The Paxillus involutus (Boletales, Paxillaceae) complex in Europe: genetic diversity and morphological description of the new species Paxillus cuprinus, typification of P. involutus s.s., and synthesis of species boundaries.
Paxillus involutus is a model species for ecological or physiological studies of ectomycorrhizal agaricomycetes. Three to six groups or species linked to it have been ecologically and morphologically distinguished. Phylogenetic studies have revealed the existence of four species in Europe: Paxillus ammoniavirescens, Paxillus obscurisporus, P. involutus, and a fourth as yet not described species. We studied 47 collections from 24 French and Italian locations, supplemented with GenBank data, in order to genetically and taxonomically delineate these species. Phylogenetic analyses of three nuclear DNA regions (rDNA internal transcribed spacer (ITS), tef1-α, and gpd) confirmed the four European species. Morphology, culture, and ecology features allowed us to delineate species boundaries and to describe the fourth species we named Paxillus cuprinus since it turns coppery with age. As there is no existing original herbarium specimen for P. involutus, one of our collections was chosen as the epitype. The low genetic diversity found in P. cuprinus correlates with stable morphological traits (basidiome colour, ovoid-amygdaliform spores with an apical constriction) and with ecological preferences (association with Betulaceae in open and temperate areas). In contrast, P. ammoniavirescens is characterized by a high genetic diversity and a high variation of its morphological and ecological features.


A multi-sectorial committee in directing HIV/AIDS-specific interventions in the occupational setting: an example from South Africa.
We present a descriptive analysis of a mechanism to coordinate and implement human immunodeficiency virus (HIV) prevention and care in the occupational setting. The mechanism we describe is a multidisciplinary committee composed of stakeholders in the occupational health environment including unions, management, medical researchers, and medical personnel. The site chosen for the analysis was a South African sugar mill in rural KwaZulu-Natal. The factory is situated in an area of high HIV seroprevalence and has a workforce of 400 employees. The committee was initiated to coordinate a combined prevention-care initiative. The issues that were important in the formation of the committee included confidentiality, trust, and the traditional roles of the stakeholder relationships. When these points were addressed through the focus on a common goal, the committee was able to function in its role as a coordinating body. Central to this success was the inclusion of all stakeholders in the process, including those with traditionally opposing interests and legitimacy conferred by the stakeholders. This committee was functionally effective and demonstrated the benefit of a freestanding committee dedicated to addressing HIV/acquired immune deficiency syndrome (AIDS) issues. We describe the implementation and feasibility of a multisectoral committee in directing HIV/AIDS initiatives in the occupational setting in rural South Africa.


Clinical testing of omnipaque and amipaque in external carotid and vertebral angiography: randomized double-blind crossover study.
Omnipaque, 300 mg l/ml, was compared with Amipaque, 300 mg l/ml, for cerebral angiography. Twelve patients were included in a randomized, double-blind, crossover study. Twenty comparisons were made in the external carotid and 21 in the vertebral artery, Both contrast media caused no or minor changes in blood pressure and heart rate. Good to excellent radiographic visualization of the cerebral arteries was obtained with both agents. The frequency of subjective reactions was almost equal, but the intensity of the reactions was less with Amipaque. No severe reactions were observed. Omnipaque is a more practical nonionic contrast medium than Amipaque because it is delivered in ready-to-use solutions.


RE-PERG, a new paradigm for glaucoma diagnosis, in myopic eyes.
To evaluate reliability of steady-state pattern electroretinogram (ssPERG) phase variability in re-test (procedure called RE-PERG) in the presence of myopia, which is known to affect ssPERG amplitude, in glaucomatous patients (GP), normal controls (NC), and myopic patients (MY). The procedure was performed on 50 GP, 35 NC, and 19 MY. All subjects were examined with RE-PERG, spectral-domain coherence tomography (SD-OCT), and standard automated perimetry (SAP). Standard deviation of phase (ssPERG SDph) and mean amplitude value (ssPERG Amp) of second harmonic (2ndH) were correlated, by means of one-way ANOVA and Pearson correlation, with mean deviation (MD) and pattern standard deviation (PSD) assessed by SAP and retinal nerve fiber layer (RNFL) and ganglion cell complex (GCC) thickness assessed by SD-OCT. Receiving operating characteristics were calculated in cohort populations with and without myopia. GP showed significant differences from the control group for MD, PSD, RNFL, GCC, ssPERG Amp, and ssPERG SDph; GP also showed significant differences from the MY group for all the parameters except for ssPERG Amp, which is reduced in both groups. In GP group, ssPERG Amp showed a specificity of 82.1% (95% confidence interval [CI]I: 66.5-92.5). In MY group, ssPERG Amp was reduced in 58% of the patients. As a consequence of this, in GP and MY groups, considered as a whole, total specificity dropped to 70.69% (95% CI: 57.3-81.9). In the GP group, ssPERG SDph showed a specificity of 84.6% (95% CI: 69.5-91.1). In both GP and MY groups, considered as a whole, ssPERG SDph total specificity increased from 84.6% to 93.1% (95% CI: 83.3-98.1). Intrinsic phase variability of ssPERG is not influenced by myopia, even in the presence of fundus alterations.


Expression of ICAM-1, TNF-alpha, NF kappa B, and MAP kinase in tubers of the tuberous sclerosis complex.
Individuals affected with tuberous sclerosis complex (TSC) develop cortical tubers characterized by disorganized cytoarchitecture and morphologically abnormal cell types, such as dysplastic neurons (DNs) and giant cells (GCs). As part of ongoing cDNA array analysis to study the molecular pathogenesis of tuber formation, we detected increased expression of intercellular adhesion molecule-1 (ICAM-1) mRNA, a cell adhesion molecule (CAM) that functions in cytokine signaling, in tubers. Western and immunohistochemical analyses revealed that ICAM-1 protein was selectively expressed in tubers, but was only minimally expressed in control cortex, adjacent nontuberal cortex, or in non-TSC focal cortical dysplasia. Increased expression of ICAM-1 was found in mice in which the Tsc1 gene was conditionally inactivated in astrocytes. Expression of molecules involved in ICAM-1 activation and cytokine signaling were increased in tubers, including tumor necrosis factor alpha (TNF-alpha), mitogen activated protein kinase (MAPK), and nuclear factor kappa B (NF-kappaB). Numerous CD68-immunoreactive macrophages were observed clustered around GCs further supporting an inflammatory response in tubers. Expression of caspase 8 and Fas support cytokine activation and detection of TUNEL reactivity suggests ongoing cell death in tubers. Specific alterations in ICAM-1, TNF-alpha, NF-kappaB1, and MAPK expression coupled with the detection of numerous CD68-immunoreactive macrophages suggests activation of proinflammatory cytokine signaling pathways in tubers that may culminate in cell death.


Multiparametric characterization of grade 2 glioma subtypes using magnetic resonance spectroscopic, perfusion, and diffusion imaging.
The purpose of this study was to derive quantitative parameters from magnetic resonance (MR) spectroscopic, perfusion, and diffusion imaging of grade 2 gliomas according to the World Health Organization and to investigate how these multiple imaging modalities can contribute to evaluating their histologic subtypes and spatial characteristics. MR spectroscopic, perfusion, and diffusion images from 56 patients with newly diagnosed grade 2 glioma (24 oligodendrogliomas, 18 astrocytomas, and 14 oligoastrocytomas) were retrospectively studied. Metabolite intensities, relative cerebral blood volume (rCBV), and apparent diffusion coefficient (ADC) were statistically evaluated. The 75th percentile rCBV and median ADC were significantly different between oligodendrogliomas and astrocytomas (P < .0001) and between oligodendrogliomas and oligoastrocytomas (P < .001). Logistic regression analysis identified both 75th percentile rCBV and median ADC as significant variables in the differentiation of oligodendrogliomas from astrocytomas and oligoastrocytomas. Group differences in metabolite intensities were not significant, but there was a much larger variation in the volumes and maximum values of metabolic abnormalities for patients with oligodendroglioma compared with the other tumor subtypes. Perfusion and diffusion imaging provide quantitative MR parameters that can help to differentiate grade 2 oligodendrogliomas from grade 2 astrocytomas and oligoastrocytomas. The large variations in the magnitude and spatial extent of the metabolic lesions between patients and the fact that their values are not correlated with the other imaging parameters indicate that MR spectroscopic imaging may provide complementary information that is helpful in targeting therapy, evaluating residual disease, and assessing response to therapy.


Superior Detection of Faces in Male Infants at 2 Months.
Females generally attend more to social information than males; however, little is known about the early development of these sex differences. With eye tracking, 2-month olds' (N = 101; 44 females) social orienting to faces was measured within four-item image arrays. Infants were more likely to detect human faces compared to objects, suggesting a functional face detection system. Unexpectedly, males looked longer at human faces than females, and only males looked faster and longer at human faces compared to objects. Females, in contrast, looked less at human faces relative to animal faces and objects, appearing socially disinterested. Notably, this is the first report of a male face detection advantage at any age. These findings suggest a unique stage in early infant social development.


Development and validation of a 6-day standard for the identification of frequent mental distress.
The goals of the current study were to assess the concurrent validity of a single-item measure of general mental distress with established, multi-item mental health measures used in population-level surveillance and to establish the optimal cutpoint for determining psychological distress (previously identified as frequent mental distress) using recently available data from the Behavioral Risk Factor Surveillance System survey. Data for this study were obtained from the core questionnaire and two optional modules available as part of the 2006 and 2007 Behavioral Risk Factor Surveillance System (BRFSS) surveys. Frequent mental distress (FMD) was identified by the number of days of self-reported poor mental health during the last 30 days. Comparisons of the number of days with poor mental health and positive scores for measures of depression and serious mental illness were calculated to identify the most efficient cutpoint for establishing FMD. Comparisons of results obtained from ROC analyses using the PHQ-8 and K6 reported 0.867 (95% CI 0.861-0.872) and 0.840 (95% CI 0.836-0.845) of the area under the curve, respectively, suggesting good accuracy. Using the Youden index, 6 days of poor mental health in the past 30 days, rather than the existing 14-day standard, was identified as the point at which the sum of the sensitivity and specificity was greatest. Results from this study suggest that a 6-day standard (FMD-6) can be used as a valid and reliable indicator of generalized mental distress with strong associations to both diagnosable depressive symptomology and serious mental illness.


