Recovered insulin response by 2 weeks of leptin administration in high-fat fed rats is associated with restored AS160 activation and decreased reactive lipid accumulation.
Leptin is an adipokine that increases fatty acid (FA) oxidation, decreases intramuscular lipid stores, and improves insulin response in skeletal muscle. In an attempt to elucidate the underlying mechanisms by which these metabolic changes occur, we administered leptin (Lep) or saline (Sal) by miniosmotic pumps to rats during the final 2 wk of a 6-wk low-fat (LF) or high-fat (HF) diet. Insulin-stimulated glucose transport was impaired by the HF diet (HF-Sal) but was restored with leptin administration (HF-Lep). This improvement was associated with restored phosphorylation of Akt and AS160 and decreased in reactive lipid species (ceramide, diacylglycerol), known inhibitors of the insulin-signaling cascade. Total muscle citrate synthase (CS) activity was increased by both leptin and HF diet, but was not additive. Leptin increased subsarcolemmal (SS) and intramyofibrillar (IMF) mitochondria CS activity. Total muscle, sarcolemmal, and mitochondrial (SS and IMF) FA transporter (FAT/CD36) protein content was significantly increased with the HF diet, but not altered by leptin. Therefore, the decrease in reactive lipid stores and subsequent improvement in insulin response, secondary to leptin administration in rats fed a HF diet was not due to a decrease in FA transport protein content or altered cellular distribution.


The primary hyperoxalurias: an algorithm for diagnosis.
The primary hyperoxalurias (PHs) are inborn errors of metabolism resulting in increased urinary excretion of oxalate. Nephrolithiasis, nephrocalcinosis, and renal failure result. Renal failure can occur as early as infancy or as late as the sixth decade of life, and if not addressed promptly, results in severe morbidity and mortality related to systemic oxalate deposition (oxalosis). Clinicians are likely to encounter few PH patients during a practicing lifetime. Definitive diagnosis requires special studies performed in only a small number of laboratories worldwide. Accordingly, delays in diagnosis are common. An evidence-based guideline for diagnosis was developed. Patients with stones or nephrocalcinosis in childhood, recurrent calcium oxalate stones in adulthood, or renal insufficiency associated with stones or nephrocalcinosis should be evaluated for PH. A systematic approach to measurement of urine oxalate, glycolate and glycerate, and plasma oxalate is provided. Age-related variation in urine oxalate requires attention to normal ranges. Molecular analysis for mutations of the AGXT gene (PH, type I) or GRHPR gene (PH, type II) is definitive in some patients, while liver enzyme analysis is required for confirmation of the diagnosis in the remainder. An evidence-based algorithm will facilitate recognition and diagnosis of patients with the PHs, permitting earlier treatment.


Benchmarking Attention-Based Interpretability of Deep Learning in Multivariate Time Series Predictions.
The adaptation of deep learning models within safety-critical systems cannot rely only on good prediction performance but needs to provide interpretable and robust explanations for their decisions. When modeling complex sequences, attention mechanisms are regarded as the established approach to support deep neural networks with intrinsic interpretability. This paper focuses on the emerging trend of specifically designing diagnostic datasets for understanding the inner workings of attention mechanism based deep learning models for multivariate forecasting tasks. We design a novel benchmark of synthetically designed datasets with the transparent underlying generating process of multiple time series interactions with increasing complexity. The benchmark enables empirical evaluation of the performance of attention based deep neural networks in three different aspects: (i) prediction performance score, (ii) interpretability correctness, (iii) sensitivity analysis. Our analysis shows that although most models have satisfying and stable prediction performance results, they often fail to give correct interpretability. The only model with both a satisfying performance score and correct interpretability is IMV-LSTM, capturing both autocorrelations and crosscorrelations between multiple time series. Interestingly, while evaluating IMV-LSTM on simulated data from statistical and mechanistic models, the correctness of interpretability increases with more complex datasets.


Flexible endoscopy for management of intraventricular brain tumors in patients with small ventricles.
Endoscopic surgery is generally withheld in patients with small ventricles due to difficulties in ventricular cannulation and intraventricular manipulation. The effectiveness of flexible endoscopy for management of intraventricular brain tumors in patients with small ventricles was evaluated. Forty-five patients who underwent endoscopic surgery with a flexible endoscope for intraventricular brain tumors were divided into small-ventricle and ventriculomegaly groups according to the frontal and occipital horn ratio (FOR). Retrospective review of these cases was performed and achievement of surgical goals and morbidity were assessed. Among the 45 patients, there were 14 with small ventricles and 31 with ventriculomegaly. In the smallventricle group, targeted tumors were located in the suprasellar region in 12 patients and in the pineal region in 2. In the ventriculomegaly group, tumors were located in the pineal region in 15 patients, in the suprasellar region in 9, in the lateral ventricle in 4, in the midbrain in 2, and in the fourth ventricle in 1. In the small-ventricle group, ventricular cannulation was successful and the surgical goals were accomplished in all patients. In ventriculomegaly group, sampling of the tumor was not diagnostic due to intraoperative hemorrhage in 1 patient. There were no significant differences in the rate of achieving the surgical goals or the morbidity between the 2 groups. Endoscopic surgery using a flexible endoscope is useful for management of intraventricular brain tumors in patients with small ventricles. A flexible endoscope allows excellent maneuverability in introducing the device into the lateral ventricle and manipulating through small ventricles.


Targeted inhibition of tumor-specific glutaminase diminishes cell-autonomous tumorigenesis.
Glutaminase (GLS), which converts glutamine to glutamate, plays a key role in cancer cell metabolism, growth, and proliferation. GLS is being explored as a cancer therapeutic target, but whether GLS inhibitors affect cancer cell-autonomous growth or the host microenvironment or have off-target effects is unknown. Here, we report that loss of one copy of Gls blunted tumor progression in an immune-competent MYC-mediated mouse model of hepatocellular carcinoma. Compared with results in untreated animals with MYC-induced hepatocellular carcinoma, administration of the GLS-specific inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES) prolonged survival without any apparent toxicities. BPTES also inhibited growth of a MYC-dependent human B cell lymphoma cell line (P493) by blocking DNA replication, leading to cell death and fragmentation. In mice harboring P493 tumor xenografts, BPTES treatment inhibited tumor cell growth; however, P493 xenografts expressing a BPTES-resistant GLS mutant (GLS-K325A) or overexpressing GLS were not affected by BPTES treatment. Moreover, a customized Vivo-Morpholino that targets human GLS mRNA markedly inhibited P493 xenograft growth without affecting mouse Gls expression. Conversely, a Vivo-Morpholino directed at mouse Gls had no antitumor activity in vivo. Collectively, our studies demonstrate that GLS is required for tumorigenesis and support small molecule and genetic inhibition of GLS as potential approaches for targeting the tumor cell-autonomous dependence on GLS for cancer therapy.


Paradox inflammatory reaction such as appendicitis epiploica and diverticulitis of the sigmoid colon under ongoing immunosuppression after previous liver transplantation (LTx).
Inflammatory reactions caused by immunosuppression appear a particular interesting disease due to its very specific and partly unclear etiopathogenesis.Based on clinical case-specific management experiences and selective references from the literature, the rare case of an acute intraabdominal inflammation as unusual complication or side effect (at the gastrointestinal [GI] tract) of the ongoing immunosuppressive medication using Mycophenolate mofetil and Tacrolimus after previous liver transplantation is to be illustrated. Medical history (hx): 1) Current: A 68-years old male patient underwent abdominal CT scan because of pain in the left lower abdomen with the suspicious diagnosis of diverticulitis leading to initiation of antibiotic therapy 24 h prior to the transferral to the own hospital for adequate liver transplantation (LTx) follow-up investigation. 2) Medication contained Sitagliptin 1 × 100 mg, Omeprazol 1 × 40 mg, Mesalazin 500 mg 3 × 2, Movicol 1 (on demand), Mycophenolate mofetil 2 × 500 mg, Tacrolimus 2 × 1 mg and Hydrochlorothiazid 1 × 2.5 mg. 3) Additional diagnoses included arterial hypertension, diabetes mellitus and urinary bladder diverticle. 4) Previous surgical intervention profile comprises resection of liver segments IV/V due to HCC (2011), orthotopic liver transplantation because of HCC caused by alcohol-induced liver cirrhosis (2013) and an intervertebral disc operation (2018). Physical examination of the abdomen revealed marked tenderness in the lower left quadrant. The abdominal wall was soft and there were no defensive tension and no peritonism. The patient was in good general condition and nutritional status. He was cardiopulmonarily stable and oriented to all qualities. Diagnostic measures showed a CRP of 38.0 (normal range, < 5) mg/L and a white blood cell count within normal range. Leading diagnoses were found using abdominal CT scan, which demonstrated an extended diverticulosis and an appendicitis epiploica within the immediate subperitoneal region of the left lower abdomen with an oval fat isodense structure in the region of the sigmoid colon with surrounding inflammatory imbibition and pronounced intestinal wall. Suspicious diagnosis was the 1st episode of an uncomplicated diverticulitis of the sigmoid colon associated with an appendicitis epiploica. Therapeutic approach was given by conservative therapy with infusion therapy, analgesia as well as inital "n. p. o." and following initiation of oral nutrition. In addition, calculated antibiotic therapy with Cefuroxime and Clont was initiated. Clinical course was uneventful, with discharge on the eighth day of hospital stay with no pathological findings and substantial improvement in clinical and laboratory findings. Further advice consisted of clinical and laboratory follow-up control investigations by the family practitioner and nutritional counselling. In addition, a colonoscopy should be performed within four months. The described case i) is either one of the many side effects of the immunosuppressive medication Mycophenolate mofetil and Tacrolimus listed as "colonic inflammation" and "gastrointestinal inflammation", respectively, or ii) can be considered an inflammatory response of a susceptible (gastro-)intestinal mucosa or the whole intestinal wall to microbes or microbial particles or agents caused by transplantation-associated immunosuppressive medication.


