatively easy for a rare sexual mutant to expand in a population dominated by asexual haploid cells if some matings occur between sexual and asexual cell types. We also study the persistence of sex in high mortality, high damage environments, in which neither the asexual diploid nor haploid can survive. The diploid cannot survive because its lower birth rate cannot overcome mortality and the haploid cannot survive because its birth rate cannot overcome gene damage. Sex can persist in these punishing environments by tuning the parameters of the sexual cycle, and the fusion and splitting rates, into a specified region, thereby reaping both benefits of damage repair and efficient replication.


Identification of sites of STAT3 action in the female reproductive tract through conditional gene deletion.
The STAT3 transcription factor is a pleiotropic transducer of signalling by hormones, growth factors and cytokines that has been identified in the female reproductive tract from oocytes and granulosa cells of the ovary to uterine epithelial and stromal cells. In the present study we used transgenic models to investigate the importance of STAT3 for reproductive performance in these different tissues. The Cre-LoxP system was used to delete STAT3 in oocytes by crossing Stat3fl/fl with Zp3-cre+ mice, or in ovarian granulosa cells and uterine stroma by crossing with Amhr2-Cre+ mice. Surprisingly, deletion of STAT3 in oocytes had no effect on fertility indicating that the abundance of STAT3 protein in maturing oocytes and fertilized zygotes is not essential to these developmental stages. In Stat3fl/fl;Amhr2-cre+ females impaired fertility was observed through significantly fewer litters and smaller litter size. Ovulation rate, oocyte fertilization and development to blastocyst were unaffected in this line; however, poor recombination efficiency in granulosa cells had yielded no net change in STAT3 protein abundance. In contrast, uteri from these mice showed STAT3 protein depletion selectively from the stomal compartment. A significant reduction in number of viable fetuses on gestational day 18, increased fetal resorptions and disrupted placental morphology were evident causes of the reduced fertility. In conclusion, this study defines an important role for STAT3 in uterine stromal cells during embryo implantation and the development of a functional placenta.


Design of multi-binding-site inhibitors, ligand efficiency, and consensus screening of avian influenza H5N1 wild-type neuraminidase and of the oseltamivir-resistant H274Y variant.
The binding sites of wild-type avian influenza A H5N1 neuraminidase, as well as those of the Tamiflu (oseltamivir)-resistant H274Y variant, were explored computationally to design inhibitors that target simultaneously several adjacent binding sites of the open conformation of the virus protein. The compounds with the best computed free energies of binding, in agreement by two docking methods, consensus scoring, and ligand efficiency values, suggest that mimicking a polysaccharide, beta-lactam, and other structures, including known drugs, could be routes for multibinding site inhibitor design. This new virtual screening method based on consensus scoring and ligand efficiency indices is introduced, which allows the combination of pharmacodynamic and pharmacokinetic properties into unique measures.


On π-stacking, C-H/π, and halogen bonding interactions in halobenzene clusters: resonant two-photon ionization studies of chlorobenzene.
Noncovalent interactions such as hydrogen bonding, π-π stacking, CH/π interactions, and halogen bonding play crucial roles in a broad spectrum of chemical and biochemical processes, and can exist in cooperation or competition. Here we report studies of the homoclusters of chlorobenzene, a prototypical system where π-π stacking, CH/π interactions, and halogen bonding interactions may all be present. The electronic spectra of chlorobenzene monomer and clusters (Clbz)(n) with n = 1-4 were obtained using resonant 2-photon ionization in the origin region of the S(0)-S(1) (ππ*) state of the monomer. The cluster spectra show in all cases a broad spectrum whose center is redshifted from the monomer absorption. Electronic structure calculations aid in showing that the spectral broadening arises in large part from inhomogeneous sources, including the presence of multiple isomers and Franck-Condon (FC) activity associated with geometrical changes induced by electronic excitation. Calculations at the M06-2x/aug-cc-pVDZ level find in total five minimum energy structures for the dimer, four π-stacked structures, and one T-shaped, and six representative minimum energy structures were found for the trimer. The calculated time-dependent density functional theory spectra using range-separated and meta-GGA hybrid functionals show that these isomers absorb over a range that is roughly consistent with the breadth of the experimental spectra, and the calculated absorptions are redshifted with respect to the monomer transition, in agreement with experiment. Due to the significant geometry change in the electronic transition, where for the dimer a transition from a parallel displaced to sandwich structure occurs with a reduced separation of the two monomers, significant FC activity is predicted in low frequency intermolecular modes.


Treatment of hyperesthetic neuropathic pain in diabetics. Decompression of the tarsal tunnel.
The authors evaluated the causal relationship between entrapment of the posterior tibial nerve and neuropathic pain and describe the results of nerve decompression in a selected group of patients with intractable pain. Painful metabolic neuropathy has, until recently, been thought to be an irreversible and essentially untreatable complication of diabetes. Recent studies have shown that metabolic deterioration is only one component of the disease process. A group of patients with intractable painful neuropathy and a positive percussion sign underwent posterior tibial nerve decompression. Nerve decompression relieved the pain in the majority of treated patients. Return of other sensory function also was noted. Painful diabetic neuropathy of the lower extremities is potentially reversible. It appears to be caused partially by nerve entrapment and can be reversed by decompression.