Health education and communication in Occupational Health Services in Finland.
This article discusses health education and communication in Occupational Health Services (OHS) based on a questionnaire study conducted in Finnish OHS in 2005. The study focused on educational activities carried out by OH professionals and directed at individual employees, work communities and groups, and representatives of client organisations. The questionnaire was sent to 1132 OH professionals--physicians, nurses, physiotherapists and psychologists--working in 130 OHS units, and representing different OHS providers in Finland. 635 respondents (162 physicians, 342 nurses, 96 physiotherapists, 35 psychologists) returned the questionnaire. The overall response rate was 58%. There were statistically significant differences in educational activities by different professional groups; differences were also related to the length of working experience in OHS. For all OH professionals, individual employees were the primary clients of health education and communication. Education was less often directed at work communities and representatives of client organisations. However, many issues related to health and well-being at work are not within the reach of individual employees. The impact of health education would be more evident if it also reached those organisational stakeholders with discretion in decision-making. Furthermore, OH personnel should pay attention to the social aspect of learning and work more with groups and work communities.


Homophilic anchorage of brain-hexokinase to mitochondria-porins revealed by specific-peptide antibody cross recognition.
In brain tumors the main source of energy is from glycolysis, which is initiated by hexokinase 1 (HK1), an enzyme bound to the mitochondrial porin. Disruption of HK binding greatly affects tumor cell survival. Little is known about the acceptor site of HK1. Therefore, a polyclonal antibody (Pab) directed to MIAAQLLAYYFTELK (MK) peptide, corresponding to the 15-amino acids of the N-terminal sequence of brain HK1 was obtained. Anti MK antibody (aMK-Pab)bound specifically to HK as shown by ELISA. The aMK-Pab binding to MK peptide was antibody-concentration dependent and was completely abolished by its preincubation with the peptide at 6 x 10-8 M. The aMK-Pab recognized cytosolic HK (cHK) and HK solubilized (sHK)from rat-brain mitochondrial preparations, but not the yeast HK which does not have the MK sequence. An anti-brain HK Pab (aHK-Pab) directed to purified HK recognized the MK peptide; aHK-Pab bound to MK and this binding was inhibited by preincubation of the antibody with the MK peptide. It was previously demonstrated that brain HK anchors to mitochondria porins, also designated as voltage dependent-anion channels (VDAC) via the MK sequence. A specific anti-VDAC antibody (aVDAC-Pab) which specifically bound the N and C-terminal sequences of VDACwas found to bind to c-HK, sHK and MK-coated wells and this binding was abolished by aVDACPabpreincubation with MK peptide. These data suggest that the three Pabs cross-react with an epitope present in HK and VDAC, and which was presented in the MK peptide. Comparison of alignment of HK or VDAC sequences, available in the protein data bank (PDB), did not allow putative homologues responsible for the cross-reaction to be identified, suggesting that the epitope is conformational. This, added to inhibition of mitochondria-isolated HK binding by the MK peptide,suggests that there is an homophilic-type interaction between HK and porin, through a peptidic structure represented at least in part in the MK peptide.


A Bayesian network classification methodology for gene expression data.
We present new techniques for the application of a Bayesian network learning framework to the problem of classifying gene expression data. The focus on classification permits us to develop techniques that address in several ways the complexities of learning Bayesian nets. Our classification model reduces the Bayesian network learning problem to the problem of learning multiple subnetworks, each consisting of a class label node and its set of parent genes. We argue that this classification model is more appropriate for the gene expression domain than are other structurally similar Bayesian network classification models, such as Naive Bayes and Tree Augmented Naive Bayes (TAN), because our model is consistent with prior domain experience suggesting that a relatively small number of genes, taken in different combinations, is required to predict most clinical classes of interest. Within this framework, we consider two different approaches to identifying parent sets which are supported by the gene expression observations and any other currently available evidence. One approach employs a simple greedy algorithm to search the universe of all genes; the second approach develops and applies a gene selection algorithm whose results are incorporated as a prior to enable an exhaustive search for parent sets over a restricted universe of genes. Two other significant contributions are the construction of classifiers from multiple, competing Bayesian network hypotheses and algorithmic methods for normalizing and binning gene expression data in the absence of prior expert knowledge. Our classifiers are developed under a cross validation regimen and then validated on corresponding out-of-sample test sets. The classifiers attain a classification rate in excess of 90% on out-of-sample test sets for two publicly available datasets. We present an extensive compilation of results reported in the literature for other classification methods run against these same two datasets. Our results are comparable to, or better than, any we have found reported for these two sets, when a train-test protocol as stringent as ours is followed.


Compression in Working Memory and Its Relationship With Fluid Intelligence.
Working memory has been shown to be strongly related to fluid intelligence; however, our goal is to shed further light on the process of information compression in working memory as a determining factor of fluid intelligence. Our main hypothesis was that compression in working memory is an excellent indicator for studying the relationship between working-memory capacity and fluid intelligence because both depend on the optimization of storage capacity. Compressibility of memoranda was estimated using an algorithmic complexity metric. The results showed that compressibility can be used to predict working-memory performance and that fluid intelligence is well predicted by the ability to compress information. We conclude that the ability to compress information in working memory is the reason why both manipulation and retention of information are linked to intelligence. This result offers a new concept of intelligence based on the idea that compression and intelligence are equivalent problems.


Correlates of caring for the drinkers and others among those harmed by another's drinking.
This study identifies the correlates of caring for harmful drinkers and others, and examines how caring for that person impacts on respondents' well-being and use of services. The study utilises the data from the 2008 Australian Alcohol Harm to Others Survey (n = 2649), in which 778 respondents reported they were harmed because of the drinking of someone they knew. Respondents were asked about the person they were most adversely affected by and whether they spent time caring for this person because of their drinking. Logistic regression models are developed to examine which factors were associated with the prevalence of caring for others. The study reveals that the respondents who cared for others because of the other's drinking reported lower quality of life than the respondents who did not have to do this. The results of the logistic regression suggest that respondents were more likely to care for the drinker if the drinker drank more (as the usual quantity of alcohol consumed increased), but less likely to care for the drinker if the drinker drank five or more drinks on more than four days per week. The findings of the study suggest that the drinking of family and friends can be a substantial burden for their households, families, friends and others. Policy approaches that reduce the amount of heavy drinking, particularly heavy drinking in a single occasion, are likely to reduce the burden of caring for others because of other's drinking.


Investigation and management of hypercalcaemia in children.
Hypercalcaemia is a far less common finding in children than in adults. It may present with characteristic symptoms or may be identified as a coincidental finding in children investigated for a variety of complaints. Assessment of hypercalcaemia requires an understanding of the normal physiological regulation of plasma calcium by the combined actions of parathyroid hormone, 1,25-dihydroxyvitamin D(3) and the calcium sensing receptor. Hypercalcaemia will usually require treatment using a number of different modalities but occasionally it can be due to a benign asymptomatic condition that requires no intervention. This article presents a logical approach to the investigation and subsequent management of this condition.


Increased computational accuracy in multi-compartmental cable models by a novel approach for precise point process localization.
Compartmental models of dendrites are the most widely used tool for investigating their electrical behaviour. Traditional models assign a single potential to a compartment. This potential is associated with the membrane potential at the centre of the segment represented by the compartment. All input to that segment, independent of its location on the segment, is assumed to act at the centre of the segment with the potential of the compartment. By contrast, the compartmental model introduced in this article assigns a potential to each end of a segment, and takes into account the location of input to a segment on the model solution by partitioning the effect of this input between the axial currents at the proximal and distal boundaries of segments. For a given neuron, the new and traditional approaches to compartmental modelling use the same number of locations at which the membrane potential is to be determined, and lead to ordinary differential equations that are structurally identical. However, the solution achieved by the new approach gives an order of magnitude better accuracy and precision than that achieved by the latter in the presence of point process input.


Integrated multi-omics single cell atlas of the human retina.
Single-cell sequencing has revolutionized the scale and resolution of molecular profiling of tissues and organs. Here, we present an integrated multimodal reference atlas of the most accessible portion of the mammalian central nervous system, the retina. We compiled around 2.4 million cells from 55 donors, including 1.4 million unpublished data points, to create a comprehensive human retina cell atlas (HRCA) of transcriptome and chromatin accessibility, unveiling over 110 types. Engaging the retina community, we annotated each cluster, refined the Cell Ontology for the retina, identified distinct marker genes, and characterized cis-regulatory elements and gene regulatory networks (GRNs) for these cell types. Our analysis uncovered intriguing differences in transcriptome, chromatin, and GRNs across cell types. In addition, we modeled changes in gene expression and chromatin openness across gender and age. This integrated atlas also enabled the fine-mapping of GWAS and eQTL variants. Accessible through interactive browsers, this multimodal cross-donor and cross-lab HRCA, can facilitate a better understanding of retinal function and pathology.


Secular and socio-economic trends in compliance with dietary targets in the north Glasgow MONICA population surveys 1986-1995: did social gradients widen?
To compare trends in the consumption of key foods over 10 years in the most deprived and least deprived quarters in north Glasgow, Scotland as defined by the Carstairs deprivation index for their postcode of domicile. Four random, cross-sectional, age- and gender-stratified population surveys carried out in 1986, 1989, 1992 and 1995. After assigning a deprivation score, food-frequency questionnaires from 2883 men and 3127 women were examined for compliance with dietary targets, examining trends by gender and within the most and least deprived quarters of the population. North Glasgow, Scotland. Over 600 men and 600 women (aged 25-64 years) in each of the four survey years who completed a lifestyle questionnaire including a food frequency section. Increasing trends in the reported consumption of fruit and vegetables and oil-rich fish were observed over the 10-year period. However, the trend to increased fruit and vegetable consumption in the most deprived groups was not significant, and in 1995 only 8% of men and 12% of women in this group claimed consumption of these foods 4 or more times a day. In general, a higher percentage of those in the least deprived group met the targets for the key foods. Trends to increasing consumption of fruit and vegetables and fish were in the right direction, but the targets for consumption of certain key foods were met by a minority of the population. The progress towards the target for fruit and vegetables showed widening social gradients with time.