Videoconference-based education for psychiatry registrars at the University of KwaZulu-Natal, South Africa.
Psychiatry registrars form the backbone of specialized psychiatric service provision in South Africa. Medical schools are centralized while clinical services need to be widespread and accessible. Video-conferencing has the potential to link registrars at satellite hospitals with academic centers. The study thus evaluated of the use of videoconferencing in a Psychiatry Education Program delivered via videoconferencing. To evaluate the implementation of the videoconference-based psychiatry registrar program, a pre- and post evaluative design was used. This involved all registrars in the 2008 and 2009 academic education program at the University of KwaZulu-Natal, South Africa. Access to education, satisfaction, suitability and costs of the psychiatry registrar education were studied. In the evaluation of the Registrar Program, general satisfaction with the videoconferencing program was reported, though concerns were expressed about the level of interaction using this mode, the quality of the transmitted pictures of the anatomy specimens and the quality of the sound. Access to education was improved with potential cost savings identified. Well supported and planned videoconference-based teaching is a feasible, cost-effective and acceptable method of supporting registrars at sites distant from academic centers.


Circulating microparticles generate and transport monomeric C-reactive protein in patients with myocardial infarction.
Elevated serum C-reactive protein (CRP) following myocardial infarction (MI) is associated with poor outcomes. Although animal studies have indicated a direct pathogenic role of CRP, the mechanism underlying this remains elusive. Dissociation of pentameric CRP (pCRP) into pro-inflammatory monomers (mCRP) may directly link CRP to inflammation. We investigated whether cellular microparticles (MPs) can convert pCRP to mCRP and transport mCRP following MI. MPs enriched in lysophosphatidylcholine were obtained from cell cultures and patient whole-blood samples collected following acute MI and control groups. Samples were analysed by native western blotting and flow cytometry. MPs were loaded with mCRP in vitro and incubated with endothelial cells prior to staining with monoclonal antibodies. In vitro experiments demonstrated that MPs were capable of converting pCRP to mCRP which could be inhibited by the anti-CRP compound 1,6 bis-phosphocholine. Significantly more mCRP was detected on MPs from patients following MI compared with control groups by western blotting and flow cytometry (P = 0.0005 for association). MPs containing mCRP were able to bind to the surface of endothelial cells and generate pro-inflammatory signals in vitro, suggesting a possible role of MPs in transport and delivery of pro-inflammatory mCRP in vascular disease. Circulating MPs can convert pCRP to pro-inflammatory mCRP in patients following MI, demonstrating for the first time mCRP generation in vivo and its detection in circulating blood. MPs can bind to cell membranes and transfer mCRP to the cell surface, suggesting a possible mCRP transport/delivery role of MPs in the circulation.


Occurrence and diversity of nitrite-dependent anaerobic methane oxidation bacteria in the sediments of the South China Sea revealed by amplification of both 16S rRNA and pmoA genes.
Nitrite-dependent anaerobic methane oxidation (n-damo) process is unique in linking the microbial carbon and nitrogen cycles, but the presence of n-damo bacteria in marine ecosystem and the associated environmental factors are still poorly understood. In the present study, detection of n-damo bacteria using 16S rRNA and pmoA gene-based PCR primers was successfully employed to reveal their diversity and distribution in the surface and subsurface sediments of the South China Sea (SCS). The widespread occurrence of n-damo bacteria in both the surface and subsurface sediments with high diversity has been confirmed in this study. The pmoA gene-amplified sequences clustered within three newly erected subclusters, namely SCS-1, SCS-2, and SCS-3, suggesting the unique niche specificity of n-damo bacteria in the marine ecosystem. Results indicated the presence of n-damo bacteria in the west Pacific Ocean with a wide distribution from the continental shelf (E201S) to the deep abyss (E407S and E407B). Community structures of n-damo bacteria in SCS are clearly different from those of nonmarine ones known. It is also found that NO x (-) and NH4 (+) affected the community structures and distribution of n-damo bacteria in the SCS sediments differently. Salinity is another important factor identified, shaping the n-damo communities in marine environments. The community based on pmoA gene-amplified sequences, and community richness and diversity based on 16S rRNA gene-amplified sequences correlated with temperature.


Effective Dosage of Midazolam to Erase the Memory of Vascular Pain During Propofol Administration.
Intravenous sedation with propofol is often administered to anxious patients in dental practice. Pain on injection of propofol is a common adverse effect. This study aimed to determine the age-adjusted doses of midazolam required to erase memory of vascular pain of propofol administration and assess whether the Ramsay Sedation Scale (RSS) after the pretreatment of midazolam was useful to predict amnesia of the vascular pain of propofol administration. A total of 246 patients with dental phobia requiring dental treatment under intravenous sedation were included. Patients were classified according to their age: 30s, 40s, 50s, and 60s. Three minutes after administration of a predetermined dose of midazolam, propofol was infused continuously. After completion of the dental procedure, patients were interviewed about the memory of any pain or discomfort in the injection site or forearm. The dosage of midazolam was determined using the Dixon up-down method. The first patient was administered 0.03 mg/kg, and if memory of vascular pain remained, the dosage was increased by 0.01 mg/kg for the next patient, and then if the memory was erased, the dosage was decreased by 0.01 mg/kg. The effective dosage of midazolam in 95% of each age group for erasing the memory of propofol vascular pain (ED95) was determined using logistic analysis. The accuracy of RSS to predict the amnesia of injection pain was assessed by receiver operating characteristic (ROC) analysis. The ED95 of midazolam to erase the memory of propofol vascular pain was 0.061 mg/kg in patients in their 30s, 0.049 mg/kg in patients in their 40s, 0.033 mg/kg in patients in their 50s, and 0.033 mg/kg in patients in their 60s. The area under the ROC curve was 0.31. The ED95 of midazolam required to erase the memory of propofol vascular pain demonstrated a downward trend with age. On the other hand, it was impossible to predict the amnesia of propofol vascular pain using the RSS.


Single cell RNA sequencing of human microglia uncovers a subset associated with Alzheimer's disease.
The extent of microglial heterogeneity in humans remains a central yet poorly explored question in light of the development of therapies targeting this cell type. Here, we investigate the population structure of live microglia purified from human cerebral cortex samples obtained at autopsy and during neurosurgical procedures. Using single cell RNA sequencing, we find that some subsets are enriched for disease-related genes and RNA signatures. We confirm the presence of four of these microglial subpopulations histologically and illustrate the utility of our data by characterizing further microglial cluster 7, enriched for genes depleted in the cortex of individuals with Alzheimer's disease (AD). Histologically, these cluster 7 microglia are reduced in frequency in AD tissue, and we validate this observation in an independent set of single nucleus data. Thus, our live human microglia identify a range of subtypes, and we prioritize one of these as being altered in AD.


Shock-induced hyperalgesia: III. Role of the bed nucleus of the stria terminalis and amygdaloid nuclei.
Rats exposed to a few moderately intense (1 mA) shocks subsequently exhibit lower vocalization thresholds to shock and thermal stimuli. They also exhibit facilitated learning in a Pavlovian conditioning paradigm. Together, these results suggest that shock exposure can enhance pain (hyperalgesia). The present study examined the role of the amygdala and bed nucleus of the stria terminalis (BNST), 2 systems that have been implicated in the induction and maintenance of negative affective states. Experiment 1 showed that lesions of the central, but not the basolateral, amygdala eliminate shock-induced hyperalgesia as measured by a decrease in vocalization thresholds to shock. Experiment 2 revealed that central nucleus lesions also prevent shock-induced sensitization of the vocalization response to heat. Anterior, but not posterior, BNST lesions had a similar effect.


The neurobiology and pharmacology of depression. A comparative overview of serotonin selective antidepressants.
Over the past decade, targeted drug design has led to significant advances in the pharmacological management of depression. A serendipitous approach to drug discovery has therefore been replaced by the development of drugs acting on predetermined neurobiological targets recognised to be involved in the pathology of depressive illness. The first of these 'designer drugs', were the selective serotonin (5-HT) re-uptake inhibitors (SSRIs), followed more recently by venlafaxine and nefazodone which, in addition to 5-HT uptake, also target noradrenaline (NA) uptake and 5-HT2 receptors, respectively. This paper reviews the biochemistry and pharmacology of depression. From this foundation, the relevance of 5-HT selectivity is discussed followed by a comparison of the clinical pharmacology and pharmacokinetics of 5-HT-selective antidepressants. Despite their common action on synaptic 5-HT uptake, structural heterogeneity among the group allows differences to be observed in kinetic and pharmacological parameters, viz. plasma half-life (T1/2), liver metabolism, protein binding, receptor affinities and selectivity ratios. This not only leeds to different attributes which assist in the successful management of a particular patient, but will also predict subtle difference in drug interaction risks and in side-effect profiles of clinical relevance. 5-HT-selective antidepressants may be more dissimilar than similar, and these differences can allow the clinician to identify clinically reliable determinates predicting side-effects and, possibly, to identify suitable patients for a particular drug.


