Summing it up: an integrative review of studies of cancer survivorship care plans (2006-2013).
In 2006, the Institute of Medicine recommended that cancer survivors who are completing primary treatment receive a survivorship care plan (SCP) based on face validity. The state of scientific knowledge regarding the SCP is unclear. The authors conducted an integrative review of existing evidence regarding SCPs. The MEDLINE/PubMed database, the Excerpta Medica Database (EMBASE), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) database were searched for relevant studies published between 2006 and 2013 using a combination of keywords: "survivors," "survivorship," "care plans," "care planning," "treatment summaries," and "cancer." Articles were included if they 1) reported results from an empirical study, 2) included cancer survivors who were diagnosed at age ≥ 18 years, 3) related to SCP, and 4) were published in English. In total, 781 records were retrieved; 77 were identified as duplicates, and 665 were abstracts or presentations that did not relate to SCPs for adults or were not empirical, which left 42 articles for inclusion in this review. Studies regarding SCP fell into 3 categories: 1) content (n=14), 2) dissemination and implementation (n=14), and 3) survivor and provider outcomes (n=14). SCPs have been endorsed and are associated with improved knowledge, but SCP use remains sporadic. Only 4 studies were randomized controlled trials (RCTs) that avoided many biases associated with observational studies. Other limitations included cross-sectional or pre-SCP-post-SCP ("pre-post") designs, limited generalizability caused by a lack of sample diversity, and a lack of systematic testing of data-collection tools. The quantity and quality of SCP research are limited. SCPs have been endorsed, but evidence of improved outcomes associated with SCP is limited. Future research that addresses the methodological concerns of extant studies is needed regarding SCP use, content, and outcomes.


Inflammatory markers and their relationships with leptin and insulin from acute mania to full remission in bipolar disorder.
Weight gain and increased production of leptin may be associated with immuno-modulation and insulin resistance in bipolar disorder. The links among inflammatory markers, leptin, and insulin of bipolar patients from acute mania to full remission remain unclear. Thirty-three healthy, bipolar I patients under 45 years of age were enrolled. We measured the circulating levels of high-sensitivity C-reactive protein (hs-CRP), anti-inflammatory mediators (interleukin-1 receptor antagonist [IL-1Ra] and soluble tumor necrosis factor receptor 1 [sTNF-R1]), leptin, and insulin during acute mania and subsequent partial and full remission. The results were compared with 33 age- and gender-matched healthy subjects. The levels of IL-1Ra and hs-CRP of bipolar patients in both acute mania and partial remission were significantly higher than their levels of control subjects. The hs-CRP level of bipolar patients was also elevated in full remission. The elevation of IL-1Ra and hs-CRP levels in acute mania was independent of each other. They were also independent of the body mass index (BMI) and levels of leptin and insulin measurements. The levels of leptin were all positively associated with insulin levels in the normal subjects and bipolar patients in three phases. However, a significant relationship between leptin and immunoparameter was only seen in full remission with sTNF-R1 (r=0.51). Furthermore, IL-1Ra was inversely correlated with sTNF-R1 (r=-0.37, p<0.05) during partly remission, and while levels of IL-1Ra tended to normalize when patients remitted, levels of hs-CRP and sTNF-R1 showed the opposite trend. Activated inflammation was found in acute mania, as evidenced by high levels of IL-1Ra, hs-CRP, and sTNF-R1. The production of leptin may be more tightly linked to insulin than the immunomodulators. Chronic inflammation may exist in bipolar patients and is reflected by elevations of IL-1Ra and hs-CRP levels in acute mania and persistent higher hs-CRP in full remission.