A pilot randomized controlled trial evaluating a web-based training program on pediatric medical traumatic stress and trauma-informed care for emergency department staff.
This pilot parallel group superiority randomized controlled trial investigated the efficacy and acceptability of a web-based training program on pediatric medical traumatic stress and trauma-informed care (Australian and New Zealand Clinical Trials Registry number: ACTRN12617001148369). Eligibility criteria for this study included being a nurse or physician working in an ED in Australia or New Zealand, being fluent in English and having Internet access. Emergency department (ED) staff (N = 71) were randomly assigned into the training (n = 32) or control group n = 39). We hypothesized that compared to the control group, ED staff in the training group would show a greater improvement in knowledge of pediatric medical traumatic stress 1-week post training and that improvement would be maintained at 1-month post training. At baseline participants completed a brief questionnaire assessing knowledge of pediatric medical traumatic stress. The training group then completed the 15-min online training program. The knowledge questionnaire was readministered to all participants' 1 week and 1 month posttraining, after which the control group gained access to the training. Acceptability was based on a program evaluation measure utilizing quantitative and qualitative items. The training group had significantly greater knowledge following training and at follow-up than the control group (p > .001, f = .42) and reported high rates of satisfaction. The results demonstrated an improvement in ED staff knowledge as a result of the training and provide preliminary support for the efficacy and acceptability of brief online training to improve the knowledge of ED staff interested in pediatric medical traumatic stress and trauma-informed care. (PsycINFO Database Record (c) 2019 APA, all rights reserved).


The type of injury dictates the mode of repair in neonatal and adult heart.
The neonatal heart possesses the unique power to regenerate in response to resection of the left ventricular apex. We sought to determine whether the type of injury affects the mode of repair and regeneration. Apical resection, or permanent left anterior descending coronary artery ligation, was induced in neonatal 1-day-old mice. Echocardiography was used to confirm and monitor cardiac injury and remodeling. Histological and immunohistochemical examinations of the resected and infarcted neonatal hearts revealed inflammation and granulation tissue formation. From day 3, early regeneration was identified at the injured sites and was characterized by dedifferentiation and proliferation of cardiomyocytes around the injured areas. The young cardiomyocytes infiltrated the granulation tissue and replaced it with a new myocardium. The ability of neonatal cardiomyocytes to proliferate was confirmed in neonatal heart organ cultures. Notably, myocardial infarction in neonatal mouse produced incomplete regeneration with a residual small infarct and, sometimes, aneurysm at 28 days after myocardial infarction. We then repeated the same experiments in the adult heart. Remarkably, myocardial infarction in the adult mouse heart produced a typical thin scar, whereas apical resection revealed an abnormal, epicardial, hemorrhagic scar 21 days after injury. Our findings suggest that the type of injury, resection, or infarction affects the mode of repair in both neonatal and adult mouse hearts. Identifying the differences in the mechanisms or repair of these 2 types of injuries could help to develop novel regenerative therapies relevant to human patients.


Natural history of primary progressive multiple sclerosis.
The relationship of primary progressive multiple sclerosis (PPMS) to relapsing-remitting MS (RRMS) and secondary progressive MS (SPMS) remains unclear. Natural history data from a population-based cohort of patients with PPMS followed for approximately 25 years demonstrate remarkable similarities in the progressive phases of PPMS and SPMS. Immunogenetic and magnetic resonance imaging studies in large numbers of patients also fail to differentiate between the two MS categories. PPMS thus resembles SPMS without the relapses, although the two forms do differ with respect to sex ratio. An unfavourable outcome in PPMS in predicted by rapid early progression of disability and involvement of three or more systems. Natural history studies provide information on likely long-term outcomes and can be used in the design and interpretation of clinical trials in PPMS. The evidence that PPMS is distinct remains weak.


A preliminary study of airborne microbial biodiversity over Peninsular Antarctica.
This study used PCR-based molecular biological identification techniques to examine the biodiversity of air sampled over Rothera Point (Antarctic Peninsula). 16S rDNA fragments of 132 clones were sequenced and identified to reveal a range of microorganisms, including cyanobacteria, actinomycetes, diatom plastids and other uncultivated bacterial groups. Matches for microorganisms that would be considered evidence of human contamination were not found. The closest matches for many of the sequences were from Antarctic clones already in the databases or from other cold environments. Whilst the majority of the sequences are likely to be of local origin, back trajectory calculations showed that the sampled air may have travelled over the Antarctic Peninsula immediately prior to reaching the sample site. As a result, a proportion of the detected biota may be of non-local origin. Conventional identification methods based on propagule morphology or culture are often inadequate due to poor preservation of characteristic features or loss of viability during airbome transfer. The application of molecular biological techniques in describing airbome microbial biodiversity represents a major step forward in the study of airborne biota over Antarctica and in the distribution of microorganisms and propagules in the natural environment.


Piezo1: properties of a cation selective mechanical channel.
Piezo ion channels have been found to be essential for mechanical responses in cells. These channels were first shown to exist in Neuro2A cells, and the gene was identified by siRNAs that diminished the mechanical response. Piezo channels are approximately 2500 amino acids long, have between 24-32 transmembrane regions, and appear to assemble into tetramers and require no other proteins for activity. They have a reversal potential around 0 mV and show voltage dependent inactivation. The channel is constitutively active in liposomes, indicating that no cytoskeletal elements are required. Heterologous expression of the Piezo protein can create mechanical sensitivity in otherwise insensitive cells. Piezo1 currents in outside-out patches were blocked by the extracellular MSC inhibitor peptide GsMTx4. Both enantiomeric forms of GsMTx4 inhibited channel activity in a manner similar to endogenous mechanical channels. Piezo1 can adopt a tonic (non-inactivating) form with repeated stimulation. The transition to the non-inactivating form generally occurs in large groups of channels, indicating that the channels exist in domains, and once the domain is compromised, the members simultaneously adopt new properties. Piezo proteins are associated with physiological responses in cells, such as the reaction to noxious stimulus of Drosophila larvae. Recent work measuring cell crowding, shows that Piezo1 is essential for the removal of extra cells without apoptosis. Piezo1 mutations have also been linked to the pathological response of red blood cells in a genetic disease called Xerocytosis. These finding suggest that Piezo1 is a key player in cells' responses to mechanical stimuli.


What are the effects of proton pump inhibitors on the small intestine?
Generally, proton-pump inhibitors (PPIs) have great benefit for patients with acid related disease with less frequently occurring side effects. According to a recent report, PPIs provoke dysbiosis of the small intestinal bacterial flora, exacerbating nonsteroidal anti-inflammatory drug-induced small intestinal injury. Several meta-analyses and systematic reviews have reported that patients treated with PPIs, as well as post-gastrectomy patients, have a higher frequency of small intestinal bacterial overgrowth (SIBO) compared to patients who lack the aforementioned conditions. Furthermore, there is insufficient evidence that these conditions induce Clostridium difficile infection. At this time, PPI-induced dysbiosis is considered a type of SIBO. It now seems likely that intestinal bacterial flora influence many diseases, such as inflammatory bowel disease, diabetes mellitus, obesity, non-alcoholic fatty liver disease, and autoimmune diseases. When attempting to control intestinal bacterial flora with probiotics, prebiotics, and fecal microbiota transplantation, etc., the influence of acid suppression therapy, especially PPIs, should not be overlooked.


Operative and Conservative Treatment of Uterine Sarcomas.
Uterine sarcomas are rare, aggressive mesenchymal tumours with a relatively poor prognosis. The term comprises various histological subtypes, such as leiomyosarcoma, endometrial stromal sarcomas as well as undifferentiated uterine sarcomas, which require different operative and systemic/radiation therapy strategies accordingly. The evidence on operative, adjuvant and palliative treatment currently available is presented here.


Medical school handoff education improves postgraduate trainee performance and confidence.
Determine postgraduate first-year (PGY-1) trainees ability to perform patient care handoffs and associated medical school training. About 173 incoming PGY-1 trainees completed an OSCE handoff station and a survey eliciting their training and confidence in conducting handoffs. Independent t-tests compared OSCE performance of trainees who reported receiving handoff training to those who had not. Analysis of variance examined differences in performance based on prior handoff instruction and across levels of self-assessed abilities, with significance set at p<0.05. About 35% of trainees reported receiving instruction and 51% reported receiving feedback about their handoff performance in medical school. Mean handoff performance score was 69.5%. Trainees who received instruction or feedback during medical school had higher total and component handoff performance scores (p<0.05); they were also more confident in their handoff abilities (p<0.001). Trainees with higher self-assessed skills and preparedness performed better on the OSCE (p<0.05). This study provides evidence that incoming trainees are not well prepared to perform handoffs. However, those who received instruction during medical school perform better and are more confident on standardized performance assessments. Given communication failures lead to uncertainty in patient care and increases in medical errors, medical schools should incorporate handoff training as required instruction.


Population-specific effects of developmental temperature on body condition and jumping performance of a widespread European frog.
All physiological processes of ectotherms depend on environmental temperature. Thus, adaptation of physiological mechanisms to the thermal environments is important for achieving optimal performance and fitness. The European Common Frog, Rana temporaria, is widely distributed across different thermal habitats. This makes it an exceptional model for studying the adaptations to different thermal conditions. We raised tadpoles from Germany and Croatia at two constant temperature treatments (15°C, 20°C), and under natural temperature fluctuations (in outdoor treatments), and tested how different developmental temperatures affected developmental traits, that is, length of larval development, morphometrics, and body condition, as well as jumping performance of metamorphs. Our results revealed population-specific differences in developmental time, body condition, and jumping performance. Croatian frogs developed faster in all treatments, were heavier, in better body condition, and had longer hind limbs and better jumping abilities than German metamorphs. The populations further differed in thermal sensitivity of jumping performance. While metamorphs from Croatia increased their jumping performance with higher temperatures, German metamorphs reached their performance maximum at lower temperatures. These population-specific differences in common environments indicate local genetic adaptation, with southern populations being better adapted to higher temperatures than those from north of the Alps.