Long-term neurocognitive and other side effects of radiotherapy, with or without chemotherapy, for glioma.
Gliomas are brain tumours arising from glial cells with an annual incidence of 4 to 11 people per 100,000. In this review we focus on gliomas with low aggressive potential in the short term, i.e. low-grade gliomas. Most people with low-grade gliomas are treated with surgery and may receive radiotherapy thereafter. However, there is concern about the possible long-term effects of radiotherapy, especially on neurocognitive functioning. To evaluate the long-term neurocognitive and other side effects of radiotherapy (with or without chemotherapy) compared with no radiotherapy, or different types of radiotherapy, among people with glioma (where 'long-term' is defined as at least two years after diagnosis); and to write a brief economic commentary. We searched the following databases on 16 February 2018 and updated the search on 14 November 2018: Cochrane Central Register of Controlled Trials (CENTRAL; 2018, Issue 11) in the Cochrane Library; MEDLINE via Ovid; and Embase via Ovid. We also searched clinical trial registries and relevant conference proceedings from 2014 to 2018 to identify ongoing and unpublished studies. Randomised and non-randomised trials, and controlled before-and-after studies (CBAS). Participants were aged 16 years and older with cerebral glioma other than glioblastoma. We included studies where patients in at least one treatment arm received radiotherapy, with or without chemotherapy, and where neurocognitive outcomes were assessed two or more years after treatment. Two review authors independently extracted data and assessed risk of bias. We assessed the certainty of findings using the GRADE approach. The review includes nine studies: seven studies were of low-grade glioma and two were of grade 3 glioma. Altogether 2406 participants were involved but there was high sample attrition and outcome data were available for a minority of people at final study assessments. In seven of the nine studies, participants were recruited to randomised controlled trials (RCTs) in which longer-term follow-up was undertaken in a subset of people that had survived without disease progression. There was moderate to high risk of bias in studies due to lack of blinding and high attrition, and in two observational studies there was high risk of selection bias. Paucity of data and risk of bias meant that evidence was of low to very low certainty. We were unable to combine results in meta-analysis due to diversity in interventions and outcomes.The studies examined the following five comparisons.Radiotherapy versus no adjuvant treatmentTwo observational studies contributed data. At the 12-year follow-up in one study, the risk of cognitive impairment (defined as cognitive disability deficits in at least five of 18 neuropsychological tests) was greater in the radiotherapy group (risk ratio (RR) 1.95, 95% confidence interval (CI) 1.02 to 3.71; n = 65); at five to six years the difference between groups did not reach statistical significance (RR 1.38, 95% CI 0.92 to 2.06; n = 195). In the other study, one subject in the radiotherapy group had cognitive impairment (defined as significant deterioration in eight of 12 neuropsychological tests) at two years compared with none in the control group (very low certainty evidence).With regard to neurocognitive scores, in one study the radiotherapy group was reported to have had significantly worse mean scores on some tests compared with no radiotherapy; however, the raw data were only given for significant findings. In the second study, there were no clear differences in any of the various cognitive outcomes at two years (n = 31) and four years (n = 15) (very low certainty evidence).Radiotherapy versus chemotherapyOne RCT contributed data on cognitive impairment at up to three years with no clear difference between arms (RR 1.43, 95% CI 0.36 to 5.70, n = 117) (low-certainty evidence).High-dose radiotherapy versus low-dose radiotherapyOnly one of two studies reporting this comparison contributed data, and at two and five years there were no clear differences between high- and low-dose radiotherapy arms (very low certainty evidence).Conventional radiotherapy versus stereotactic conformal radiotherapyOne study involving younger people contributed limited data from the subgroup aged 16 to 25 years. The numbers of participants with neurocognitive impairment at five years after treatment were two out of 12 in the conventional arm versus none out of 11 in the stereotactic conformal radiotherapy arm (RR 4.62, 95% CI 0.25 to 86.72; n = 23; low-certainty evidence).Chemoradiotherapy versus radiotherapyTwo RCTs tested for cognitive impairment. One defined cognitive impairment as a decline of more than 3 points in MMSE score compared with baseline and reported data from 2-year (110 participants), 3-year (91 participants), and 5-year (57 participants) follow-up with no clear difference between the two arms at any time point. A second study did not report raw data but measured MMSE scores over five years in 126 participants at two years, 110 at three years, 69 at four years and 53 at five years. Authors concluded that there was no difference in MMSE scores between the two study arms (P = 0.4752) (low-certainty evidence).Two RCTs reported quality of life (QoL) outcomes for this comparison. One reported no differences in Brain-QoL scores between study arms over a 5-year follow-up period (P = 0.2767; no raw data were given and denominators were not stated). The other trial reported that the long-term results of health-related QoL showed no difference between the arms but did not give the raw data for overall HRQoL scores (low-certainty evidence).We found no comparative data on endocrine dysfunction; we planned to develop a brief economic commentary but found no relevant economic studies for inclusion. Radiotherapy for gliomas with a good prognosis may increase the risk of neurocognitive side effects in the long term; however the magnitude of the risk is uncertain. Evidence on long-term neurocognitive side effects associated with chemoradiotherapy is also uncertain. Neurocognitive assessment should be an integral part of long-term follow-up in trials involving radiotherapy for lower-grade gliomas to improve the certainty of evidence regarding long-term neurocognitive effects. Such trials should also assess other potential long-term effects, including endocrine dysfunction, and evaluate costs and cost effectiveness.


Investigating factors influencing 4th-year physiotherapy students' opinions of cardiorespiratory physiotherapy as a career path.
Recruitment and retention issues in cardiorespiratory physiotherapy (CRP) have led to concerns for the future of this specialist area of physiotherapy. This study evaluated the career choices of student physiotherapists and elicited factors that influenced their perceptions of CRP. A postal questionnaire to two schools of physiotherapy in New Zealand and two in Australia was administered. Final year students were randomly selected and invited to complete the questionnaire. Details of respondents' clinical experience, future career intentions, and perceptions of CRP as a specialism were ascertained. A response rate of 61% (n=149) was obtained. Although the majority of respondents had undertaken cardiorespiratory placements, only 3% of respondents reported being "extremely interested" in specializing in CRP. The variety and timing of clinical placements and educational and clinical supervision were key factors that had the potential to both positively and negatively influence students' opinions of CRP. An understanding of the role of CRP beyond that of inpatient care appeared limited. To promote uptake of CRP as a career option, clinicians, educators, and managers should strive to provide positive clinical placements and educational opportunities. The extensive scope of clinical practice of cardiorespiratory physiotherapists could be a greater focus within physiotherapy curricula.


Cell to Cell Variability of Radiation-Induced Foci: Relation between Observed Damage and Energy Deposition.
Most studies that aim to understand the interactions between different types of photon radiation and cellular DNA assume homogeneous cell irradiation, with all cells receiving the same amount of energy. The level of DNA damage is therefore generally determined by averaging it over the entire population of exposed cells. However, evaluating the molecular consequences of a stochastic phenomenon such as energy deposition of ionizing radiation by measuring only an average effect may not be sufficient for understanding some aspects of the cellular response to this radiation. The variance among the cells associated with this average effect may also be important for the behaviour of irradiated tissue. In this study, we accurately estimated the distribution of the number of radiation-induced γH2AX foci (RIF) per cell nucleus in a large population of endothelial cells exposed to 3 macroscopic doses of gamma rays from 60Co. The number of RIF varied significantly and reproducibly from cell to cell, with its relative standard deviation ranging from 36% to 18% depending on the macroscopic dose delivered. Interestingly, this relative cell-to-cell variability increased as the dose decreased, contrary to the mean RIF count per cell. This result shows that the dose effect, in terms of the number of DNA lesions indicated by RIF is not as simple as a purely proportional relation in which relative SD is constant with dose. To analyse the origins of this observed variability, we calculated the spread of the specific energy distribution for the different target volumes and subvolumes in which RIF can be generated. Variances, standard deviations and relative standard deviations all changed similarly from dose to dose for biological and calculated microdosimetric values. This similarity is an important argument that supports the hypothesis of the conservation of the association between the number of RIF per nucleus and the specific energy per DNA molecule. This comparison allowed us to calculate a volume of 1.6 μm3 for which the spread of the specific energy distribution could explain the entire variability of RIF counts per cell in an exposed cell population. The definition of this volume may allow to use a microdosimetric quantity to predict heterogeneity in DNA damage. Moreover, this value is consistent with the order of magnitude of the volume occupied by the hydrated sugar-phosphate backbone of the DNA molecule, which is the part of the DNA molecule responsible for strand breaks.


Characterization of disulfide bonds by planned digestion and tandem mass spectrometry.
The identification of disulfide bonds provides critical information regarding the structure and function of a protein and is a key aspect in understanding signaling cascades in biological systems. Recent proteomic approaches using digestion enzymes have facilitated the characterization of disulfide-bonds and/or oxidized products from cysteine residues, although these methods have limitations in the application of MS/MS. For example, protein digestion to obtain the native form of disulfide bonds results in short lengths of amino acids, which can cause ambiguous MS/MS analysis due to false positive identifications. In this study we propose a new approach, termed planned digestion, to obtain sufficient amino acid lengths after cleavage for proteomic approaches. Application of the DBond software to planned digestion of specific proteins accurately identified disulfide-linked peptides. RNase A was used as a model protein in this study because the disulfide bonds of this protein have been well characterized. Application of this approach to peptides digested with Asp-N/C (chemical digestion) and trypsin under acid hydrolysis conditions identified the four native disulfide bonds of RNase A. Missed cleavages introduced by trypsin treatment for only 3 hours generated sufficient lengths of amino acids for identification of the disulfide bonds. Analysis using MS/MS successfully showed additional fragmentation patterns that are cleavage products of S-S and C-S bonds of disulfide-linkage peptides. These fragmentation patterns generate thioaldehydes, persulfide, and dehydroalanine. This approach of planned digestion with missed cleavages using the DBond algorithm could be applied to other proteins to determine their disulfide linkage and the oxidation patterns of cysteine residues.


Comparative Effectiveness of Injection Therapies for Hemiplegic Shoulder Pain in Stroke: A Systematic Review and Network Meta-Analysis.
Hemiplegic shoulder pain (HSP) hampers post-stroke functional recovery and is not well managed with conservative treatments. This systematic review aimed to examine the various injection therapies for HSP and investigate their effectiveness at different time points. The protocol of this meta-analysis was registered on INPLASY with a registration number of INPLASY202180010. PubMed, EMBASE, and Scopus were searched from their inception to 4 August 2021 for the clinical studies investigating comparative effectiveness of different injection regimens for treating hemiplegic shoulder pain in patients with stroke. The primary outcome was the weighted mean difference (WMD) on the visual analog scale (VAS) of pain reduction in the fourth-week and between the fourth and twenty-fourth weeks. Ranking probabilities of the WMD for each treatment were obtained using simulations. Seventeen studies with 595 participants were included. The network meta-analysis showed that at the fourth-week, intra-muscular botulinum toxin (BoNT) injections and suprascapular nerve blocks (SSNB) were superior to a placebo, with WMDs of 1.55 (95% CI, 0.09 to 3.01) and 1.44 (95% CI, 0.07 to 2.80), respectively. SSNB possessed the highest probability (53.3%) and appeared to be the best treatment in the fourth-week, followed by intra-muscular BoNT injections (42.6%). Intramuscular BoNT injections were better than the placebo, with a WMD of 1.57 (95% CI, 0.30 to 2.84) between the 4th and 24th weeks. Intramuscular BoNT injections had the highest probability (79.8%) as the best treatment between the 4th and 24th weeks. SSNB was likely to rank first in relieving HSP at the fourth post-treatment week, whereas intra-muscular BoNT injections had the highest probability to achieve the best treatment effectiveness in the post-injection period between the fourth and twenty-fourth weeks. However, as some of the included studies used a non-randomized controlled design, more randomized controlled trials are needed in the future to validate and better understand the short- and long-term efficacy of different injection therapies for management of HSP.