Decision-Making in People With Dementia or Mild Cognitive Impairment: A Narrative Review of Decision-Making Tools.
This review summarized the applicability of various decision-making tools for helping people with dementia or mild cognitive impairment (MCI) and their families make decisions. This study was a narrative literature review. The protocol of this review was registered in the International Prospective Register of Systematic Reviews (PROSPERO ID: CRD42020182259). People with dementia or MCI and their families were included in this study. This review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. We searched the Cochrane Library, PubMed, Embase, Cumulative Index to Nursing and Allied Health Literature, and Chinese Electronic Periodical Services databases from inception to May 2021. The Joanna Briggs Institute Critical Appraisal Checklists for a variety of study designs were used. Topics related to decision-making were categorized as everyday activity decisions or medical treatment decisions. Various types of decision-making tools were identified, and we observed that decision aids can be modified and used for both everyday activity decisions and medical treatment decisions. In addition to highlighting decision aids for specific decisional issues and topics, we also elucidated other validated tools that can be used to facilitate the decision-making process. This study highlighted the topics involved in decision-making and using decision-making tools. The current review provides information that can help individuals and health care professionals choose optimal decision-making tools. On the basis of our findings, future studies can determine the most appropriate tools for intervention or outcome measures.


Postmatch Perceived Exertion, Feeling, and Wellness in Professional Soccer Players.
To assess postmatch perceived exertion, feeling, and wellness according to the match outcome (winning, drawing, or losing) in professional soccer players. In total, 12 outfield players were followed during 52 official matches where the outcomes (win, draw, or lose) were noted. Following each match, players completed both a 10-point Borg scale modified by Foster and an 11-point Hardy and Rejeski scale rating of perceived feeling. Rating of perceived sleep quality, stress, fatigue, and muscle soreness was collected separately on a 7-point scale the day following each match. Player rating of perceived exertion was higher by a very large magnitude following a loss compared with a draw or a win and higher by a small magnitude after a draw compared with a win. Players felt more pleasure after a win compared with a draw or loss and more displeasure after a loss compared with draw. The players reported a largely and moderately better perceived sleep quality, less stress, and fatigue following a win compared with a draw or a loss and a moderately bad perceived sleep quality, higher stress, and fatigue following a draw compared with a loss. In contrast, only a trivial-small change was observed in perceived muscle soreness between all outcomes. Match outcomes moderately to largely affect rating of perceived exertion, feeling, sleep quality, stress, and fatigue, whereas perceived muscle soreness remains high regardless of the match outcome. However, winning a match decreases the strain and improves both pleasure and wellness in professional soccer players.


Cold Plasma Treatment as an Alternative for Ochratoxin a Detoxification and Inhibition of Mycotoxigenic Fungi in Roasted Coffee.
Ochratoxin A (OTA) produced by mycotoxigenic fungi (Aspergillus and Penicillium spp.) is an extremely toxic and carcinogenic metabolite. The use of cold plasma to inhibit toxin-producing microorganisms in coffee could be an important alternative to avoid proliferation of mycotoxigenic fungi. Roasted coffee samples were artificially inoculated with A. westerdijikiae, A. steynii, A. versicolor, and A. niger, and incubated at 27 °C over 21 days for OTA production. Samples were cold plasma treated at 30 W input power and 850 V output voltage with helium at 1.5 L/min flow. OTA production in coffee was analyzed by high performance liquid chromatography coupled to a mass spectrometer (HPLC-MS). After 6 min of treatment with cold plasma, fungi were completely inhibited (4 log reduction). Cold plasma reduces 50% of OTA content after 30 min of treatment. Toxicity was estimated for extracts of artificially contaminated roasted coffee samples using the brine shrimp (Artemia salina) lethality assay. Toxicity for untreated roasted coffee was shown to be "toxic", while toxicity for cold plasma treated coffee was reduced to "slightly toxic". These results suggested that cold plasma may be considered as an alternative method for the degradation and reduction of toxin production by mycotoxigenic fungi in the processing of foods and feedstuffs.


Impaired energetics in heart failure - a new therapeutic target.
Heart failure is a syndrome of huge and growing importance worldwide. It is widely accepted that the energy status of the myocardium in heart failure is impaired, irrespective of etiology. Agents which modify cardiac substrate utilisation have the potential to ameliorate this energy deficiency by increasing cardiac mechanical efficiency. This may represent a new therapeutic paradigm in heart failure. In this review we discuss existing and new agents that alter cardiac substrate use and summarise the data on clinical efficacy.