Changes in the genomic content of circulating Bordetella pertussis strains isolated from the Netherlands, Sweden, Japan and Australia: adaptive evolution or drift?
Bordetella pertussis is the causative agent of human whooping cough (pertussis) and is particularly severe in infants. Despite worldwide vaccinations, whooping cough remains a public health problem. A significant increase in the incidence of whooping cough has been observed in many countries since the 1990s. Several reasons for the re-emergence of this highly contagious disease have been suggested. A particularly intriguing possibility is based on evidence indicating that pathogen adaptation may play a role in this process. In an attempt to gain insight into the genomic make-up of B. pertussis over the last 60 years, we used an oligonucleotide DNA microarray to compare the genomic contents of a collection of 171 strains of B. pertussis isolates from different countries. The CGH microarray analysis estimated the core genome of B. pertussis, to consist of 3,281 CDSs that are conserved among all B. pertussis strains, and represent 84.8% of all CDSs found in the 171 B. pertussis strains. A total of 64 regions of difference consisting of one or more contiguous CDSs were identified among the variable genes. CGH data also revealed that the genome size of B. pertussis strains is decreasing progressively over the past 60 years. Phylogenetic analysis of microarray data generated a minimum spanning tree that depicted the phylogenetic structure of the strains. B. pertussis strains with the same gene content were found in several different countries. However, geographic specificity of the B. pertussis strains was not observed. The gene content was determined to highly correlate with the ptxP-type of the strains. An overview of genomic contents of a large collection of isolates from different countries allowed us to derive a core genome and a phylogenetic structure of B. pertussis. Our results show that B. pertussis is a dynamic organism that continues to evolve.


Electroejaculation in men with spinal cord injury: a step-by-step video demonstration.
To demonstrate the proper technique to perform electroejacuation (EEJ) in men with spinal cord injury (SCI) for the purpose of inducing ejaculation. A video demonstration of the proper technique to perform EEJ in men with SCI using the Seager model 14 electroejaculation machine. Major university medical center. Men with SCI; institutional review board approval was obtained, and all subjects signed an informed consent form. Spinal cord injury occurs mostly in young men where the majority suffer from ejaculatory dysfunction. The method of choice to induce ejaculation in penile vibratory stimulation (PVS). PVS is successful in 86% of men with SCI whose level of injury is T10 or rostral. If PVS fails or the level is Caudal to T10, the patient is referred for EEJ. This video will demonstrate the proper technique for successful ejaculation using EEJ. Patients with history of autonomic dysreflexia or their level of injury is T6 or rostral are pretreated with 10-20 mg of nifedipine sublingually 10 minutes before stimulation. The patient is then placed in the lateral decubitus position. The bladder is emptied, and a buffer is instilled. An anoscopy is performed, and a rectal probe is placed. A current is delivered until an antegrade ejaculation is retrieved. A retrograde specimen is collected and examined for sperm identification. Patients with complete SCI (no sensory or motor function is preserved in sacral segments S4-S5) can undergo EEJ without anesthesia. Patients with incomplete SCI (significant nerve sparing or normal sensations) will experience pain during stimulation, and general anesthesia is recommended without the use of muscle relaxing agents. Successful ejaculation after performing EEJ in men with SCI. Electroejacuation is successful in 95% of men with SCI and in nearly 100% if general anesthesia is used. Outcomes of in vitro fertilization or intracytoplasmic sperm injection after EEJ showed 37.5% pregnancy rate per cycle, 50.0% pregnancy rate per couple, 33.3% live birth rate per cycle, and 43.8% live birth rate per couple. No complications due to EEJ were observed in 953 trials, and none occurred in the patients presented in this video demonstration. Electroejacuation is a safe and reliable method for induction of ejaculation in men with SCI who fail a trial of PVS.


A decade of surgically removed small renal masses in the Netherlands: characteristics and trends in type of surgery and pathologic reporting.
To assess nationwide the pathologic characteristics and trends in type of surgery and pathologic reporting in surgically managed renal tumors ≤ 4 cm. A review of all pathologic reports of primary small renal masses operated on in the Netherlands during the period 1995 to 2005 was performed. The data source was a nationwide central archive of histocytopathology (Patologisch Anatomisch Landelijk Geautomatiseerde Archief). Tumors were stratified into three groups: ≤ 2, 2.1 to 3.0, and 3.1 to 4.0 cm. Age, sex, type of operation, and tumor pathology were analyzed. For renal-cell carcinomas, grade (3-tiers Fuhrman) and stage (2002 Tumor, Node, Metastasis) were assessed. Trends in type of surgery (radical or partial nephrectomy [PN]) and pathologic reporting during the study period were analyzed. Of all operated primary kidney tumors, 25.3% were ≤ 4.0 cm. The mean age of the patients was 63.1 years (standard deviation 11.7), and the male/female ratio was 3:2. Only 7.5% were benign tumors, and 9.8% were locally advanced (≥ T₃). Tumors ≤ 3.0 cm were more likely to be benign (P = 0.006) and of lower stage (P ≤ 0.001) than tumors of 3.1 to 4 cm. PN was performed in 16.5% of the cases. Grade and subtype were reported in 55% of the cases. The rate of PNs performed increased during the decade. There was a trend in increased reporting of grade and subtype. A quarter of all the operated primary kidney tumors were ≤ 4 cm. Smaller tumors were more likely to be benign and of lower stage. A cutoff size regarding biologic aggressiveness can be settled at the 3 cm size. The PN rate increased along the decade. Grade and subtype reporting rates remained suboptimal, although a positive trend was noted.


High-performance polyurethane nanocomposites based on UPy-modified cellulose nanocrystals.
Densely H-bonding assemblies are the key strategy found by nature to enhance the rupture strength of natural polymers without sacrificing their toughness, such as spider silk, while it still remains a great challenge using such intriguing strategy to prepare high-performance synthesized polymer or biopolymer enhanced polymer nanocomposites. To address this challenge, we report here a bio-inspired strategy using densely H-bonding assembly for facile fabrication of high performance polyurethane (PU) nanocomposites reinforced by hydroxyl-rich cellulose nanocrystals (CNCs) functionalized with 2-ureido-4-[1 H]-pyrimidinone motifs (CNC-UPy) containing self-complementary hydrogen bonds. These PU/CNC-UPy nanocomposites showed remarkably improved mechanical strength without sacrificing the elongation at break and toughness compared to pure PU matrix. Differential scanning calorimetry(DSC) results indicated that CNC-UPy could induce the formation of long range ordering of hard segment domains, due to the strong hydrogen bonding interactions between UPy motifs attached on CNC-UPy and PU matrix. Furthermore, wide angle X-ray diffraction (WAXD) measurements demonstrated that the strain-induced crystallization (SIC) was enhanced significantly by introducing CNC-UPy into PU, leading to a large stress at break. The enhanced interfacial H-bonding interactions between CNC and PU though UPy anchoring could overcome the inherent trade-off between the stiffness and toughness of polymer composites. The proposed bio-inspired strategy using densely H-bonding assembly will be with more extensive application prospects.


Adipose-derived mesenchymal stem cells as stable source of tumor necrosis factor-related apoptosis-inducing ligand delivery for cancer therapy.
Adipose-derived mesenchymal stromal/stem cells (AD-MSC) may offer efficient tools for cell-based gene therapy approaches. In this study, we evaluated whether AD-MSC could deliver proapoptotic molecules for cancer treatment. Human AD-MSCs were isolated and transduced with a retroviral vector encoding full-length human tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a proapoptotic ligand that induces apoptosis in a variety of human cancers but not normal tissues. Although several studies have documented the antitumor activity of recombinant human TRAIL, its use in vivo is limited by a short half-life in plasma due to a rapid clearance by the kidney. We found that these limitations can be overcome using stably transduced AD-MSC, which could serve as a constant source of TRAIL production. AD-MSC armed with TRAIL targeted a variety of tumor cell lines in vitro, including human cervical carcinoma, pancreatic cancer, colon cancer, and, in combination with bortezomib, TRAIL-resistant breast cancer cells. Killing activity was associated with activation of caspase-8 as expected. When injected i.v. or s.c. into mice, AD-MSC armed with TRAIL localized into tumors and mediated apoptosis without significant apparent toxicities to normal tissues. Collectively, our results provide preclinical support for a model of TRAIL-based cancer therapy relying on the use of adipose-derived mesenchymal progenitors as cellular vectors.


Activity levels and return to work following total knee arthroplasty in patients under 65 years of age.
Little is known about employment following total knee arthroplasty (TKA). This study aims to identify factors which predict return to work following TKA in patients of working age in the United Kingdom. We prospectively assessed 289 patients (289 TKAs) aged ≤ 65 years who underwent TKA between 2010 and 2013. There were 148 women. The following were recorded pre-operatively: age, gender, body mass index, social deprivation, comorbidities, indication for surgery, work status and nature of employment, activity level as assessed by the University of California, Los Angeles (UCLA) activity score and Oxford Knee Score (OKS). The intention of patients to return to work or to retire was not assessed pre-operatively. At a mean of 3.4 years (2 to 4) post-operatively, the return to work status, OKS, the EuroQol-5 dimensions (EQ-5D) score, UCLA activity score and Work, Osteoarthritis and joint-Replacement (WORQ) score were obtained. Univariate and multivariate analyses were performed. Of 261 patients (90%) who were working before TKA, 105 (40%) returned to any job, including 89 (34%) who returned to the same job at a mean of 13.5 weeks (2 to 104) post-operatively. A total of 108 (41%) retired following TKA and 18 remained on welfare. Patients not working before the operation did not return to work. Median UCLA scores improved in 125 patients (58%) from 4 (mild activity) to 6 (moderate activity) (p < 0.001). Significant (p < 0.05) factors which were predictive of return to any work included age, heavy or moderate manual work, better post-operative UCLA, OKS and EQ-5D general health scores. Significant predictive factors of return to the same work included age, heavy or moderate manual work and post-operative OKS. Multivariate analysis confirmed heavy or moderate manual work and age to independently predict a return to either any or the same work. All patients aged < 50 years who were working pre-operatively returned to any work as did 60% of those aged between 50 and 54 years, 50% of those aged between 55 and 59 years and 24% those aged between 60 and 65 years. If working pre-operatively, patients aged < 50 years invariably returned to work following TKA, but only half of those aged between 50 to 60 years returned. High post-operative activity levels and patient reported outcome measures do not predict return to work following TKA. Cite this article: Bone Joint J 2017;99-B:1037-46.