Photobiomodulation Facilitates Rat Cutaneous Wound Healing by Promoting Epidermal Stem Cells and Hair Follicle Stem Cells Proliferation.
Cutaneous wound healing represents a common fundamental phenomenon requiring the participation of cells of distinct types and a major concern for the public. Evidence has confirmed that photobiomodulation (PBM) using near-infrared (NIR) can promote wound healing, but the cells involved and the precise molecular mechanisms remain elusive. Full-thickness skin defects with a diameter of 1.0 cm were made on the back of rats and randomly divided into the control group, 10 J, 15 J, and 30 J groups. The wound healing rate at days 4, 8, and 12 postoperatively was measured. HE and Masson staining was conducted to reveal the histological characteristics. Immunofluorescence staining was performed to label the epidermal stem cells (ESCs) and hair follicle stem cells (HFSCs). Western blot was performed to detect the expressions of proteins associated with ESCs and HFSCs. Cutaneous wound tissues were collected for RNA sequencing. Gene ontology and the Kyoto Encyclopedia of Genes and Genomes analysis was performed, and the hub genes were identified using CytoHubba and validated by qRT-PCR. PBM can promote reepithelialization, extracellular matrix deposition, and wound healing, increase the number of KRT14+/PCNA+ ESCs and KRT15+/PCNA+ HFSCs, and upregulate the protein expression of P63, Krt14, and PCNA. Three hundred and sixty-six differentially expressed genes (DEGs) and 7 hub genes including Sox9, Krt5, Epcam, Cdh1, Cdh3, Dsp, and Pkp3 were identified. These DEGs are enriched in skin development, cell junction, and cadherin binding involved in cell-cell adhesion etc., while these hub genes are related to skin derived stem cells and cell adhesion. PBM accelerates wound healing by enhancing reepithelialization through promoting ESCs and HFSCs proliferation and elevating the expression of genes associated with stem cells and cell adhesion. This may provide a valuable alternative strategy to promote wound healing and reepithelialization by modulating the proliferation of skin derived stem cells and regulating genes related to cell adhesion.


Examining the controllability of sepsis using genetic algorithms on an agent-based model of systemic inflammation.
Sepsis, a manifestation of the body's inflammatory response to injury and infection, has a mortality rate of between 28%-50% and affects approximately 1 million patients annually in the United States. Currently, there are no therapies targeting the cellular/molecular processes driving sepsis that have demonstrated the ability to control this disease process in the clinical setting. We propose that this is in great part due to the considerable heterogeneity of the clinical trajectories that constitute clinical "sepsis," and that determining how this system can be controlled back into a state of health requires the application of concepts drawn from the field of dynamical systems. In this work, we consider the human immune system to be a random dynamical system, and investigate its potential controllability using an agent-based model of the innate immune response (the Innate Immune Response ABM or IIRABM) as a surrogate, proxy system. Simulation experiments with the IIRABM provide an explanation as to why single/limited cytokine perturbations at a single, or small number of, time points is unlikely to significantly improve the mortality rate of sepsis. We then use genetic algorithms (GA) to explore and characterize multi-targeted control strategies for the random dynamical immune system that guide it from a persistent, non-recovering inflammatory state (functionally equivalent to the clinical states of systemic inflammatory response syndrome (SIRS) or sepsis) to a state of health. We train the GA on a single parameter set with multiple stochastic replicates, and show that while the calculated results show good generalizability, more advanced strategies are needed to achieve the goal of adaptive personalized medicine. This work evaluating the extent of interventions needed to control a simplified surrogate model of sepsis provides insight into the scope of the clinical challenge, and can serve as a guide on the path towards true "precision control" of sepsis.


Ticagrelor Monotherapy After PCI in High-Risk Patients With Prior MI: A Prespecified TWILIGHT Substudy.
The aim of this study was to evaluate if patients with prior myocardial infarction (MI) could benefit from ticagrelor monotherapy in terms of bleeding reduction without any compromise in ischemic event prevention. Patients with history of MI who undergo percutaneous coronary intervention (PCI) remain at risk for recurrent ischemic events. The optimal antithrombotic strategy for this cohort remains debated. In this prespecified analysis of the randomized TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients after Coronary Intervention) trial, the authors evaluated the impact of history of MI on treatment effect of ticagrelor monotherapy versus ticagrelor plus aspirin in patients undergoing PCI with drug-eluting stent with at least 1 clinical and 1 angiographic high-risk feature and free from adverse events at 3 months after index PCI. The primary endpoint was Bleeding Academic Research Consortium type 2, 3, or 5 bleeding, and the key secondary endpoint was the composite of all-cause death, MI, or stroke, both at 12 months after randomization. A total of 1,937 patients (29.7%) with and 4,595 patients (70.3%) without prior MI were randomized to ticagrelor and placebo or ticagrelor and aspirin. At 1 year after randomization, patients with prior MI experienced higher rates of death, MI, or stroke (5.7% vs 3.2%; P < 0.001) but similar BARC types 2 to 5 bleeding (5.0% vs 5.5%; P = 0.677) compared with patients without prior MI. Ticagrelor monotherapy consistently reduced the risk for the primary bleeding outcome in patients with (3.4% vs 6.7%; HR: 0.50; 95% CI: 0.33-0.76) and without (4.2% vs 7.0%; HR: 0.58; 95% CI: 0.45-0.76; Pinteraction = 0.54) prior MI. Rates of the key secondary ischemic outcome were not significantly different between treatment groups irrespective of history of MI (prior MI, 6.0% vs 5.5% [HR: 1.09; 95% CI: 0.75-1.58]; no prior MI, 3.1% vs 3.3% [HR: 0.92; 95% CI: 0.67-1.28]; Pinteraction = 0.52). Ticagrelor monotherapy is associated with significantly lower risk for bleeding events compared with ticagrelor plus aspirin, without any compromise in ischemic prevention, among high-risk patients with history of MI undergoing PCI. (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention [TWILIGHT]; NCT02270242).


Community structure, population structure and topographical specialisation of Gyrodactylus (monogenea) ectoparasites living on sympatric stickleback species.
In order to disentangle the contribution of host and parasite biology to host specificity, we compared the structure and population dynamics of the Gyrodactylus (von Nordmann, 1832) flatworm community living on sympatric three-spined Gasterosteus aculeatus L. and nine-spined Pungitius pungitius (L.) stickleback. Between April 2002 and March 2003, a small lowland creek was sampled monthly. Species identity of about 75% of the worms per host was determined with a genetic nuclear marker (ITS1). Each stickleback species hosted a characteristic gill- and fin-parasitic Gyrodactylus: G. arcuatus Bychowsky, 1933 and G. gasterostei Gläser, 1974 respectively infecting the three-spined stickleback, with G. rarus Wegener, 1910 and G. pungitii Malmberg, 1964 infecting the nine-spined stickleback. Host size and seasonal dynamics were strong determinants of parasite abundance. A strong interaction between host and parasite species determined infection levels and affected three levels of parasite organisation: community structure, population structure and topographical specialisation. Community and population structure were shaped by asymmetric cross-infections, resulting in a net transmission of the Gyro-dactylus species typical of the nine-spined stickleback towards the three-spined stickleback. Host density was not a major determinant of parasite exchange. Aggregation and topographical specialisation of the Gyrodactylus species of the three-spined stickleback were more pronounced than that of the nine-spined stickleback.


Neurovascular deconvolution of optical signals as a proxy for the true neuronal inputs.
Since the Kalman filter and Monte Carlo techniques, much theoretical work has been put into the development of signal deconvolution tools. Among recent developments taking place in neuroscience are Dynamic Expectation Maximization, Generalized Filtering and the Cubature Kalman Filter. While there are exciting prospects to use these tools for Dynamic Causal Modeling and other analyses of networks, there has been comparatively little work to validate the algorithms on controlled experimental data. In this work, the latest evolution of these tools, the square-root cubature Kalman smoother (SCKS), is tested for its effectiveness on multimodal neurovascular data. Multispectral intrinsic optical imaging and electrophysiological measurements of Wistar rats are used in combination with somatosensory stimulation. The Buxton-Friston (B-F) balloon model is then deconvolved with the SCKS algorithm to obtain the estimated neuronal inputs u(t) from the hemodynamic measurements (flow, oxy- and deoxygenated hemoglobin). The estimated neuronal inputs are compared to the stimulation protocol and a sensitivity and specificity analysis is carried out. SCKS succeeds in recovering most of the stimulations. Next, the estimated inputs are compared to actual measures of neuronal activity: local field potentials (LFPs) and multiunit activity (MUA). Good sensitivity of the technique is obtained with both LFPs and MUA over the whole recordings, with the area of the ROC curves favoring LFPs. A weak correlation between SCKS estimated inputs and LFPs is found outside stimulation periods, significant at one standard deviation. Finally, the accuracy of state reconstructions is studied and SCKS reconstructed states are highly concordant with measured states.


Crystal Structure of African Swine Fever Virus dUTPase Reveals a Potential Drug Target.
E165R, a highly specific dUTP nucleotidohydrolase (dUTPase) encoded by the African swine fever virus (ASFV) genome, is required for productive replication of ASFV in swine macrophages. Here, we solved the high-resolution crystal structures of E165R in its apo state and in complex with its product dUMP. Structural analysis explicitly defined the architecture of the active site of the enzyme as well as the interaction between the active site and the dUMP ligand. By comparing the ASFV E165R structure with dUTPase structures from other species, we found that the active site of E165R is highly similar to those of dUTPases from Mycobacterium tuberculosis and Plasmodium falciparum, against which small-molecule chemicals have been developed, which could be the potential drug or lead compound candidates for ASFV. Our results provide important basis for anti-ASFV drug design by targeting E165R.IMPORTANCE African swine fever virus (ASFV), an Asfivirus affecting pigs and wild boars with up to 100% case fatality rate, is currently rampaging throughout China and some other countries in Asia. There is an urgent need to develop therapeutic and preventive reagents against the virus. Our crystallographic and biochemical studies reveal that ASFV E165R is a member of trimeric dUTP nucleotidohydrolase (dUTPase) family that catalyzes the hydrolysis of dUTP into dUMP. Our apo-E165R and E165R-dUMP structures reveal the constitutive residues and the configuration of the active center of this enzyme in rich detail and give evidence that the active center of E165R is very similar to that of dUTPases from Plasmodium falciparum and Mycobacterium tuberculosis, which have already been used as targets for designing drugs. Therefore, our high-resolution structures of E165R provide useful structural information for chemotherapeutic drug design.