Extract of Pelargonium sidoides (EPs 7630) inhibits the interactions of group A-streptococci and host epithelia in vitro.
EPs 7630 is an extract of the root of the South African geranium Pelargonium sidoides. Clinical data have shown that this herbal drug preparation can be used to treat upper respiratory tract infections (URTI). The objective of this study was to investigate the impact of EPs 7630 on group A-streptococci (GAS) adhering to and invading host epithelial cells in vitro. Adhesion was assessed by a flow cytometric adhesion assay using calcein-AM-stained S. pyogenes (DSM 2071) as test organism, and HEp-2 cells and buccal epithelial cells (BEC) as substrata. For cell invasion, HEp-2 cell monolayers were infected with S. pyogenes. Intracellular bacteria were determined using a penicillin/gentamicin-protection assay. EPs 7630 was applied in therapeutically relevant concentrations between 0 and 30 microg/ml in both test systems. Compared to controls, EPs 7630 significantly reduced GAS adhesion to HEp-2 cells in a concentration-dependent manner by up to 46% (p<0.001). This was semi-quantitatively confirmed by fluorescence microscopy. Adhesion kinetics additionally indicated a specific antagonistic effect on GAS adhesion. Pre-treatment of epithelial cells or GAS with EPs 7630 showed that it targets GAS rather than HEp-2 cells. However when using BEC as substrata, GAS adhesion increased 7-fold under the influence of EPs 7630 (p<0.001). In viability assays, HEp-2 suspension contained over 90% vital cells, whereas only 10% of the BEC were viable. EPs 7630 reduced GAS invasion of HEp-2 cells significantly when the data taken at time points 60, 120, and 180 min (p=0.026) were analyzed. In conclusion, EPs 7630 develops complementary anti-infective properties: Firstly, EPs 7630 reduces bacterial adhesion to intact epithelial cells and thus protects the organism from bacterial colonization and infection/super-infection. Secondly, EPs 7630 enhances the attachment of bacteria to decaying BEC. In this way pathogens may be trapped and rendered inactive. Thirdly, the inhibition of GAS invasion of epithelial cells protects the host from microorganisms that may have evaded host defences and antibiotic treatment, and therefore prevents recurrent infections. Thus, our investigations provide a rational basis for the treatment of URTI with EPs 7630.


HPV 16 antibody prevalence in Jamaica and the United States reflects differences in cervical cancer rates.
Human papillomavirus (HPV) is widely accepted as the primary etiologic agent in the development of cervical cancer. DNA of a particular HPV type, HPV 16, is found in about half of tumors tested. Inconsistent with this causal relationship, however, population-based studies of HPV DNA prevalence have often failed to find high rates of anogenital HPV infection in countries with high cervical cancer rates. To examine this issue, we used serology to compare HPV 16 exposure in healthy volunteer blood donors in the United States (n = 278) and similar subjects from a country with 3-fold higher cervical cancer rates, Jamaica (n = 257). Jamaican sexually transmitted disease (STD) patients (n = 831) were also studied to examine in detail the relation of HPV 16 antibodies with sexual history. Serology was conducted using an ELISA employing HPV 16 virus-like particles (VLPs). Age-adjusted seroprevalence rates were greatest among male (29%) and female (42%) STD patients, intermediate in male (19%) and female (24%) Jamaican blood donors and lowest among male (3%) and female (12%) U.S. blood donors. The higher seroprevalence in women was significant, and prevalence tended to increase with age. In multivariate logistic regression, controlling for age and gender, Jamaican blood donors were 4.2-fold (95% CI 2.4-7.2) and STD patients 8.1-fold (95% CI 5.0-13.2) more likely to have HPV 16 VLP antibodies than U.S. blood donors. Among STD patients, HPV 16 antibodies were associated with lifetime number of sex partners and years of sexual activity, as well as other factors. Our data suggest that HPV 16 VLP antibodies are strongly associated with sexual behavior. Moreover, exposure to HPV 16 appears to be much greater in Jamaica than in the United States, consistent with the high rate of cervical cancer in Jamaica.