Investigating the potential role of BDNF and PRL genotypes on antidepressant response in depression patients: A prospective inception cohort study in treatment-free patients.
Brain-derived neurotrophic factor (BDNF) is associated with response to antidepressant drugs in mood and anxiety disorders. Prolactin (PRL) is a pituitary hormone with behavioural effects, acting as a neurotrophic factor within the brain and may be involved in antidepressant response. To investigate the relationship between BDNF and PRL genotypes with antidepressant drug response. Prospective inception cohort of 186 Russian treatment-free participants (28 men and 158 women) between 18 and 70 years clinically diagnosed with depressive disorder who initiated antidepressant medication. DNA polymorphisms were genotyped for PRL rs1341239, BDNF rs6265 and rs7124442. Primary outcome was measured by differences in Hamilton Depression Rating Scale (∆HAM-D) scores between baseline/week two, week two/week four, and baseline/week four. Linear regression and independent t-test determined the significance between polymorphisms and ∆HAM-D. Comparisons between genotypes did not reveal any significant differences in scores during the first two weeks of treatment. In the latter two weeks, BDNF rs7124442 homozygous C patients responded significantly worse in comparison to homozygous T patients during this period. Further analysis within women and in post-menopausal women found a similar comparison between alleles. Study lasted four weeks, which may be considered short to associate genuine antidepressant effects. Patients taking tricylic antidepressants were noted to have a significant improvement in ∆HAM-D compared to patients taking SSRIs. Homozygous C BDNF rs712442 patients were found to respond significantly worse in the last two weeks of treatment.


Trichothecenes and zearalenone production by Fusarium equiseti and Fusarium semitectum species isolated from Argentinean soybean.
Fusarium equiseti and Fusarium semitectum represent the most abundant species in the Fusarium complex isolated from flowers, soybean pods and seeds in Argentina. The aim of the present study was to assess the production of major type A and type B trichothecenes (diacetoxyscirpenol, neosolaniol, T-2 toxin and HT-2 toxin, nivalenol, deoxynivalenol) and zearalenone by 40 F. equiseti and 22 F. semitectum isolates on rice culture. Mycotoxins were determined by HPLC with fluorescence detection after derivatisation with 1-anthronylnitrile for type A trichothecenes (i.e. diacetoxyscirpenol, neosolaniol, T-2 toxin and HT-2 toxin), by HPLC with UV detection for type B trichothecenes (i.e. nivalenol and deoxynivalenol), and by TLC for zearalenone. A total of 22 of 40 F. equiseti isolates produced diacetoxyscirpenol, nivalenol and ZEA alone or in combination, whereas only two of 20 F. semitectum isolates were nivalenol and ZEA producers. Both Fusarium species did not produce any deoxynivalenol, neosolaniol, T-2 toxin and HT-2 toxin. The variable retention in toxigenicity displayed by both fungal species suggests that these species have a saprophytic lifestyle in the soybean agroecosystem in Argentina.


[Germinating requirements of common vines from Chaco Serrano of Córdoba, Argentina].
Vines are conspicuous elements of floras in different ecosystems. Patterns of distribution and ecology of this group has been studied at regional scales, mainly in tropical areas, but less is known about factors affecting their distribution at smaller scales. In this study, the germinating requirements of common vines from two plant communities (open shrubland and woodland) in xerophytic mountain forests (Chaco serrano) were studied. A total of 21 species were selected and classified as typical of woodland, shrubland, or indifferent. Experimental treatments were three temperature regimes (15-5 degrees C, 25-15 degrees C and 35-20 degrees C), in light (12-12h daily photoperiod) and in continuous darkness. Total germination percentage, the relative light germination (RLG) and germination rate (T50) were recorded. Among results we found that the temperature was the main factor triggering the germination process. No differences in the mean RLG and T50 between woodland and shrubland patches were found. The patterns observed in this work support the idea that, independently of patch type, germination is associated with temperature of the time of the year when most of the rainfall occurs. Germination of the studied species would be responding to macroclimate's factors (seasonality of climate and rainfall), rather than to a microclimate. This indicates that differences in species composition between patches would not be due to the factors studied, rather than to characteristics of the later stages of the cycle life. 1523. Epub 2012 December 01.


A case of post-traumatic complex auditory hallucinosis treated with rTMS.
Previous studies of auditory hallucinations in schizophrenia found that the hallucinations were reduced by the application of transcranial magnetic stimulation (rTMS). Here we describe a case of traumatic brain injury associated with continuous music hallucinations. An MRI scan showed a structural lesion of the right temporal pole and a PET scan indicated a hyperactive area of the posterior right temporal lobe. We hypothesized that rTMS applied to the right temporal area would reduce this activity and the corresponding hallucinations. The patient's music hallucinations were significantly reduced by rTMS treatment. A PET scan following treatment also indicated that rTMS treatment reduced brain activity in the right temporal lobe. This case provides initial evidence that rTMS may be a successful treatment of syndromes associated with hyperactive brain areas.


An Immunohistochemical Study of Anogenital Mammary-Like Glands.
Although the normal histology of anogenital mammary-like glands (AGMLG) has been studied, no systemic investigation has been performed on the immunoprofile of these structures. We studied intact AGMLG with a broad panel of antibodies. The immunoprofile of AGMLG is similar to that of a normal breast tissue, and there are similarities to eccrine glands and coils about cytokeratin expression. Our immunohistochemical data may contribute to understanding of the pathogenesis of lesions arising from AGMLG.


The effect of virtual reality during dental treatment on child anxiety and behavior.
Virtual reality, a three-dimensional computer generated world, has been shown to relax adults during dental treatment. The purpose of this study was to investigate the effect of virtual reality on the behavior and anxiety of children during dental treatment. The behavior, anxiety and heart rate of twenty-six children, ages five to seven years were evaluated for the first five minutes of two restorative treatment visits. Thirteen children viewed virtual reality at their first restorative visit and not the second, and thirteen children viewed virtual reality at the second restorative visit and not the first. Before and immediately following the restorative visits, each child was instructed to draw a human figure. The restorative appointments were video recorded and heart rate monitored. The drawings and videotapes were rated independently by two examiners. The Koppitz method of evaluating drawings was used to measure anxiety. The Frankl behavior rating scale was used to evaluate behavior. Differences (ANOVA) in behavior (p < or = 0.50) and anxiety (p < or = 0.65) were not significant. The overall pulse rate was significantly lower (ANOVA p < or = 0.001) when the child was wearing glasses and viewing virtual reality. In conclusion, virtual reality during dental treatment had no significant effect on the behavior or anxiety but significantly reduced the pulse.


Transcranial direct current stimulation enhances sucking of a liquid bolus in healthy humans.
Transcranial direct current stimulation (tDCS) is a non-invasive technique used for modulating cortical excitability in vivo in humans. Here we evaluated the effect of tDCS on behavioral and electrophysiological aspects of physiological sucking and swallowing. Twelve healthy subjects underwent three tDCS sessions (anodal, cathodal and sham stimulation) on separate days in a double-blind randomized order. The active electrode was placed over the right swallowing motor cortex. Repeated sucking and swallowing acts were performed at baseline and at 15 and 60 min after each tDCS session and the mean liquid bolus volume ingested at each time point was measured. We also calculated average values of the following electrophysiological parameters: 1) area and 2) duration of the rectified EMG signal from the suprahyoid/submental muscles related to the sucking and swallowing phases; 3) EMG peak amplitude for the sucking and swallowing phases; 4) area and peak amplitude of the laryngeal-pharyngeal mechanogram; 5) oropharyngeal delay. The volume of the ingested bolus significantly increased (by an average of about 30% compared with the baseline value) both at 15 and at 60 min after the end of anodal tDCS. The electrophysiological evaluation after anodal tDCS showed a significant increase in area and duration of the sucking phase-related EMG signal. Anodal tDCS leads to stronger sucking of a liquid bolus in healthy subjects, likely by increasing recruitment of cortical areas of the swallowing network. This finding might open up interesting perspectives for the treatment of patients suffering from dysphagia due to various pathological conditions.


CD40-TNF activation in mice induces extended sickness behavior syndrome co-incident with but not dependent on activation of the kynurenine pathway.
The similarity between sickness behavior syndrome (SBS) in infection and autoimmune disorders and certain symptoms in major depressive disorder (MDD), and the high co-morbidity of autoimmune disorders and MDD, constitutes some of the major evidence for the immune-inflammation hypothesis of MDD. CD40 ligand-CD40 immune-activation is important in host response to infection and in development of autoimmunity. Mice given a single intra-peritoneal injection of CD40 agonist antibody (CD40AB) develop SBS for 2-3days characterized by weight loss and increased sleep, effects that are dependent on the cytokine, tumor necrosis factor (TNF). Here we report that CD40AB also induces behavioral effects that extend beyond acute SBS and co-occur with but are not mediated by kynurenine pathway activation and recovery. CD40AB led to decreased saccharin drinking (days 1-7) and decreased Pavlovian fear conditioning (days 5-6), and was without effect on physical fatigue (day 5). These behavioral effects co-occurred with increased plasma and brain levels of kynurenine and its metabolites (days 1-7/8). Co-injection of TNF blocker etanercept with CD40AB prevented each of SBS, reduced saccharin drinking, and kynurenine pathway activation in plasma and brain. Repeated oral administration of a selective indoleamine 2,3-dioxygenase (IDO) inhibitor blocked activation of the kynurenine pathway but was without effect on SBS and saccharin drinking. This study provides novel evidence that CD40-TNF activation induces deficits in saccharin drinking and Pavlovian fear learning and activates the kynurenine pathway, and that CD40-TNF activation of the kynurenine pathway is not necessary for induction of the acute or extended SBS effects.


Visualising the ionome in resistant and susceptible plant-pathogen interactions.
At the morphological and anatomical levels, the ionome, or the elemental composition of an organism, is an understudied area of plant biology. In particular, the ionomic responses of plant-pathogen interactions are scarcely described, and there are no studies on immune reactions. In this study we explored two X-ray fluorescence (XRF)-based ionome visualisation methods (benchtop- and synchrotron-based micro-XRF [µXRF]), as well as the quantitative inductively coupled plasma optical emission spectroscopy (ICP-OES) method, to investigate the changes that occur in the ionome of compatible and incompatible plant-pathogen interactions. We utilised the agronomically important and comprehensively studied interaction between potato (Solanum tuberosum) and the late blight oomycete pathogen Phytophthora infestans as an example. We used one late blight-susceptible potato cultivar and two resistant transgenic plant lines (only differing from the susceptible cultivar in one or three resistance genes) both in control and P. infestans-inoculated conditions. In the lesions from the compatible interaction, we observed rearrangements of several elements, including a decrease of the mobile macronutrient potassium (K) and an increase in iron (Fe) and manganese (Mn), compared with the tissue outside the lesion. Interestingly, we observed distinctly different distribution patterns of accumulation at the site of inoculation in the resistant lines for calcium (Ca), magnesium (Mg), Mn and silicon (Si) compared to the susceptible cultivar. The results reveal different ionomes in diseased plants compared to resistant plants. Our results demonstrate a technical advance and pave the way for deeper studies of the plant-pathogen ionome in the future.