Microsatellite instability induced mutations in DNA repair genes CtIP and MRE11 confer hypersensitivity to poly (ADP-ribose) polymerase inhibitors in myeloid malignancies.
Inactivation of the DNA mismatch repair pathway manifests as microsatellite instability, an accumulation of mutations that drives carcinogenesis. Here, we determined whether microsatellite instability in acute myeloid leukemia and myelodysplastic syndrome correlated with chromosomal instability and poly (ADP-ribose) polymerase (PARP) inhibitor sensitivity through disruption of DNA repair function. Acute myeloid leukemia cell lines (n=12) and primary cell samples (n=18), and bone marrow mononuclear cells from high-risk myelodysplastic syndrome patients (n=63) were profiled for microsatellite instability using fluorescent fragment polymerase chain reaction. PARP inhibitor sensitivity was performed using cell survival, annexin V staining and cell cycle analysis. Homologous recombination was studied using immunocytochemical analysis. SNP karyotyping was used to study chromosomal instability. RNA silencing, Western blotting and gene expression analysis was used to study the functional consequences of mutations. Acute myeloid leukemia cell lines (4 of 12, 33%) and primary samples (2 of 18, 11%) exhibited microsatellite instability with mono-allelic mutations in CtIP and MRE11. These changes were associated with reduced expression of mismatch repair pathway components, MSH2, MSH6 and MLH1. Both microsatellite instability positive primary acute myeloid leukemia samples and cell lines demonstrated a downregulation of homologous recombination DNA repair conferring marked sensitivity to PARP inhibitors. Similarly, bone marrow mononuclear cells from 11 of 56 (20%) patients with de novo high-risk myelodysplastic syndrome exhibited microsatellite instability. Significantly, all 11 patients with microsatellite instability had cytogenetic abnormalities with 4 of them (36%) possessing a mono-allelic microsatellite mutation in CtIP. Furthermore, 50% reduction in CtIP expression by RNA silencing also down-regulated homologous recombination DNA repair responses conferring PARP inhibitor sensitivity, whilst CtIP differentially regulated the expression of homologous recombination modulating RecQ helicases, WRN and BLM. In conclusion, microsatellite instability dependent mutations in DNA repair genes, CtIP and MRE11 are detected in myeloid malignancies conferring hypersensitivity to PARP inhibitors. Microsatellite instability is significantly correlated with chromosomal instability in myeloid malignancies.


Hearing evaluation with ABR in pediatric patients with celiac disease.
Celiac disease (CD) is an autoimmune and genetic disease that is triggered by gluten intolerance. We aimed to investigate whether Celiac disease have any effect on Auditory Brainstem Response (ABR) waves compare to a healthy control group, and present its association with sensorineural hearing loss (SNHL). Thirty-eight patients aged 2 to 16 years old were included in the study. The patients had confirmed diagnosis of Celiac disease through duodenal biopsies and transglutaminase Antibody (Ab) (+). The control group consisted of 18 children aged 3 to 17 years old who were all admitted to the pediatric gastroenterology department due to complaints of constipation and transglutaminase Ab (-).All children underwent Auditory-Brain-Stem-Evoked Responses (ABR). The data were gathered using click stimulus at 10/s frequency 90dB HL. The results of ABR examination did not show any difference between the patient group and control group as regards the latency of the waves I, III, V. No difference was observed between the two groups in the interpeak latecies I-III, I-V and III-V. None of the patients was observed to have clinical hearing loss. The exact pathogenesis of neurological damages observed in Celiac disease is still unknown. Humoral immune mechanisms are the most frequently attributed cause. Although no significant difference was found in hearing values between the study group and healthy control group, there is a need for further research on this subject.


Endosymbiotic and host proteases in the digestive tract of the invasive snail Pomacea canaliculata: diversity, origin and characterization.
Digestive proteases of the digestive tract of the apple snail Pomacea canaliculata were studied. Luminal protease activity was found in the crop, the style sac and the coiled gut and was significantly higher in the coiled gut. Several protease bands and their apparent molecular weights were identified in both tissue extracts and luminal contents by gel zymography: (1) a 125 kDa protease in salivary gland extracts and in the crop content; (2) a 30 kDa protease throughout all studied luminal contents and in extracts of the midgut gland and of the endosymbionts isolated from this gland; (3) two proteases of 145 and 198 kDa in the coiled gut content. All these proteases were inhibited by aprotinin, a serine-protease inhibitor, and showed maximum activity between 30°C and 35°C and pH between 8.5 and 9.5. Tissue L-alanine-N-aminopeptidase activity was determined in the wall of the crop, the style sac and the coiled gut and was significantly higher in the coiled gut. Our findings show that protein digestion in P. canaliculata is carried out through a battery of diverse proteases originated from the salivary glands and the endosymbionts lodged in the midgut gland and by proteases of uncertain origin that occur in the coiled gut lumen.


Who uses residential aged care now, how has it changed and what does it mean for the future?
Objective This paper presents past trends in resident characteristics and usage patterns in residential aged care and explores implications for the future. Methods Time series analyses were undertaken of national aged care administrative datasets and the Australian Bureau of Statistics Surveys of Disability, Ageing and Carers. Results Although the number of people in residential care has continued to increase, resident profiles have changed as a result of higher growth rates in the number of men and of people aged 65-74 years and 90 years and over, and a decline in the number of women aged 75-89 years. Relative to population size, usage rates are declining across all age groups, the average length of stay is shortening, and dependency levels appear to be rising. Conclusion Changing trends in residential aged care use, when combined with key trends in the broader population of older Australians, offer useful insights in planning for the future. What is known about the topic? Trends in the changing characteristics of permanent aged care residents and patterns of use of Australian residential aged care have received sparse attention in scholarly journals. Government reports and databases contain useful statistics, but they do not provide a coherent analysis and interpretation of the implications of these trends or situate them in broader population patterns. What does this paper add? The analyses in this paper demonstrate patterns of change and continuity in the use of residential care over the past decade, and locate those changes in the context of broader trends in the ageing population. Together, this provides useful insights into current and likely future trends, as well as a basis for imagining an improved residential aged care system in the future. What are the implications for practitioners? These analyses illustrate how data on aged care services, demographic trends and disease patterns can be used to consider the challenges that have affected our residential aged care system in the past and how that may be addressed in the future.


Muller cell expression of genes implicated in proliferative vitreoretinopathy is influenced by substrate elastic modulus.
Matrix stiffness is recognized increasingly as a significant factor in cell and tissue function. To understand better the mechanosensitivity of Müller cells and its association with vitreoretinal disorders, we examined morphology, propagation, and expression of genes in Müller cells that were cultured on substrates of varying elastic moduli. A conditionally immortalized mouse Müller cell line was cultured on laminin-coated polyacrylamide substrates with calibrated Young's moduli. Glass was used as a control. Phase contrast, fluorescence, and atomic force microscopy were used to study cell morphology and propagation. Expression of extracellular matrix (ECM) genes was analyzed using quantitative reverse-transcription PCR. The adherent area, stiffness, and propagation of Müller cells all are affected by matrix stiffness, but to different extents and with different ranges of sensitivity. Of 85 ECM genes tested 11 showed a continuous >4-fold increase or decrease in mRNA expression as a function of the substrate elastic modulus. The changes were statistically significant in four genes: connective tissue growth factor (Ctgf, P = 0.04), tenascin C (Tnc, P = 0.035), Collagen Iα1 (Col1a1, P = 0.0001), and Collagen IVα3 (Col4a3, P = 0.05), with all showing increased expression on softer substrates. There are significant changes in morphology, cytoskeletal integrity, and gene regulation in Müller cells as a function of the stiffness of the substrate. Changes in local tissue elastic modulus may have a role in vitreoretinal disorders. These findings also may have implications for strategies for improved integration of retinal prosthetics, and for stem cell therapies, particularly targeting the transcriptional regulators YAP and TAZ.


A kinetic model of the circulatory regulation of tissue plasminogen activator.
A computer simulation was developed to study the regulation of active tissue plasminogen activator (t-PA) levels in plasma by kinetically modeling t-PA secretion, t-PA inhibition by plasminogen activator inhibitor type 1 (PAI-1), and hepatic clearance of t-PA, PAI-1 and t-PA/PAI-1 complex throughout a simplified human circulatory system. The model indicates that as the active PAI-1 concentration increases, the percent of t-PA in the active form decreases exponentially. Further, the reaction between t-PA and PAI-1 substantially reduces the half-lives of both active factors. By adjusting the t-PA and PAI-1 secretion rates to provide the best fit between simulated and measured circadian variations in t-PA, PAI-1 and complex, the model predicts that the diurnal rhythm in active t-PA levels is principally due to changes in the rate of PAI-1 secretion and not to variations in the t-PA secretion rate. In conclusion, the model predicts that PAI-1 is an important regulator of the concentration, half-life and circadian variation of active t-PA.


[The limbical mechanisms of regulations of respiratory neurons in hypoxia conditions].
The structures of limbic system have great integration in vegetative reactions. In the oxygen deficiency conditions we studied influence of irritation of limbical cortex, orbitofrontal cortes, hipotalamys, septum and hippocampus (CA1 and CA3 areas) on the impulse activity of respiratory neurons. Phases of hypoxia were the model of experiment. Irritation some of this structures on normoxia and 4-5 thousand meters higher, we discover inhibiting influense on respiratory neurons; some structures irritation had activating influence. In difficult conditions of hypoxia (7.5-8 thousand meters) on the reduction of the impulse activity of neurons, stimulation induced uncharacteristic reactions. Those different reactions of irritation limbic structures have regulation sense on respitatory neurons.


Fungus-fermented soybeans benefit the life cycle of Japanese quail (Coturnix coturnix japonica).
Feeding quail chicks diets containing soybeans fermented with two cultures of Aspergilli (A. oryzae N.R.R.L. 451 and A. oryzae N.R.R.L. 506) resulted in significantly superior weight gains (p less than 0.05) through a 4-week growth period and confirmed previous observations made with identical cultures in broiler studies. Subsequent hen-day egg production and egg size were changed little by diets containing fermented soybeans. The numerical increases in fertility and hatchability were not significant. Progeny also responded to the fermented soybean diets, some carry-over effects were evident.