The impact of sedation on brain mapping: a prospective, interdisciplinary, clinical trial.
During awake craniotomies, patients may either be awake for the entire duration of the surgical intervention (awake-awake-awake craniotomy, AAA) or initially sedated (asleep-awake-asleep craniotomy, SAS). To examine whether prior sedation in SAS may restrict brain mapping, we conducted neuropsychological tests in patients by means of a standardized anesthetic regimen comparable to an SAS. We prospectively examined patients undergoing surgery either under total intravenous anesthesia (TIVA) or under regional anesthesia with slight sedation (RAS). The tests included the DO40 picture-naming test, the digit span, the Regensburg Word Fluency Test, and the finger-tapping test. Each test was conducted 3 times for every patient in the TIVA and RAS groups, once before surgery and twice within about 35 minutes after the end of sedation. Patients undergoing AAA were examined preoperatively and intraoperatively. In the AAA group, no significant difference was found between preoperative and intraoperative test results. In the TIVA and RAS groups, postoperative tests showed worse results than preoperative tests. In most tests, patients improved from the first to the second postoperative test. Cognitive and motor performance were significantly influenced by prior sedation in the TIVA and RAS groups, but not in the AAA group. Therefore, prior sedation may be assumed to cause a change in the baselines, which may compromise brain mapping and thus endanger a patient's neurological outcome in the case of an SAS.


Developmental and hormonal regulation of the monocarboxylate transporter 2 (MCT2) expression in the mouse germ cells.
During spermatogenesis, postmeiotic germ cells utilize lactate produced by Sertoli cells as an energy metabolite. While the hormonal regulation of lactate production in Sertoli cells has been relatively well established, the transport of this energy substrate to the germ cells, particularly via the monocarboxylate transporters (MCTs), as well as the potential endocrine control of such a process remain to be characterized. Here, we report the developmentally and hormonally regulated expression of MCT2 in the testis. At Day 18, MCT2 starts to be expressed in germ cells as detected by Northern blot. The mRNA are translated into protein (40 kDa) in elongating spermatids. Ultrastructural analysis demonstrated that MCT2 protein is localized to the outer face of the cell membrane of spermatid tails. MCT2 mRNA levels are under the control of the endocrine, specifically follicle-stimulating hormone (FSH) and testosterone, and paracrine systems. Indeed, a 35-day-old rat hypophysectomy resulted in an 8-fold increase in testicular MCT2 mRNA levels. Conversely, FSH and LH administration to the hypophysectomized rats reduced MCT2 mRNA levels to the basal levels observed in intact animals. The decrease in MCT2 mRNA levels was confirmed in vitro using isolated seminiferous tubules incubated with FSH or testosterone. FSH or testosterone inhibited in a dose-dependent manner MCT2 mRNA levels with maximal inhibitory doses of 2.2 ng/ml and 55.5 ng/ml for FSH and testosterone, respectively. In addition to the endocrine control, TNFalpha and TGFbeta also exerted an inhibitory effect on MCT2 mRNA levels with a maximal effect at 10 ng/ml and 6.6 ng/ml for TGFbeta and TNFalpha, respectively. Together with previous studies, the present data reinforce the concept that among the key functions of the endocrine/paracrine systems in the testis is the control of the energy metabolism occurring in the context of Sertoli cell-germ cell metabolic cooperation where lactate is produced in somatic cells and transported to germ cells via, at least, MCT2.


Invasive fungal infections secondary to acute-on-chronic liver failure: a retrospective study.
Although the consequences of invasive fungal infections (IFIs) secondary to chronic hepatitis B infections secondary IFIs are serious, the incidence and main pathogenic factors of IFIs in acute-on-chronic liver failure (ACLF) patients remain unclear. This study included 1200 hepatitis B patients who were treated in the Department of Infectious Diseases, Shanghai Changzheng Hospital from January 2006 to January 2009. Patients with ACLF were screened according to the diagnostic guidelines for liver failure. Patients with ACLF and secondary IFI were the disease group, and patients with ACLF without secondary IFI were the controls. The incidence of IFI, mortality, and possible IFI causes in two groups were evaluated retrospectively. Sixty patients with ACLF had secondary IFI, of which 14 were confirmed cases and 46 were suspected cases. The incidence of IFI was 47.62% for ACLF patients. Logistic regression analysis showed that the level of hepatitis B viral (HBV) DNA was an important risk factor for secondary IFI in ACLF patients. Receiver operating characteristic curve analysis suggested that when the number of HBV DNA copies was higher than 3.16 × 10(3) copies ml(-1) , the possibility of secondary IFI in ACLF patients increased significantly, while white blood cell levels showed protective effects for these patients. The incidence of IFI is high in ACLF patients and high hepatitis B virus DNA levels may be an independent risk factor of secondary IFI in these patients.


Decoding movement trajectories through a T-maze using point process filters applied to place field data from rat hippocampal region CA1.
Firing activity from neural ensembles in rat hippocampus has been previously used to determine an animal's position in an open environment and separately to predict future behavioral decisions. However, a unified statistical procedure to combine information about position and behavior in environments with complex topological features from ensemble hippocampal activity has yet to be described. Here we present a two-stage computational framework that uses point process filters to simultaneously estimate the animal's location and predict future behavior from ensemble neural spiking activity. First, in the encoding stage, we linearized a two-dimensional T-maze, and used spline-based generalized linear models to characterize the place-field structure of different neurons. All of these neurons displayed highly specific position-dependent firing, which frequently had several peaks at multiple locations along the maze. When the rat was at the stem of the T-maze, the firing activity of several of these neurons also varied significantly as a function of the direction it would turn at the decision point, as detected by ANOVA. Second, in the decoding stage, we developed a state-space model for the animal's movement along a T-maze and used point process filters to accurately reconstruct both the location of the animal and the probability of the next decision. The filter yielded exact full posterior densities that were highly nongaussian and often multimodal. Our computational framework provides a reliable approach for characterizing and extracting information from ensembles of neurons with spatially specific context or task-dependent firing activity.