Color Stability and Staining Susceptibility of Direct Resin-Based Composites after Light-Activated In-Office Bleaching.
This study evaluated color stability and staining susceptibility of five direct resin-based composites (RBCs) subjected to light-activated in-office bleaching with 40% hydrogen peroxide (HP). The test materials included 5 RBCs, which consisted of one nano-filled, one sub-micron, one bulk-filled, and two nano-hybrid RBC types. Ten disc-shaped specimens of each RBC were fabricated and divided into bleaching (BLE) and non-bleaching (CON) groups (n = 5 for each group). Specimens were then immersed in red wine solution over 4 h. A spectrophotometer was used to obtain Commission Internationale de l'Eclairage (CIE) L*a*b* parameters for each of the following periods tested: before bleaching (TBA), after bleaching (TBL), and after staining (TST). Color stability and staining susceptibility were evaluated using two metrics, CIEDE2000 color differences (ΔE00) and whiteness variations using the whiteness index (ΔWID). Data were analyzed using repeated measures two-way analysis of variance (ANOVA) (α = 0.05). Statistically significant and clinically unaccepted ΔE00 and ΔWID were observed for all tested specimens between TBA and TBL. The nano-hybrid type RBCs showed the highest discoloration among materials after bleaching treatment. The BLE group exhibited significantly higher ΔE00 and ΔWID than the CON group for all the tested RBCs between TBA and TST. The sub-micron type RBC showed the highest discoloration among materials after immersion in the red wine. Conclusion. The light-activated in-office bleaching with 40% HP's influences on color and whiteness index were material-dependent. The use of bleaching treatment also increased the susceptibility to red wine for all RBCs.


Switching Thin Films of Azobenzene-Containing Metal-Organic Frameworks with Visible Light.
Stimuli-responsive molecules change their properties when exposed to external signals, such as light, and enable the preparation of smart materials. UV light, which often destroys organic materials, is typically required for activating the desired response of photoswitchable compounds, significantly limiting the potential applications of light-operated smart materials. Herein, we present the first metal-organic framework (MOF), which enables reversible modulation of key properties upon irradiation with visible light only. The fluorinated azobenzene side groups in the MOF structure can be reversibly switched between the trans and cis state by green and violet light, avoiding UV light. It was demonstrated that the uptake of guest molecules by these MOF films can be switched in a fully remote-controlled way. The membrane separation of hydrogen/hydrocarbon mixtures was investigated. The light-induced changes of the MOF pore size result in the switching of the permeation and of the selection factor.


Clinical remission of rheumatoid arthritis in a multicenter real-world study in Asia-Pacific region.
Clinical remission is an attainable goal for Rheumatoid Arthritis (RA). However, data on RA remission rates from multinational studies in the Asia-Pacific region are limited. We conducted a cross-sectional multicentric study to evaluate the clinical remission status and the related factors in RA patients in the Asia-Pacific region. RA patients receiving standard care were enrolled consecutively from 17 sites in 11 countries from APLAR RA SIG group. Data were collected on-site by rheumatologists with a standardized case-report form. Remission was analyzed by different definitions including disease activity score using 28 joints (DAS28) based on ESR and CRP, clinical disease activity index (CDAI), simplified disease activity index (SDAI), Boolean remission definition, and clinical deep remission (CliDR). Logistic regression was used to determine related factors of remission. A total of 2010 RA patients was included in the study, the overall remission rates were 62•3% (DAS28-CRP), 35•5% (DAS28-ESR), 30•8% (CDAI), 26•5% (SDAI), 24•7% (Boolean), and 17•1% (CliDR), respectively, and varied from countries to countries in the Asia-Pacific region. Biological and targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) prescription rate was low (17•9%). Compared to patients in non-remission, patients in remission had higher rates of b/tsDMARDs usage and lower rates of GC usage. The favorable related factors were male sex, younger age, fewer comorbidities, fewer extra-articular manifestations (EAM), and use of b/tsDMARDs, while treatment with GC was negatively related to remission. Remission rates were low and varied in the Asia-Pacific region. Treatment with b/tsDMARDs and less GC usage were related to higher remission rate. There is an unmet need for RA remission in the Asia-Pacific region.