Comparative cytogenetic analysis of the genus symphysodon (discus fishes, cichlidae): chromosomal characteristics of retrotransposons and minor ribosomal DNA.
As part of a genetic screening program for wild Discus fishes, we analyzed karyotypes and cytogenetic characteristics of Symphysodon aequifasciatus, S. discus and S. haraldi using C-banding and fluorescent in situ hybridization (FISH) with the Rex3 retrotransposon and 5S rDNA probes in mitotic and meiotic chromosomes. In the 3 species, diploid chromosome number was 2n = 60 and karyotypes contained predominantly meta-submetacentric chromosomes. C-banding showed blocks of constitutive heterochromatin mainly in the pericentromeric region. Physical mapping of repetitive 5S rDNA sequences and Rex3 retrotransposons in mitotic and meiotic chromosomes showed partial colocalization of constitutive heterochromatin and repetitive elements. Correlations among the accumulation of repetitive elements, heterochromatinization and chromosome rearrangements have been hypothesized to explain the karyotype differentiation in the Symphysodon genus. The role of repetitive elements in adaptation to highly diverse habitats, as well as in the generation of the phenotypic and genetic variability found in wild Discus populations, needs to be further investigated.


Differences in Physiological Signals Due to Age and Exercise Habits of Subjects during Cycling Exercise.
Numerous studies indicated the physical benefits of regular exercise, but the neurophysiological mechanisms of regular exercise in elders were less investigated. We aimed to compare changes in brain activity during exercise in elderly people and in young adults with and without regular exercise habits. A total of 36 healthy young adults (M/F:18/18) and 35 healthy elderly adults (M/F:20/15) participated in this study. According to exercise habits, each age group were classified into regular and occasional exerciser groups. ECG, EEG, and EMG signals were recorded using V-AMP with a 1-kHz sampling rate. The participants were instructed to perform three 5-min bicycle rides with different exercise loads. The EEG spectral power of elders who exercised regularly revealed the strongest positive correlation with their exercise intensity by using Pearson correlation analysis. The results demonstrate that exercise-induced significant cortical activation in the elderly participants who exercised regularly, and most of the p-values are less than 0.001. No significant correlation was observed between spectral power and exercise intensity in the elders who exercised occasionally. The young participants who exercised regularly had greater cardiac and neurobiological efficiency. Our results may provide a new exercise therapy reference for adult groups with different exercise habits, especially for the elders.


Gastric emptying of solids in children: reference values for the (13) C-octanoic acid breath test.
(99m) Technetium scintigraphy ((99m) TS) is the 'gold standard' for measuring gastric emptying (GE), but it is associated with a radiation exposure. For this reason, the (13) C-octanoic acid breath test ((13) C-OBT) was developed for measuring GE of solids. The objective of this study was to determine normal values for gastric half-emptying time (t1/2 GE) of solids in healthy children. Gastric emptying of a standardized solid test meal consisting of a pancake evaluated with (99m) TS and (13) C-OBT was compared in 22 children aged between 1 and 15 years with upper gastrointestinal symptoms. Subsequently, the (13) C-OBT was used to determine normal values for GE of the same solid test meal in 120 healthy children aged between 1 and 17 years. The results showed a significant correlation (r = 0.748, p = 0.0001) between t1/2 GE measured with both techniques in the group of children with upper gastrointestinal symptoms. In the group of healthy children, mean t1/2 GE was 157.7 ± 54.0 min (range 71-415 min), but t1/2 GE decreased with age between 1 and 10 years and remained stable afterward. There was no influence of gender, weight, height, body mass index, and body surface area on t1/2 GE. Normal values for GE of solids measured with the (13) C-OBT using a standardized methodology were determined in healthy children. We propose to use this method and corresponding reference ranges to study GE of solids in children with gastrointestinal problems.


A Highly Sensitive Cell-Based TLR Reporter Platform for the Specific Detection of Bacterial TLR Ligands.
Toll-like receptors (TLRs) are primary pattern recognition receptors (PRRs), which recognize conserved microbial components. They play important roles in innate immunity but also in the initiation of adaptive immune responses. Impurities containing TLR ligands are a frequent problem in research but also for the production of therapeutics since TLR ligands can exert strong immunomodulatory properties even in minute amounts. Consequently, there is a need for sensitive tools to detect TLR ligands with high sensitivity and specificity. Here we describe the development of a platform based on a highly sensitive NF-κB::eGFP reporter Jurkat JE6-1 T cell line for the detection of TLR ligands. Ectopic expression of TLRs and their coreceptors and CRISPR/Cas9-mediated deletion of endogenously expressed TLRs was deployed to generate reporter cell lines selectively expressing functional human TLR2/1, TLR2/6, TLR4 or TLR5 complexes. Using well-defined agonists for the respective TLR complexes we could demonstrate high specificity and sensitivity of the individual reporter lines. The limit of detection for LPS was below 1 pg/mL and ligands for TLR2/1 (Pam3CSK4), TLR2/6 (Fsl-1) and TLR5 (flagellin) were detected at concentrations as low as 1.0 ng/mL, 0.2 ng/mL and 10 pg/mL, respectively. We showed that the JE6-1 TLR reporter cells have the utility to characterize different commercially available TLR ligands as well as more complex samples like bacterially expressed proteins or allergen extracts. Impurities in preparations of microbial compounds as well as the lack of specificity of detection systems can lead to erroneous results and currently there is no consensus regarding the involvement of TLRs in the recognition of several molecules with proposed immunostimulatory functions. This reporter system represents a highly suitable tool for the definition of structural requirements for agonists of distinct TLR complexes.


The determination and localization of sialic acid in guinea-pig granulocytes.
When intact guinea-pig granulocytes (polymorphonuclear leucocytes) disrupted by sonication or with detergent were treated with neuraminidase from Vibrio cholerae, 3.1--3.2 nmol of sialic acid/10(7) cells was released. By using a chromatographic procedure for the specific determination of total cell sialic acid, this releasable portion was found to constitute 70% of the total sialate. All of the neuraminidase-releasable sialic acid of the cells could be removed by enzymic treatment of intact cells with neuraminidase. It thus seemed likely that the neuraminidase-releasable sialic acid is all on the cell surface. To make sure that the result was not due to entry of neuraminidase into the cells, the enzyme was bound covalently to Sepharose 6B, and intact polymorphonuclear leucocytes were treated with the bound enzyme. All of the neuraminidase-releasable sialic acid could still be removed, though more slowly. The cells remained intact and only 1.5--2% of the bound enzyme was released from the Sepharose during incubation. Freed enzyme could have been responsible, at the very most, for release of 18% of the sialic acid. Fractionation studies showed that the nucleus and cytoplasm contain low amounts of sialic acid and that the neuraminidase-releasable sialic acid distributes in a manner similar to the distribution of 5'-nucleotidase, an unambiguous marker for the plasma membrane in these cells. Thus neuraminidase-releasable sialate constitutes a clear marker for the membrane of polymorphonuclear leucocytes. Most of the neuraminidase-insensitive sialate was present in the granule fraction. Removal of sialic acid from intact polymorphonuclear leucocytes did not affect their ecto-AMPase, -ATPase and -p-nitrophenyl phosphatase activities.


A phase II basket trial of Dual Anti-CTLA-4 and Anti-PD-1 Blockade in Rare Tumors (DART SWOG 1609 Cohort 47) in patients with gestational trophoblastic neoplasia.
The efficacy of immune checkpoint blockade in gestational trophoblastic neoplasia (GTN) remains uncertain. We report the results of the GTN cohort of SWOG S1609 dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors (DART). This prospective, open label phase II trial evaluated ipilimumab plus nivolumab across multiple rare tumor cohorts, including GTN. Eligible patients received nivolumab 240 mg intravenously (IV) every 2 weeks and ipilimumab 1 mg/kg IV every 6 weeks. The primary endpoint was overall response rate [ORR; complete response (CR) + partial response (PR)] by quantitative serum β-hCG; secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Four patients with refractory GTN enrolled and received therapy. At 11 months of ongoing follow-up, three of four patients responded [ORR = 75% (CR, 25%, n=1, tumor mutation burden=1 mutation/megabase; PD-L1 tumor proportion score=50%); PR, 50%, n=2)]. Responders included malignant gestational trophoblastic neoplasm (n=1, CR, PFS 11+ months) and choriocarcinoma (n=2, both PRs, PFS 10+ and 6+ months). One patient with epithelioid trophoblastic tumor experienced disease progression. The 6-month PFS was 75% (95% confidence interval: 43-100%), and the median PFS was not reached (range, 35-339+ days); all 4 patients were alive at last follow-up. Two patients experienced grade 3 immune-related toxicity (arthralgia and colitis); there were no grade ≥ 4 events. Ipilimumab plus nivolumab demonstrated efficacy in chemotherapy-refractory GTN, an ultra-rare cancer affecting young women. Three out of four patients achieved ongoing objective responses with a reasonable safety profile at 6-11+ months.


New evidence for a 67,000-year-old human presence at Callao Cave, Luzon, Philippines.
Documentation of early human migrations through Island Southeast Asia and Wallacea en route to Australia has always been problematic due to a lack of well-dated human skeletal remains. The best known modern humans are from Niah Cave in Borneo (40-42ka), and from Tabon Cave on the island of Palawan, southwest Philippines (47+/-11ka). The discovery of Homo floresiensis on the island of Flores in eastern Indonesia has also highlighted the possibilities of identifying new hominin species on islands in the region. Here, we report the discovery of a human third metatarsal from Callao Cave in northern Luzon. Direct dating of the specimen using U-series ablation has provided a minimum age estimate of 66.7+/-1ka, making it the oldest known human fossil in the Philippines. Its morphological features, as well as size and shape characteristics, indicate that the Callao metatarsal definitely belongs to the genus Homo. Morphometric analysis of the Callao metatarsal indicates that it has a gracile structure, close to that observed in other small-bodied Homo sapiens. Interestingly, the Callao metatarsal also falls within the morphological and size ranges of Homo habilis and H. floresiensis. Identifying whether the metatarsal represents the earliest record of H. sapiens so far recorded anywhere east of Wallace's Line requires further archaeological research, but its presence on the isolated island of Luzon over 65,000 years ago further demonstrates the abilities of humans to make open ocean crossings in the Late Pleistocene.