Incidence of Midline Catheter Complications Among Hospitalized Patients.
The use of midline catheters has increased to reduce excessive use of central venous access devices, and additional data on midline catheter complications are needed. This study aimed to describe midline catheter complications among hospitalized patients. This retrospective study included a random sample of 300 hospitalized patients with a midline catheter insertion in 2019. The primary outcome was a composite end point of 8 complications: occlusion, bleeding at insertion site, infiltration/extravasation, catheter-related thrombosis, accidental removal, phlebitis, hematoma, and catheter-related infection. Midline catheter failure was defined as removal prior to the end of therapy due to complications. Among 300 midline catheters, the incidence of the composite end point of 1 or more midline complications was 38% (95% confidence interval, 33%-44%). Complications included occlusion (17.0%), bleeding at insertion site (12.0%), infiltration/extravasation (10.0%), catheter-related thrombosis (4.0%), accidental removal (3.0%), phlebitis (0.3%), hematoma (0.3%), and catheter-related infection (0.3%). Midline catheter failure occurred in 16% of midline catheters (n = 48) due to infiltration/extravasation (n = 27), accidental removal (n = 10), catheter-related thrombosis (n = 9), occlusion (n = 4), and catheter-related infection (n = 1). Three catheters had 2 types of failure. The most common complications of occlusion and bleeding rarely resulted in midline catheter failure. The most common causes of midline catheter failure were infiltration/extravasation, accidental removal, and catheter-related thrombosis.


Strategies to Build Trust and Recruit African American and Latino Community Residents for Health Research: A Cohort Study.
This study used Community Partnered Participatory Research (CPPR) to address low participation of racial and ethnic minorities in medical research and the lack of trust between underrepresented communities and researchers. Using a community and academic partnership in July 2012, residents of a South Los Angeles neighborhood were exposed to research recruitment strategies: referral by word-of-mouth, community agencies, direct marketing, and extant study participants. Among 258 community members exposed to recruitment strategies, 79.8% completed the study. Exposed individuals identified their most important method for learning about the study as referral by study participants (39.8%), community agencies (30.6%), word-of-mouth (17.5%), or direct marketing promotion (12.1%). Study completion rates varied by recruitment method: referral by community agencies (88.7%), referral by participants (80.4%), direct marketing promotion (86.2%), word of mouth (64.3%). Although African American and Latino communities are often described as difficult to engage in research, we found high levels of research participation and completion when recruitment strategies emerged from the community itself. This suggests recruitment strategies based on CPPR principles represent an important opportunity for addressing health disparities and our high rates of research completion should provide optimism and a road map for next steps.


Healthy behaviours and mental health: findings from the German Health Update (GEDA).
Health risk behaviours such as smoking, physical inactivity and poor diet are independently associated with depression. However, there is a paucity of data examining associations between combined healthy behaviours and mental distress and depression. Using cross-sectional data from a nationwide population-based sample of adults in Germany [German Health Update (GEDA) 2009 and 2010 telephone surveys; n = 21 940 women, n = 17 061 men], we examined associations between five healthy behaviours and frequent mental distress (FMD) and self-reported diagnosed depression in the past 12 months. Healthy behaviours included non-smoking, low-risk alcohol drinking, regular sport, maintaining normal weight and healthy fruit and vegetable consumption. Multiple logistic regression analyses adjusted for potential confounders examined associations between the combined number of healthy behaviours and FMD and self-reported diagnosed depression. FMD was reported by 13.6 and 8.0% and diagnosed depression in the last 12 months by 8.3 and 4.7% of women and men, respectively. At least four of five assessed healthy behaviours were reported by 29.1% of women and 17.8% of men. Compared with those with less than two healthy behaviours, women and men with at least four behaviours were about half as likely to report FMD [odds ratio (OR) 0.53, 95% confidence interval (CI) 0.44-0.64, and OR 0.52, 95% CI 0.41-0.66, respectively) and women with at least four behaviours were less likely to report diagnosed depression (OR 0.76, 95% CI 0.61-0.95). A higher number of healthy behaviours are associated with a lower prevalence of FMD for both women and men and of self-reported diagnosed depression in women.


Electron-microscopic investigation of muscle mitochondria in chronic fatigue syndrome.
Patients with chronic fatigue syndrome (CFS) suffer from disabling physical and mental fatigue. Abnormalities in mitochondrial function can lead to fatigue and weakness. Ultrastructural mitochondrial abnormalities have been reported to be present in CFS patients. We obtained percutaneous needle muscle biopsies from 15 CFS patients and 15 age- and sex-matched controls. We investigated previously reported ultrastructural abnormalites in CFS: subsarcolemmal mitochondrial aggregates, intermyofibrillar mitochondrial aggregates, mitochondrial circumference, area, pleomorphism and the presence of compartmentalization of the inner mitochondrial membrane. All of the steps of tissue processing, electron microscopy and data abstracting and analysis were performed in a totally blinded fashion. All of our data were rigorously quantified. We found no difference in any of these studied parameters between CFS patients and controls. Although there is no ultrastructural mitochondrial abnormality in CFS patients, other lines of evidence suggest the presence of a possible functional mitochondrial abnormality.


The degradation of promyelocytic leukemia and Sp100 proteins by herpes simplex virus 1 is mediated by the ubiquitin-conjugating enzyme UbcH5a.
Infected cell protein 0 (ICP0) of herpes simplex virus 1 expresses two E3 ubiquitin (Ub) ligase activities mapping in the domains encoded by exons 2 and 3, respectively. Site 1 (exon 3) is responsible for the degradation of the E2 Ub-conjugating enzyme cdc34 whereas site 2 (exon 2) is associated with a ring finger and has been shown to mediate the degradation of promyelocytic leukemia (PML) and Sp100 proteins and the dispersal of nuclear domain 10 (ND10). In in vitro assays site 2 polyubiquitylates the E2 enzymes UbcH5a and UbcH6 but not other (e.g., UbcH7) enzymes. In this article, we show that ectopic expression of dominant negative UbcH5a carrying the substitution C85A delayed or blocked the degradation of PML and Sp100 and dispersal of ND10 whereas ectopic expression of wild-type UbcH5a or dominant negative UbcH6 and UbcH7 carrying the substitutions C131A and C86A, respectively, had no effect. These results link the degradation of PML and Sp100 and the dispersal of ND10 to the E3 activities of ICP0 associated with the UbcH5a E2 enzyme.


The Development of Neuroendocrine Disturbances over Time: Longitudinal Findings in Patients after Traumatic Brain Injury and Subarachnoid Hemorrhage.
Previous reports suggest that neuroendocrine disturbances in patients with traumatic brain injury (TBI) or aneurysmal subarachnoid hemorrhage (SAH) may still develop or resolve months or even years after the trauma. We investigated a cohort of n = 168 patients (81 patients after TBI and 87 patients after SAH) in whom hormone levels had been determined at various time points to assess the course and pattern of hormonal insufficiencies. Data were analyzed using three different criteria: (1) patients with lowered basal laboratory values; (2) patients with lowered basal laboratory values or the need for hormone replacement therapy; (3) diagnosis of the treating physician. The first hormonal assessment after a median time of three months after the injury showed lowered hormone laboratory test results in 35% of cases. Lowered testosterone (23.1% of male patients), lowered estradiol (14.3% of female patients) and lowered insulin-like growth factor I (IGF-I) values (12.1%) were most common. Using Criterion 2, a higher prevalence rate of 55.6% of cases was determined, which correlated well with the prevalence rate of 54% of cases using the physicians' diagnosis as the criterion. Intraindividual changes (new onset insufficiency or recovery) were predominantly observed for the somatotropic axis (12.5%), the gonadotropic axis in women (11.1%) and the corticotropic axis (10.6%). Patients after TBI showed more often lowered IGF-I values at first testing, but normal values at follow-up (p < 0.0004). In general, most patients remained stable. Stable hormone results at follow-up were obtained in 78% (free thyroxine (fT4) values) to 94.6% (prolactin values).


Free radicals in viral pathogenesis: molecular mechanisms involving superoxide and NO.
The importance of free radical molecular species in the pathogenesis of various viral diseases has been increasingly recognized in recent years. Oxygen radicals such as superoxide (O2-) and hydroxyl radical (.OH) have been implicated as possible pathogenic molecules in viral disease pathogenesis. Much attention has been given to another simple inorganic radical [nitric oxide (NO)] in the host's defense mechanism and pathogenesis of virus infection. The NO synthesis pathway, in particular, the inducible isoform of NO synthase (iNOS), is expressed in different viral diseases via induction of proinflammatory cytokines such as interferon-gamma. iNOS produces an excessive amount of NO for a long time compared with other constitutive isoforms of NOS (i.e., neuronal NOS and endothelial NOS). Recent studies indicate that NO and O2- are produced in excess during the host's defense responses against various intruding microbes. Reactive nitrogen oxide species such as peroxynitrite (ONOO-) and NOx (NO2 and N2O3) are produced in biological systems through the reaction of NO with either O2- or O2. Among these reactive nitrogen species, ONOO- and its biological actions are of considerable interest in that ONOO- causes oxidation and nitration of amino acid residues of proteins and guanine of DNA, lipid peroxidation, and DNA cleavage. Because the ONOO- is formed via a diffusion-limited fast reaction of NO and O2-, it may be a dominant nitrogen oxide species during the host's defense reactions, when both NO and O2- are produced in excess. Thus, understanding the role of NO and oxygen radical generation in virus infections will provide insight into not only viral pathogenesis but also the host-pathogen interaction in microbial infections at a molecular level.