Evaluation of near-side oblique frontal impacts using THOR with SD3 shoulder.
Within the EC Seventh Framework project THORAX, the Mod-Kit THOR was upgraded with a new thorax and shoulder. The aim of this study was to investigate whether the THOR ATD met a set of prerequisites to a greater extent than Hybrid III and by that measure whether the dummy could serve as a potential tool for future evaluation of serious head and chest injuries in near-side oblique frontal impacts. A small-overlap/oblique sled system was used to reflect occupant forces observed in oblique frontal crashes. The head and thoracic response from THOR was evaluated for 3 combinations: belt only with no deformation of the driver's side door (configuration A), belt only in combination with a predeformed door (configuration B), and prepretensioning belt and driver airbag (PPT+DAB) in combination with a predeformed door (configuration C). To evaluate head injury risk, the head injury criterion (HIC) and brain injury criteria (BrIC) were used. For evaluation of the thoracic injury risk, 3 injury criteria proposed by the THORAX project were evaluated: Dmax, DcTHOR, and strain (dummy rib fractures). Unlike Hybrid III, the THOR with SD3 shoulder interacted with the side structure in a near-side oblique frontal impact. HIC values for the 3 test configurations corresponded to a 90% (A) and 100% (B and C) risk of Abbreviated Injury Scale (AIS) 2+ head injury, and BrIC values resulted in a 100% risk of AIS 2+ head injury in configurations A and B. In C the risk was reduced to 75%. The AIS 2+ thoracic injury risks based on Dmax were similar (14-18%) for all tests. Based on DcTHOR, AIS 2+ injury risk increased from 29 to 53% as the predeformed door side was introduced (A to B), and the risk increased, to 64%, as a PPT+DAB was added (C). Considering the AIS 2+ injury risk based on strain, tests in A resulted in an average of 3 dummy rib fractures (17%). Introducing the predeformed door (B) increased the average of dummy fractures to 5 (39%), but in C the average number of dummy rib fractures decreased to 4 (28%). THOR with an SD3 shoulder should be the preferred ATD rather than the Hybrid III for evaluating head and thorax injuries in oblique frontal impacts. Thoracic interaction with the predeformed door was not well captured by the 3D IR-Traccs; hence, use of deflection as an injury predictor in oblique loading is insufficient for evaluating injury risk in this load case. However, injury risk evaluation may be performed using the strain measurements, which characterize loading from seat belt and airbag as well as the lateral contribution of the structural impact in the loading condition used in this study.