The stability of the hip after the use of a proximal femoral endoprosthesis for oncological indications: analysis of variables relating to the patient and the surgical technique.
Instability of the hip is the most common mode of failure after reconstruction with a proximal femoral arthroplasty (PFA) using an endoprosthesis after excision of a tumour. Small studies report improved stability with capsular repair of the hip and other techniques, but these have not been investigated in a large series of patients. The aim of this study was to evaluate variables associated with the patient and the operation that affect post-operative stability. We hypothesised an association between capsular repair and stability. In a retrospective cohort study, we identified 527 adult patients who were treated with a PFA for tumours. Our data included demographics, the pathological diagnosis, the amount of resection of the abductor muscles, the techniques of reconstruction and the characteristics of the implant. We used regression analysis to compare patients with and without post-operative instability. A total of 20 patients out of 527 (4%) had instability which presented at a mean of 35 days (3 to 131) post-operatively. Capsular repair was not associated with a reduced rate of instability. Bivariate analysis showed that a posterolateral surgical approach (odds ratio (OR) 0.11, 95% confidence interval (CI) 0.02 to 0.86) and the type of implant (p = 0.046) had a significant association with reduced instability; age > 60 years predicted instability (OR 3.17, 95% CI 1.00 to 9.98). Multivariate analysis showed age > 60 years (OR 5.09, 95% CI 1.23 to 21.07), female gender (OR 1.73, 95% CI 1.04 to 2.89), a malignant primary bone tumour (OR 2.04, 95% CI 1.06 to 3.95), and benign condition (OR 5.56, 95% CI 1.35 to 22.90), but not metastatic disease or soft-tissue tumours, predicted instability, while a posterolateral approach (OR 0.09, 95% CI 0.01 to 0.53) was protective against instability. No instability occurred when a synthetic graft was used in 70 patients. Stability of the hip after PFA is influenced by variables associated with the patient, the pathology, the surgical technique and the implant. We did not find an association between capsular repair and improved stability. Extension of the tumour often dictates surgical technique; however, our results indicate that PFA using a posterolateral approach with a hemiarthroplasty and synthetic augment for soft-tissue repair confers the lowest risk of instability. Patients who are elderly, female, or with a primary benign or malignant bone tumour should be counselled about an increased risk of instability. Cite this article: Bone Joint J 2017;99-B:531-7.


Identification of directed influence: Granger causality, Kullback-Leibler divergence, and complexity.
Detecting and characterizing causal interdependencies and couplings between different activated brain areas from functional neuroimage time series measurements of their activity constitutes a significant step toward understanding the process of brain functions. In this letter, we make the simple point that all current statistics used to make inferences about directed influences in functional neuroimage time series are variants of the same underlying quantity. This includes directed transfer entropy, transinformation, Kullback-Leibler formulations, conditional mutual information, and Granger causality. Crucially, in the case of autoregressive modeling, the underlying quantity is the likelihood ratio that compares models with and without directed influences from the past when modeling the influence of one time series on another. This framework is also used to derive the relation between these measures of directed influence and the complexity or the order of directed influence. These results provide a framework for unifying the Kullback-Leibler divergence, Granger causality, and the complexity of directed influence.


The Effect of Egg Consumption in Hyperlipidemic Subjects during Treatment with Lipid-Lowering Drugs.
Background. Limiting egg consumption to avoid high cholesterolemia is recommended to reduce risk of cardiovascular disease. However, recent evidences suggest that cholesterol from diet has limited influence on serum cholesterol. Objective. To assess the effect of egg consumption on lipid profiles in hyperlipidemic adults treated with lipid-lowering drugs. Material and Method. Sixty hyperlipidemic subjects, mean age of 61 years, who had been treated with lipid-lowering drugs. Every subject was assigned to consume additional 3 eggs per day with their regular diet for 12 weeks. Measurements for lipid profiles and body compositions were performed. Results. An additional consumption of 3 eggs per day for 12 weeks increased HDL-cholesterol by 2.46 ± 6.81 mg/dL (P < 0.01) and decreased LDL-cholesterol to HDL-cholesterol ratio by 0.13 ± 0.46 (P < 0.05). No significant changes were found in other lipid profiles. Body weight and body mass index were significantly increased at 12th week by 0.52 ± 1.83 kg and 0.31 ± 0.99 kg/m(2), respectively (P < 0.05). Conclusion. In hyperlipidemic adults who were treated with lipid-lowering drugs, the consumption of additional 3 eggs per day to their regular diet will increase the level of HDL-cholesterol and decrease the ratio of LDL-cholesterol to HDL-cholesterol.


Nuclear MET requires ARF and is inhibited by carbon nanodots through binding to phospho-tyrosine in prostate cancer.
Nuclear receptor tyrosine kinases (nRTKs) are aberrantly upregulated in many types of cancers, but the regulation of nRTK remains unclear. We previously showed androgen deprivation therapy (ADT) induces nMET in castration-resistant prostate cancer (CRPC) specimens. Through gene expression microarray profiles reanalysis, we identified that nMET signaling requires ARF for CRPC growth in Pten/Trp53 conditional knockout mouse model. Accordingly, aberrant MET/nMET elevation correlates with ARF in human prostate cancer (PCa) specimens. Mechanistically, ARF elevates nMET through binding to MET cytoplasmic domain to stabilize MET. Furthermore, carbon nanodots resensitize cancer cells to MET inhibitors through DNA damage response. The inhibition of phosphorylation by carbon nanodots was identified through binding to phosphate group of phospho-tyrosine via computational calculation and experimental assay. Thus, nMET is essential to precision therapy of MET inhibitor. Our findings reveal for the first time that targeting nMET axis by carbon nanodots can be a novel avenue for overcoming drug resistance in cancers especially prostate cancer.


[Does evidence of implant occlusion exist?].
This article reviews epidemiologic studies and basic researches concerning the mechanical risk factors that cause overload in implant occlusion. When natural teeth are adjacent to an implant, occlusal contact on the implant prosthesis requires a reduced initial mechanical load on the implant. This is called the implant-protected occlusion concept. However, few studies support this concept, and several researchers are concerned about the influence on the temporomandibular joint and the adjacent teeth when using this occlusal concept. It is thought that the same initial mechanical load on the implant and adjacent teeth does not result in an overload on the implant itself. The influence of a non-axial load, large cantilevers, and offset loading with a large occlusal table is greater than that of the axial load because of the bending moment. However, no epidemiologic study supports the biological influences of overloading. Meta-analysis of the connection of natural teeth and implants shows the biological and prosthetical risks.


[31P NMR spectroscopy of muscular diseases: correlation with MR imaging].
The spectra of normal and abnormal muscle were examined by 31P MR spectroscopy using a 2 Tesla system. Exercise tests on normal and abnormal muscle were also carried out. Abnormal muscles showed characteristic changes in the phosphorus spectrum, when compared with normal muscles, both at rest and after exercise; these were compared with the data from the MR images. The advantages and limitations of the method are discussed.


[Structural and functional changes in the liver in chronic recurrent cholecystitis].
Destructive, inflammatory and sclerotic alterations of the hepatic tissue, increased content of lipid inclusions, lysosomes and microbodies in hepatocytes, vesiculation of the endoplasmic reticulum and depletion of ribosomal granules in it were revealed by morphological examinations of liver samples from the gall bladder bed from patients will rarely, frequently and continuously recurring chronic cholecystitis. A relationship between resorption of lipid structures, content of lysosomes and microbodies, and glycogen accumulation in hepatic cells was found. The destructive morphological changes correlated with reduced capacity of the liver to absorb radioactive label, an increase of alanine transaminase level in the blood, and decreased oxidative processes in the mitochondrial fraction of the liver. The results of the study attest to the involvement of the liver in the pathological process in accord with the rate of cholecystitis recurrency.


Value of procalcitonin as a biomarker for postoperative hospital-acquired pneumonia after abdominal surgery.
Hospital-acquired pneumonia (HAP) is a common complication after abdominal surgery. The aim of this study was to evaluate the role of procalcitonin (PCT) and C-reactive protein (CRP) as early biomarkers for the diagnosis of postoperative HAP after abdominal surgery. This study was conducted on 100 patients undergoing abdominal surgery. White blood cell counts, highest body temperature, and serum levels of CRP and PCT were recorded preoperatively and daily postoperatively until postoperative day (POD) 5. Chest radiography was performed preoperatively and daily postoperatively until POD 5. HAP was diagnosed in 14% of patients. Regarding the biomarkers studied after POD 1, CRP and PCT were significantly higher in patients with HAP than in those without HAP (P < 0.05). On POD 2, PCT had higher sensitivity and specificity (84% and 72%, respectively) than those for CPR (70% and 60%, respectively). The cut-off value of PCT on POD 2 was 1.4 ng/ml. On POD 3, 4, and 5, the sensitivity and specificity of PCT and CRP were not significantly different. PCT and CRP are accurate biomarkers for early prediction of postoperative HAP after abdominal surgery. The diagnostic ability of PCT was significantly better than that of CRP on POD 2. After POD 2, the diagnostic ability was not significantly different between the biomarkers.


TGF-beta 1 alone and in combination with calcium hydroxide is synergistic to TGF-beta 1 production by osteoblasts in vitro.
To examine the effects of calcium hydroxide (Ca(OH)2), transforming growth factor-beta (TGF-beta 1), and Ca(OH)2/TGF-beta 1 coadministration on TGF-beta 1 and interleukin-6 (IL-6) synthesis by early (subculture 1) and late (subculture 5) osteoblast cultures. Early and late cultures were established using bone cells harvested from 21-day-old fetal rat calvaria. Cell cultures of both early and late osteoblasts were divided into four groups: group 1, control; group 2, cells challenged with Ca(OH)2; group 3, cells challenged with TGF-beta 1; and group 4, cells challenged with Ca(OH)2 and TGF-beta 1 in combination. TGF-beta 1 and IL-6 levels for all groups were determined using ELISA methodology. ANOVA and Tukey HS analyses revealed that osteoblasts of groups 3 and 4 significantly increased (P < 0.001) TGF-beta 1 synthesis in both early and late cultures of osteoblasts. IL-6 was not detected in any of the groups considered in this study. Exogenous TGF-beta 1 has an autocrine effect on cell cultures of osteoblasts. Administration of TGF-beta 1 alone or in combination with Ca(OH)2 increases the synthesis of TGF-beta 1 in osteoblast cultures. Ca(OH)2 and TGF-beta 1 are compatible when placed in a culture of osteoblasts. Ca(OH)2 provides a favourable environment for the anabolic effects of TGF-beta 1.


An aryne-based three-component access to α-aroylamino amides.
Aryne chemistry has recently received widespread attention and isocyanides have been reported as efficient nucleophilic partners in a set of multicomponent transformations. In this study, we demonstrate that tertiary α-monosubstituted α-isocyanoacetamides are efficaciously coupled with water and benzyne to offer a direct and metal-free access to densely functionalized α-benzoylamino amides, without competing with the intramolecular cyclization to 5-aminooxazoles. Despite the formation of the aryl anion as a key intermediate, the reaction displays a stereoconservative course, allowing for the preparation of enantiomerically pure α-benzoylamino amides. Finally, the synthetic utility of the reported MCR was exemplified by the preparation of proglumide, a cholecystokinin antagonist.