Practical use of home blood pressure monitoring in chronic kidney disease.
Despite the availability of blood pressure (BP)-lowering medications and dietary education, hypertension is still poorly controlled in the chronic kidney disease (CKD) population. As glomerular filtration rate declines, the number of medications required to achieve BP targets increases, which may lead to reduced patient adherence and therapeutic inertia by the clinician. Home BP monitoring (HBPM) has emerged as a means of improving diagnostic accuracy, risk stratification, patient adherence, and therapeutic intervention. The definition of hypertension by HBPM is an average BP >135/85 mm Hg. Twelve readings over the course of 3-5 days are sufficient for clinical decision making. Diagnostic accuracy is especially important in the CKD population as approximately half of these patients have either white coat hypertension or masked hypertension. Preliminary data suggest that HBPM outperforms office BP monitoring in predicting progression to end-stage renal disease or death. When combined with additional support such as telemonitoring, medication titration, or behavioral therapy, HBPM results in a sustained improvement in BP control. HBPM must be adapted to provide information on the phenomena of nondipping (absence of nocturnal fall in BP) and reverse dipping (paradoxical increase in BP at night). These diurnal patterns are more prevalent in the CKD population and are important cardiovascular risk factors. Ambulatory BP monitoring provides nocturnal BP readings and unlike HBPM may be reimbursed by Medicare when certain criteria are met. Further studies are needed to determine whether HBPM is cost-effective in the current US healthcare system.


Assessment of owner perceptions of caregiver burden, veterinarian-client relationship and satisfaction with the provider in canine pruritus: An experimental vignette study.
Complicated treatments for skin disease are linked to owner-caregiver burden and poorer perception of the veterinarian-client relationship, regardless of disease severity. Using experimental vignettes, we explored the impact on owner perception of the interaction of treatment complexity and skin disease outcomes. We hypothesised that: (i) vignette conditions involving injection therapy would result in lower burden, better veterinary-client relationship and greater satisfaction relative to multimodal therapy conditions; (ii) the vignette condition of injection therapy with a completely effective outcome would be superior to all other conditions; (iii) ineffective vignette conditions would be inferior to all other conditions; and (iv) the vignette condition injection with a mostly effective outcome would be similar or superior to the multimodal therapy with a completely effective outcome condition. Three hundred and nine owners of pruritic dogs recruited from a general veterinary practice, pet-related podcast, or social media dog allergy group. Participants were presented with six counterbalanced online vignettes representing three levels of treatment effectiveness (Completely Effective, Mostly Effective, Ineffective) and two treatment regimens (Multimodal, Injection). Measurements of participant perceptions of caregiver burden, veterinarian-client relationship and satisfaction were recorded. Injection with perfect outcome was superior to other conditions (p < 0.001). Conditions with poor effectiveness were inferior (p < 0.001). Comparison of Injection with a mostly effective outcome to Multimodal treatment with perfect outcome yielded small-to-medium effects of preference for the latter in veterinarian-client relationship and satisfaction (p < 0.01); no difference was observed for caregiver burden. When good effectiveness was assured, injection was preferred (p < 0.001). Owners preferred a Completely Effective outcome and were prepared to select the Injection regimen or Multimodal therapy to achieve this; Injection was preferred when effectiveness was assured.


Pharmacological stimulation of sigma-1 receptors has neurorestorative effects in experimental parkinsonism.
The sigma-1 receptor, an endoplasmic reticulum-associated molecular chaperone, is attracting great interest as a potential target for neuroprotective treatments. We provide the first evidence that pharmacological modulation of this protein produces functional neurorestoration in experimental parkinsonism. Mice with intrastriatal 6-hydroxydopamine lesions were treated daily with the selective sigma-1 receptor agonist, PRE-084, for 5 weeks. At the dose of 0.3 mg/kg/day, PRE-084 produced a gradual and significant improvement of spontaneous forelimb use. The behavioural recovery was paralleled by an increased density of dopaminergic fibres in the most denervated striatal regions, by a modest recovery of dopamine levels, and by an upregulation of neurotrophic factors (BDNF and GDNF) and their downstream effector pathways (extracellular signal regulated kinases 1/2 and Akt). No treatment-induced behavioural-histological restoration occurred in sigma-1 receptor knockout mice subjected to 6-hydroxydopamine lesions and treated with PRE-084. Immunoreactivity for the sigma-1 receptor protein was evident in both astrocytes and neurons in the substantia nigra and the striatum, and its intracellular distribution was modulated by PRE-084 (the treatment resulted in a wider intracellular distribution of the protein). Our results suggest that sigma-1 receptor regulates endogenous defence and plasticity mechanisms in experimental parkinsonism. Boosting the activity of this protein may have disease-modifying effects in Parkinson's disease.


Differential uterine expression of estrogen and progesterone receptors correlates with uterine preparation for implantation and decidualization in the mouse.
The present investigation examined the spatiotemporal expression of estrogen receptors (ER-alpha and ER-beta) and progesterone receptor (PR) in the periimplantation mouse uterus (days 1-8). ER-alpha messenger RNA (mRNA) was detected at much higher levels in the periimplantation uterus compared with that of ER-beta mRNA, the levels of which were very low in all uterine cells during this period. Results of in situ hybridization demonstrated expression of ER-alpha mRNA primarily in the luminal and glandular epithelia on days 1 and 2 of pregnancy. On days 3 and 4, the accumulation was localized primarily in stromal cells in addition to its presence in the epithelium. Following implantation on day 5, the accumulation of this mRNA was more condensed in the luminal and glandular epithelia, but declined in the subluminal epithelial stroma at the sites of implanting embryos. On days 6-8, the accumulation of ER-alpha mRNA was primarily localized in the secondary decidual zone (SDZ) with more intense localization in the subepithelial cells at the mesometrial pole. In contrast, signals were very low to undetectable in the primary decidual zone (PDZ), and no signals were detected in implanting embryos. The undifferentiated stroma underneath the myometrium also showed positive signals. The immunolocalization of ER-alpha protein correlated with the mRNA localization. Western blot analysis showed down-regulation of ER-alpha in day 8 decidual cell extracts consistent with the down-regulation of ER-alpha mRNA in decidual cells immediately surrounding the embryo on this day. The expression pattern of PR was also dynamic in the periimplantation uterus. On day 1, the accumulation of PR mRNA was very low to undetectable, whereas only a modest level of accumulation in the epithelium was noted on day 2. On days 3 and 4, the accumulation of this mRNA was detected in both the epithelium and stroma. In contrast, the expression was restricted only to the stroma with increased signals at the sites of implantation on day 5. On days 6-8, PR mRNA accumulation increased dramatically throughout the deciduum. The localization of immunoreactive PR correlated with the mRNA distribution in the periimplantation uterus. Taken together, the results demonstrate that the expression of ER-alpha, ER-beta, and PR is differentially regulated in the periimplantation mouse uterus. This compartmentalized expression of ER and PR provides information regarding the sites of coordinated effects ofestrogen and progesterone in the preparation of the uterus for implantation and decidualization during early pregnancy.


Daily injections of fluoxetine induce dose-dependent desensitization of hypothalamic 5-HT1A receptors: reductions in neuroendocrine responses to 8-OH-DPAT and in levels of Gz and Gi proteins.
The present studies examined the dose-response relationship of fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptors, as measured from the reduced neuroendocrine responses to a 5-HT1A agonist. Because hypothalamic Gz proteins mediate the ACTH and oxytocin responses to 5-HT1A receptor activation, we also determined the effect of fluoxetine on the levels of Gz proteins in the hypothalamus. Rats were injected daily for 14 days with saline or with fluoxetine doses of 0.3, 1, 3, 5, 7. 5, or 10 mg/kg/day. Fluoxetine produced a dose-dependent reduction in the oxytocin, ACTH, and corticosterone responses to the 5-HT1A agonist 8-hydroxy-2-(dipropylamino)tetralin (8-OH-DPAT, 50 micrograms/kg, s.c.). The lowest fluoxetine dose that significantly, although incompletely, reduced the neuroendocrine responses to 8-OH-DPAT was 5 mg/kg/day. The 10 mg/kg/day dose of fluoxetine maximally inhibited all neuroendocrine responses to 8-OH-DPAT. Hypothalamic levels of Gz protein were reduced by both the 7.5 and 10 mg/kg/day doses of fluoxetine, whereas Gi1 protein levels were reduced only after the highest dose (10 mg/kg/day) of fluoxetine. Gi2, Gi3, and Go levels were not reduced by any fluoxetine dose. Cytosolic levels of Gi1 and Gz proteins were unaltered, indicating that reductions in Gz and Gi1 proteins are not caused by a redistribution of the proteins from the membrane into the cytosol. The results from the present study indicate that fluoxetine-induced desensitization of hypothalamic postsynaptic 5-HT1A receptor systems is dose-dependent and may be caused in part by reductions in the hypothalamic levels of Gz proteins.


International Society of Gynecological Pathologists (ISGyP) Endometrial Cancer Project: Guidelines From the Special Techniques and Ancillary Studies Group.
The aim of this article is to propose guidelines and recommendations in problematic areas in pathologic reporting of endometrial carcinoma (EC) regarding special techniques and ancillary studies. An organizing committee designed a comprehensive survey with different questions related to pathologic features, diagnosis, and prognosis of EC that was sent to all members of the International Society of Gynecological Pathologists. The special techniques/ancillary studies group received 4 different questions to be addressed. Five members of the group reviewed the literature and came up with recommendations and an accompanying text which were discussed and agreed upon by all members of the group. Twelve different recommendations are made. They address the value of immunohistochemistry, ploidy, and molecular analysis for assessing prognosis in EC, the value of steroid hormone receptor analysis to predict response to hormone therapy, and parameters regarding applying immunohistochemistry and molecular tests for assessing mismatch deficiency in EC.


Highly Anthropomorphic Finger Design with A Novel Friction Clutch for Achieving Human-like Reach-and-Grasp Movements.
In the design of prosthetic hand fingers, achieving human-like movement while meeting anthropomorphic demands such as appearance, size, and lightweight is quite challenging. Human finger movement involves two distinct motion characters during natural reach-and-grasp tasks: consistency in the reaching stage and adaptability in the grasping stage. The former one enhances grasp stability and reduces control complexity; the latter one promotes the adaptability of finger to various objects. However, conventional tendon-driven prosthetic finger designs typically incorporate bulky actuation modules or complex tendon routes to reconcile the consistency and adaptability. In contrast, we propose a novel friction clutch consisting of a single tendon and slider, which is simple and compact enough to be configurated within the metacarpal bone. Through tactfully exploiting the friction force to balance the gravity effect on each phalanx during finger motion, this design effectively combines both consistency and adaptability. As a result, the prosthetic finger can maintain consistent motion unaffected by any spatial posture during reaching, execute adaptive motion during grasping, and automatically switch between them, resulting in human-like reach-and-grasp movements. Additionally, the proposed finger achieves a highly anthropomorphic design, weighing only 18.9 g and possessing the same size as an adult's middle finger. Finally, a series of experiments validate the theoretical effectiveness and motion performance of the proposed design. Remarkably, the mechanical principle of the proposed friction clutch is beneficial to achieve highly anthropomorphic design, providing not only a new strategy to prosthetic hand design but also great potential in hand rehabilitation.