Stent placement compared with balloon angioplasty for obstructed coronary bypass grafts. Saphenous Vein De Novo Trial Investigators.
Treatment of stenosis in saphenous-vein grafts after coronary-artery bypass surgery is a difficult challenge. The purpose of this study was to compare the effects of stent placement with those of balloon angioplasty on clinical and angiographic outcomes in patients with obstructive disease of saphenous-vein grafts. A total of 220 patients with new lesions in aortocoronary-venous bypass grafts were randomly assigned to placement of Palmaz-Schatz stents or standard balloon angioplasty. Coronary angiography was performed during the index procedure and six months later. As compared with the patients assigned to angioplasty, those assigned to stenting had a higher rate of procedural efficacy, defined as a reduction in stenosis to less than 50 percent of the vessel diameter without a major cardiac complication (92 percent vs. 69 percent, P<0.001), but they had more frequent hemorrhagic complications (17 percent vs. 5 percent, P<0.01). Patients in the stent group had a larger mean (+/-SD) increase in luminal diameter immediately after the procedure (1.92+/-0.30 mm, as compared with 1.21+/-0.37 mm in the angioplasty group; P<0.001) and a greater mean net gain in luminal diameter at six months (0.85+/-0.96 vs. 0.54+/-0.91 mm, P=0.002). Restenosis occurred in 37 percent of the patients in the stent group and in 46 percent of the patients in the angioplasty group (P=0.24). The outcome in terms of freedom from death, myocardial infarction, repeated bypass surgery, or revascularization of the target lesion was significantly better in the stent group (73 percent vs. 58 percent, P = 0.03). As compared with balloon angioplasty, stenting of selected venous bypass-graft lesions resulted in superior procedural outcomes, a larger gain in luminal diameter, and a reduction in major cardiac events. However, there was no significant benefit in the rate of angiographic restenosis, which was the primary end point of the study.


IAOseq: inferring abundance of overlapping genes using RNA-seq data.
Overlapping transcription constitutes a common mechanism for regulating gene expression. A major limitation of the overlapping transcription assays is the lack of high throughput expression data. We developed a new tool (IAOseq) that is based on reads distributions along the transcribed regions to identify the expression levels of overlapping genes from standard RNA-seq data. Compared with five commonly used quantification methods, IAOseq showed better performance in the estimation accuracy of overlapping transcription levels. For the same strand overlapping transcription, currently existing high-throughput methods are rarely available to distinguish which strand was present in the original mRNA template. The IAOseq results showed that the commonly used methods gave an average of 1.6 fold overestimation of the expression levels of same strand overlapping genes. This work provides a useful tool for mining overlapping transcription levels from standard RNA-seq libraries. IAOseq could be used to help us understand the complex regulatory mechanism mediated by overlapping transcripts. IAOseq is freely available at http://lifecenter.sgst.cn/main/en/IAO_seq.jsp.


Sustained enhancements in inhibitory control depend primarily on the reinforcement of fronto-basal anatomical connectivity.
What are the neurophysiological determinants of sustained supra-normal inhibitory control performance? We addressed this question by coupling multimodal neuroimaging and behavioral investigations of experts in fencing who underwent more than 20,000 h of inhibitory control training over 15 years. The superior control of the experts manifested behaviorally as a speeding-up of inhibition processes during a Go/NoGo task and was accompanied by changes in bilateral inferior frontal white matter microstructure. In the expert group, inhibition performance correlated positively with the fractional anisotropy (FA) of white matter tracts projecting to the basal ganglia, and the total training load with the FA in supplementary motor areas. Critically, the experts showed no changes in grey matter volume or in the functional organization of the fronto-basal inhibitory control network. The fencers' performance and neural activity during a 2-back working memory task did not differ from those of the controls, ensuring that their expertise was specific to inhibitory control. Our results indicate that while phasic changes in the patterns of neural activity and grey matter architecture accompany inhibitory control improvement after short- to medium- term training, long-lasting inhibitory control improvements primarily depend on the reinforcement of fronto-basal structural connectivity.


Detection of scarred and viable myocardium using a new magnetic resonance imaging technique: blood oxygen level dependent (BOLD) MRI.
The identification of viable myocardium in patients with impaired left ventricular contraction secondary to coronary heart disease is important clinically as such myocardium is likely to benefit from revascularisation. Blood oxygen level dependent (BOLD) magnetic resonance imaging (MRI) relies on changes in deoxyhaemoglobin concentration under stress for signal generation and could be used for the differentiation between scarred and viable myocardium. To assess the signal change on BOLD MRI in viable and scarred myocardium as identified by positron emission tomography (PET). 19 patients with impaired left ventricular contraction and at least one akinetic area were enrolled. They underwent rest and dipyridamole stress MRI, using a double breath hold T2* weighted, ECG gated sequence to produce BOLD contrast images, and cine-MRI for wall thickening assessment. Dynamic perfusion and metabolic PET images followed the MRI. Signal change on BOLD MRI and the wall thickening were compared between rest and stress images in hibernating and scarred segments identified by PET on two short axis slices of mid ventricle, with eight segments each. Using PET, 68 segments were identified as hibernating and 42 as scarred. The hibernating segments were found on BOLD MRI to have an average signal change between rest and stress of -9.53%, compared with -2.15% in the scarred segments (p = 0.008). The average wall thickening was 8.7 mm in the hibernating segments compared with 5.9 mm in the scarred segments (p < 0.0001). BOLD MRI with wall thickening may differentiate scarred and viable myocardium and help identify suitable patients for revascularisation. Further larger studies are needed to establish a threshold for detection, sensitivity, and specificity.