Limited impact of multiple 5' single-nucleotide polymorphisms on the transcriptional control of the human beta 2-adrenoceptor gene.
The human beta(2)-adrenoceptor (beta(2)-AR) is subject to agonist-induced down-regulation. The degree of down-regulation is associated with certain single-nucleotide polymorphisms (SNPs) through yet unknown mechanisms. The 5'-leader sequence of the beta(2)-AR gene contains several SNPs that are in strong linkage disequilibrium. The -367 T/C polymorphism, in particular, has been shown to affect transcriptional activity in reporter gene assays. In the present study we analysed the impact of this -367 SNP on the transcription rate of the beta(2)-AR gene in the context of the complete natural locus. Taking advantage of the additional full disequilibrium with the +79 SNP in the beta(2)-AR coding sequence, allele-specific transcript quantification was performed in PBMCs of six -367 heterozygous mild asthmatic patients. Our data are in line with the reported impact of the -367 SNP and give no indication of additional haplotype-related effects on beta(2)-AR transcription. We further show that the -367 SNP affects the binding of a yet unidentified transcription factor complex, whose binding activity is not modulated by pharmacological compounds that induce or down-regulate beta(2)-AR expression, suggesting a role in constitutive steady state expression rather than in inducible expression. As the beta(2)-AR allele with a higher transcription rate associates with stronger agonist-induced down-regulation, it is not likely that the -367 SNP is causally related to the degree of down-regulation.


[Posteromedial approach and plating for a tibial plateau fracture with a posterior fragment].
Tibial plateau fractures account for 1% of all fractures. Ten percent of them involve the medial plateau. The spectrum of lesions ranges from undisplaced fractures to devastating fractures involving the entire tibial plateau, which warrant extensive surgical management. The orthopedic surgery literature suggests that positive functional and radiographic results depend on the type of approach, the quality of reduction and the type of implant used. Ambispective case report: seven patients were enrolled, with fracture of the medial tibial plateau and a posterior fragment. A posterior plate was placed after a posteromedial approach, between August 2012 and August 2013. Fractures were staged according to the Khan classification. Functional and radiographic results were assessed using the Rasmussen scale. Frequency and descriptive statistics were used. Pain was measured using a visual analog scale (VAS), with scores ranging from two to four. Flexion ranged between 40° and 110°, with a minimum extension deficit of 15° and a maximum of 40°. Four subjects had varus deformity, three had valgus deformity. The posteromedial approach and placement of a posterior plate for tibial plateau fractures results in ranges of motion that permit an appropriate function and involve mild pain. Varus angulation occurs in patients with bilateral tibial plateau fractures.


Characterization of Micrococcus antarcticus sp. nov., a psychrophilic bacterium from Antarctica.
A Gram-positive, cold-adapted, aerobic, spherical actinobacterium (strain T2T) with a quite low cardinal growth temperature was isolated from Chinese Great-Wall station in Antarctica. Sequence comparisons of the 16S rDNA indicated the isolate to be a phylogenetic member of the genus Micrococcus, family Micrococcaceae, in which it represents a novel lineage. The phylogenetic distinctness of the isolate with respect to the type strains Micrococcus luteus and Micrococcus lylae was supported by DNA-DNA similarity values of less than 40%. Chemotaxonomic properties supported the placement of the isolate in the genus Micrococcus. The diagnostic diamino acid of the cell-wall peptidoglycan is lysine. The predominant menaquinones are MK-8 and MK-8(H2). The G + C content of the DNA of the isolate is 66.4 mol%. Genotypic, morphological and physiological characteristics were used to describe a new species of Micrococcus, for which the name Micrococcus antarcticus is proposed. The type strain is T2T (= AS 1.2372T).


Warning signs for suicide within a week of healthcare contact in Veteran decedents.
This study examined warning signs for suicide observed in the final day(s) of life in Veteran decedents who received healthcare from Veterans Health Administration (VHA) (N=381), using data obtained from detailed chart reviews. Veterans who died within a week (7 days) of healthcare contact (18%) were compared to those who died later (82%). Multivariate logistic regression was used to examine differences in suicidal thoughts, psychiatric symptoms, and somatic symptoms as documented at the last visit, after controlling for demographic variables. A second multivariate regression examined whether the identified warning signs were also risk factors for suicide within a month (30 days) of contact. Documented suicidal ideation, OR (95% CI)=3.46 (1.15-10.38), and psychotic symptoms, OR (95% CI)=2.67 (1.11-6.42), at the last visit increased the likelihood of suicide within a week of healthcare contact. Both variables also increased the odds of suicide within a month of contact. The assessment of suicidal ideation is critical to identify Veterans at immediate risk. However, recognition of psychotic symptoms may also improve identification. In addition to indicating immediate risk, some warning signs may also suggest on-going risk.


Flexible treatment strategies in chronic disease: clinical and research implications.
Multiple treatments are available for nearly all the mood disorders. This range of treatment options adds a new dimension of choice to clinical decision making. In addition to prescribing the best initial treatment, clinicians should have an algorithm for deciding if and when to make subsequent changes in treatment to take advantage of second-line treatment options when necessary. This article aims to 1) show that a wide variety of clinical decisions can be framed as choices among adaptive (within-patient) threshold-based strategies or algorithms, illustrating the generality of the concept; 2) illustrate two ways to design randomized clinical trials to compare treatment strategies with each other to decide which strategy is best; and 3) discuss some of the advantages offered by these designs, in terms of both patient acceptability and adherence to experimental protocols.


Hepatitis B-positive donors in renal transplantation: increasing the deceased donor pool.
It is reasonable to transplant HbsAg-positive kidneys into recipients who are themselves hepatitis B surface antigen (HbsAg) positive with appropriate antiviral treatment after transplantation. Although there are limited data regarding the hepatitis B virus (HBV) transmission risk following transplantation of kidneys from HbsAg-positive donors into HBV-immune recipients, current literature suggests that the risk of chronic infection in the recipient can be prevented by using antiviral agents or by boosting protective anti-HBs titers. The risk of chronic HBV infection following transplantation of kidneys from HbsAg-positive donors for HBV-naive recipients is high but can be minimized by administering lifelong antiviral therapy. Such a policy could be considered in an urgent situation. The most cost-effective antiviral prophylaxis strategy is lifelong lamivudine. Kidneys from HBsAg neg/anti-HBcore pos recipients are associated with a low rate of chronic HBV infection in the recipient and therefore can no longer be regarded as marginal donors. Booster vaccination to achieve protective HBV immunity or lifelong lamivudine therapy should prevent posttransplant HBV infection. Hence, we believe that strategies allowing transplantation of kidneys from donors with HBV can be undertaken safely with careful selection and matching of donors and recipients increasing access to kidney transplantation.


Effects of injected iron and siderophores on infections in normal and immune mice.
The fate of virulent and avirulent strains of Salmonella typhimurium in untreated and iron-injected mice and in transferrin-containing media demonstrated a direct relationship between bacterial virulence and the ability of bacteria to acquire transferrin-bound iron. Effects of injected iron on the development of infections with virulent and avirulent bacterial strains were determined in normal and immune mice by determinations of bacterial numbers in tissue homogenates and the mortality of infected animals. Results showed that infected and iron-injected mice died much more rapidly and frequently from overwhelming infections than infected and saline-injected mice. The infection-promoting effect of iron varied with the degree of bacterial virulence; the more virulent the bacteria, the more helpful was iron for the development of lethal infections. Siderophores promoted lethal infections in mice infected with virulent but not with avirulent bacteria. Experiments with vaccinated animals showed that iron exerted a deleterious effect on acquired immunity. Immune mice infected with virulent bacteria and injected with iron developed lethal infections as rapidly and nearly as frequently as similarly treated normal mice. Siderophores did not promote the development of lethal infections in immune mice. The effectiveness of iron, but not of siderophores, to promote bacterial infections in vaccinated mice revealed that acquired immunity is dependent upon the activity of an iron-neutralizable antibacterial system.


[Inheritance of human finger and palm dermatoglyphic characteristics].
The degree of genetic determination of 25 quantitative dermatoglyphic characteristics has been studied on family: twin material: 45 pairs of MZ and 75 single-sex DZ twins; and 53 single-sex "parent-child" pairs. Approximating formulae were used to estimate main components of phenotypic variance due to additive interaction of genetic factors, to non-linear effects (intralocus dominance) and to the effect of total-familiar and random environmental factors. All the finger dermatoglyphic characteristics studied had a high degree of genetic determination (G greater than 0,80), and for most of them the contribution into the large variance of intralocus dominance effects was comparable with that of additive gene interaction, included in the determination of these characters. There are some palm dermatoglyphic characteristics ("ad" distance "cd" comb counting, "bad", "adt" and "cda" angles), which degree of genetic determination is low (G less than 0,35). At least ten quantitative finger and palm dermatogliphic characteristics with a high degree of genetic determination can be used for special studies in frames of multidimentional genetical analysis, including determination of twin zygosity type. Earlier described "indices" (using twin data) of relative role of genetic and environment factors in the determination of populational variability of quantitative characters are considered. None of them is shown to be a reliable estimate of the coefficient of genetic character determination. The use of these indices in practical studies can result in wrong conclusions on the degree and the character of genetic determination of quantitative characters.


Immune complex effects on murine macrophages. I. Immune complexes suppress interferon-gamma induction of Ia expression.
We have studied the effects of immune complexes on the expression of macrophage surface proteins in vitro. Increased expression of the H-2 molecules I-A, I-E, and K on the macrophage membrane was induced by in vitro culture with crude lymphokine or interferon-gamma. Expression of all three of the molecules was additionally increased by stimulating the cultures with heat-killed Listeria monocytogenes. Addition of soluble immune complexes to the cultures did not have any effect on macrophage expression of these proteins. However, significant inhibition of lymphokine or interferon-gamma induction of I-A, I-E, and H-2K was observed when macrophages were cultured on plates to which immune complexes had been bound. This inhibition was dose dependent, required an immunoglobulin (Ig) molecule with an intact Fc portion, did not require the presence of T cells, and occurred in the presence of indomethacin. Complexes containing IgG1, IgG2a, IgG2b, and IgE, but not IgM or IgA, antibodies mediated the inhibitory effect.