A partial genomic DNA clone for the alpha subunit of the mouse complement receptor type 3 and cellular adhesion molecule Mac-1.
A genomic clone coding for the alpha subunit of the mouse complement receptor type 3 and the cellular adhesion molecule Mac-1 has been isolated directly from a genomic library using synthetic oligonucleotide probes based on the amino-terminal amino acid sequence of the protein. The identity of the clone has been established by DNA sequencing and in vitro translation of hybrid-selected mRNA. The gene is present in a single copy in the murine genome. The region containing the amino-terminal exon has been sequenced. RNA gel blotting shows that the Mac-1 alpha-subunit mRNA is 6 kilobases in length. Mac-1 alpha-subunit mRNA is present in macrophages but not T lymphoma or L cells. During gamma interferon-stimulated maturation of the mouse premyelocytic cell line M1, Mac-1 alpha-subunit mRNA is induced. This corresponds with the tissue distribution of the Mac-1 alpha subunit, showing expression is regulated at least partially at the message level.


Distribution and characteristics of Listeria monocytogenes isolates from surface waters of the South Nation River watershed, Ontario, Canada.
Listeria monocytogenes is a facultative intracellular pathogen thought to be widely distributed in the environment. We investigated the prevalence and characteristics of L. monocytogenes isolates from surface waters derived from catchments within the South Nation River watershed (Ontario, Canada). This watershed is dominated by urban and rural development, livestock and crop production, and wildlife habitats. From June to November 2005, a total of 314 surface water samples were collected biweekly from 22 discrete sampling sites characterized by various upstream land uses. Presumptive Listeria spp. were isolated using a selective enrichment and isolation procedure, and 75 L. monocytogenes isolates were identified based on colony morphology, hemolytic activity, and amplification of three pathogenicity genes: iap, inlA, and hlyA. Thirty-two of 314 (10%) surface water samples were positive for the presence of L. monocytogenes, but detection ranged between 0 and 27% depending on the sampling date. Isolates belonging to serovar group 1/2a, 3a (50%) and group 4b, 4d, 4e (32%) were dominant. L. monocytogenes populations were resolved into 13 EcoRI ribotypes and 21 ApaI and 21 AscI pulsotypes. These had Simpson indexes of discrimination of up to 0.885. Lineage I-related isolates were dominant (61%) during the summer, whereas lineage II isolates were dominant (77%) in the fall. Isolates were, on average, resistant to 6.1 +/- 2.1 antibiotics out of 17 tested. Half of the L. monocytogenes isolates exhibited potential virulence linked to the production of a functional internalin A, and some isolates were found to be moderately to highly virulent by in vitro Caco-2 plaque formation assay (up to 28% of entry). There was a statistically significant link between the occurrence of L. monocytogenes and proximity to an upstream dairy farm and degree of cropped land. Our data indicate that L. monocytogenes is widespread in the studied catchments, where it could represent a public health issue related to agricultural land use.


Does increased investment in coronary angiography and revascularisation reduce socioeconomic inequalities in utilisation?
To investigate whether additional resources for tertiary cardiology services, aimed at increasing coronary angiography and revascularisation rates, can improve socioeconomic equity of utilisation. Cross sectional ecological study, using the Super Profile classification of enumeration districts and ischaemic heart disease (IHD) standardised mortality ratios (SMR) as a proxy for need. The degree of equity before the provision of extra resources was determined using data for April 1992 to March 1994, and the corresponding picture after, using data for April 1994 to March 1996. South Humberside (United Health-Grimsby and Scunthorpe Health Authority, a district of the former Yorkshire Region, before the April 1996 boundary changes). Patients with a primary diagnosis of IHD aged > or = 25 years who underwent investigation by angiography, or treatment by coronary artery bypass grafting or percutaneous transluminal coronary angioplasty, as a primary procedure. In 1992/4, before concerted intervention, both investigation and revascularisation rates, although increasing, were low in Grimsby and Scunthorpe district compared with most other districts in the Yorkshire Region. Also, there was a decreasing trend across Super Profile Lifestyle groups from the Affluent Achievers to the Have-Nots despite a two-fold increase in SMRs indicating the greater need of the more deprived. After appointing a consultant general physician with an interest in cardiology in the Scunthorpe district general hospital in 1994; arranging for both the Grimsby physician and the Scunthorpe physician to undertake angiography at a neighbouring district tertiary cardiology centre in 1995; together with significant additional health authority investment in cardiac procedures in 1995/6, district rates increased considerably, (a 41% increase in investigation and a 47% increase in revascularisation rates). Also, after additional resource input began, the trend for angiographies across socioeconomic groups clearly became more equitable, although increased equity for revascularisations is less apparent. Early indications are that additional resources for tertiary cardiology may have reduced socioeconomic inequities in angiography, without being specifically targeted at the needier, more deprived groups. Improvement in socioeconomic equity of utilisation of revascularisation is not yet clear, although data for April 1996 to March 1998 (after a lengthier intervention period) may confirm improved equity. Should this not be so, it might be necessary to specifically target resources to the deprived to increase equity in revascularisation.


Independent component analysis-based algorithm for automatic identification of Raman spectra applied to artistic pigments and pigment mixtures.
A new method has been developed to automatically identify Raman spectra, whether they correspond to single- or multicomponent spectra. The method requires no user input or judgment. There are thus no parameters to be tweaked. Furthermore, it provides a reliability factor on the resulting identification, with the aim of becoming a useful support tool for the analyst in the decision-making process. The method relies on the multivariate techniques of principal component analysis (PCA) and independent component analysis (ICA), and on some metrics. It has been developed for the application of automated spectral analysis, where the analyzed spectrum is provided by a spectrometer that has no previous knowledge of the analyzed sample, meaning that the number of components in the sample is unknown. We describe the details of this method and demonstrate its efficiency by identifying both simulated spectra and real spectra. The method has been applied to artistic pigment identification. The reliable and consistent results that were obtained make the methodology a helpful tool suitable for the identification of pigments in artwork or in paint in general.


In vitro characterization and preclinical immunogenicity of Typhax, a typhoid fever protein capsular matrix vaccine candidate.
Typhax is an investigational typhoid fever vaccine candidate that was GMP manufactured applying Protein Capsular Matrix Vaccine (PCMV) technology. It consists of Vi polysaccharide antigen, derived from S. Typhi, non-covalently entrapped in a glutaraldehyde catalyzed cross-linked α-poly-L-lysine and CRM197 protein matrix. Analysis of Typhax determined the average molecular weight of the vaccine particles was approximately 6 x 106 Daltons, corresponding to particles containing 1-2 molecules of Vi polysaccharide and 10-20 molecules of CRM197 protein. The ratio of the concentration of Vi to CRM197 protein in Typhax is 2.4:1. Preclinical immunogenicity studies in mice demonstrated that Typhax was immunogenic and elicited a significant increase in anti-Vi IgG antibody titers following each immunization. The anti-Vi IgG antibody response elicited by Typhax in rabbits increased as the dose increased from 0.1 µg to 2.5 µg. Further, at the 2.5 and 10 µg dose levels, the anti-Vi IgG antibody titers increased after the second and third immunizations. At the 10 µg dose level, 100% of rabbits seroconverted. In the non-human primate (NHP) study, 100% seroconversion was observed at both 2.5 µg and 10 µg dose levels after the first immunization. A murine in vivo immunopotency study demonstrated that Typhax stored at 4°C was stable for at least 30 months. Collectively, the Typhax in vitro profile, preclinical immunogenicity studies, and rabbit toxicology study indicate that Typhax is a viable typhoid fever vaccine candidate for Phase 1 clinical trial evaluation.


Effects of Hesperidin on H₂O₂-Treated Chondrocytes and Cartilage in a Rat Osteoarthritis Model.
BACKGROUND The purpose of this research was to investigate the effects of hesperidin on hydrogen peroxide (H₂O₂)-induced chondrocytes injury and cartilage degeneration in a rat model of osteoarthritis (OA). MATERIAL AND METHODS Chondrocytes were isolated from rat knee joints and treated with hesperidin alone or combined with H₂O₂. Then, Cell Counting Kit-8 (CCK-8) assay was used to assess cell viability. Activity of reactive oxygen species (ROS) and levels of malondialdehyde (MDA) were estimated. Cell apoptosis was assessed by flow cytometry assay. In addition, gene expression levels were measured for caspase 3, tumor necrosis factor-alpha (TNF-α), interleukin-1beta (IL-1β), collagen type II (Col2a1), aggrecan, (sex-determining region Y)-box 9 (SOX9), matrix metalloproteinase (MMP)-13, and inducible nitric oxide synthase (iNOS) through quantitative real-time polymerase chain reaction (qPCR). To examine the effects on cartilage destruction in vivo, hesperidin or vehicle control were orally administrated in a surgically-induced osteoarthritis (OA) model. RESULTS The results indicated that hesperidin pretreatment of chondrocytes reduce H₂O₂-induced cytotoxicity and apoptosis. Hesperidin pretreatment decreased the formation of MDA and intracellular ROS, including chondrocyte apoptosis. Hesperidin also reversed the activity of H₂O₂ on inhibiting the Col2a1, aggrecan, and SOX9 gene expression and increasing the gene expression of caspase 3, IL-1β, TNFα, iNOS, and MMP13. In addition, hesperidin administration markedly attenuated cartilage destruction and reduced IL-1β and TNF-α levels in a surgically-induced OA model. CONCLUSIONS Our study suggests that hesperidin can prevent H₂O₂-induced chondrocytes injury through its antioxidant effects in vitro and reduce cartilage damage in a rat model of OA.