Multi-branch Convolutional Neural Network for Identification of Small Non-coding RNA genomic loci.
Genomic regions that encode small RNA genes exhibit characteristic patterns in their sequence, secondary structure, and evolutionary conservation. Convolutional Neural Networks are a family of algorithms that can classify data based on learned patterns. Here we present MuStARD an application of Convolutional Neural Networks that can learn patterns associated with user-defined sets of genomic regions, and scan large genomic areas for novel regions exhibiting similar characteristics. We demonstrate that MuStARD is a generic method that can be trained on different classes of human small RNA genomic loci, without need for domain specific knowledge, due to the automated feature and background selection processes built into the model. We also demonstrate the ability of MuStARD for inter-species identification of functional elements by predicting mouse small RNAs (pre-miRNAs and snoRNAs) using models trained on the human genome. MuStARD can be used to filter small RNA-Seq datasets for identification of novel small RNA loci, intra- and inter- species, as demonstrated in three use cases of human, mouse, and fly pre-miRNA prediction. MuStARD is easy to deploy and extend to a variety of genomic classification questions. Code and trained models are freely available at gitlab.com/RBP_Bioinformatics/mustard.


Administration of insulin-like growth factor-I improves fatigue resistance of skeletal muscles from dystrophic mdx mice.
Muscle fatigue occurs in many neuromuscular diseases, including the muscular dystrophies, and it contributes to a loss of functional capacity and reduced quality of life for affected patients. An improvement in fatigue resistance has been observed in diaphragm muscles of mdx mice following insulin-like growth factor-I (IGF-I) administration. Whether similar treatment can improve locomotor muscle function in mdx mice is not known. We examined the efficacy of IGF-I administration (1 mg/kg daily s.c. for 8 weeks) on structural, metabolic, and functional properties of extensor digitorum longus (EDL) and soleus muscles of mdx mice, and tested the hypothesis that IGF-I treatment would improve function in these muscles. After treatment, muscles were more resistant to fatigue during repeated maximal contractions than muscles from untreated mice, an improvement associated with increased muscle fiber succinate dehydrogenase activity in the absence of changes in cellular (single-fiber) contractile activation characteristics. The findings have important clinical implications, not just for the dystrophinopathies, but for all neuromuscular pathologies where fatigue of locomotor muscles limits functional capacity and decreases quality of life.


Outcome prediction in mechanically ventilated neurologic patients by junior neurointensivists.
Physician prediction of outcome in critically ill neurologic patients impacts treatment decisions and goals of care. In this observational study, we prospectively compared predictions by neurointensivists to patient outcomes at 6 months. Consecutive neurologic patients requiring mechanical ventilation for 72 hours or more were enrolled. The attending neurointensivist was asked to predict 6-month 1) functional outcome (modified Rankin scale [mRS]), 2) quality of life (QOL), and 3) whether supportive care should be withdrawn. Six-month functional outcome was determined by telephone interviews and dichotomized to good (mRS 0-3) and poor outcome (mRS 4-6). Of 187 eligible patients, 144 were enrolled. Neurointensivists correctly predicted 6-month functional outcome in 80% (95% confidence interval [CI], 72%-86%) of patients. Accuracy for a predicted good outcome was 63% (95% CI, 50%-74%) and for poor outcome 94% (95% CI, 85%-98%). Excluding patients who had life support withdrawn, accuracy for good outcome was 73% (95% CI, 60%-84%) and for poor outcome 87% (95% CI, 74%-94%). Accuracy for exact agreement between neurointensivists' mRS predictions and actual 6-month mRS was only 43% (95% CI, 35%-52%). Predicted accuracy for QOL was 58% (95% CI, 39%-74%) for good/excellent and 67% (95% CI, 46%-83%) for poor/fair. Of 27 patients for whom withdrawal of care was recommended, 1 patient survived in a vegetative state. Prediction of long-term functional outcomes in critically ill neurologic patients is challenging. Our neurointensivists were more accurate in predicting poor outcome than good outcome in patients requiring mechanical ventilation >or=72 hours.


Anticholinergic drugs and negative outcomes in the older population: from biological plausibility to clinical evidence.
The use of medication with anticholinergic properties is widespread among older subjects. Many drugs of common use such as antispasmodics, bronchodilators, antiarrhythmics, antihistamines, anti-hypertensive drugs, antiparkinson agents, skeletal muscle relaxants, and psychotropic drugs have been demonstrated to have an anticholinergic activity. The most frequent adverse effects are dry mouth, nausea, vomiting, constipation, abdominal pain, urinary retention, blurred vision, tachycardia and neurologic impairment such as confusion, agitation and coma. A growing evidence from experimental studies and clinical observations suggests that drugs with anticholinergic properties can cause physical and mental impairment in the elderly population. However, the morbidity and management issues associated with unwanted anticholinergic activity are underestimated and frequently overlooked. Moreover, their possible relation with specific negative outcome in the elderly population is still not firmly established. The aim of the present review was to evaluate the relationship between the use of drugs with anticholinergic activity and negative outcomes in older persons. We searched PubMed and Cochrane combining the search terms "anticholinergic", "delirium", "cognitive impairment", "falls", "mortality" and "discontinuation". Medicines with anticholinergic properties may increase the risks of functional and cognitive decline, morbidity, institutionalization and mortality in older people. However, such evidences are still not conclusive probably due to possible confounding factors. In particular, more studies are needed to investigate the effects of discontinuation of drug with anticholinergic properties. Overall, minimizing anticholinergic burden should always be encouraged in clinical practice to improve short-term memory, confusion and delirium, quality of life and daily functioning.


Plastic and immobile: Unequal intergenerational mobility by genetic sensitivity score within sibling pairs.
Contrary to traditional biological arguments, the differential susceptibility model suggests genotype may moderate rather than mediate parent-child economic similarity. Using family fixed effects models of Add Health sibling data, I investigate the relationship between an index of sensitive genotypes and intergenerational mobility. Full, same sex sibling comparisons hold constant parental characteristics and address the non-random distribution of genotype that reduces internal validity in nationally representative samples. Across multiple measures of young adult financial standing, those with more copies of sensitive genotypes achieve lower economic outcomes than their sibling if they are from a low income context but fare better from a high income context. This genetic sensitivity to parental income entails lower intergenerational mobility. Results support the differential susceptibility model and contradict simplistic genetic explanations for intergenerational inequality, suggesting sensitive genotypes are not inherently positive or negative but rather increase dependence on parental income and reduce mobility.


A 6-year follow-up of a large European cohort of children with attention-deficit/hyperactivity disorder-combined subtype: outcomes in late adolescence and young adulthood.
There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome (including pharmacological treatment) of a large cohort of participants with ADHD-combined type (N = 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children's Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1-3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children's Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (R (2) = 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (R (2) = 17.8 %). Pharmacological treatment had no (beneficial) impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors.


Cores of swirling particle motion in unsteady flows.
In nature and in flow experiments particles form patterns of swirling motion in certain locations. Existing approaches identify these structures by considering the behavior of stream lines. However, in unsteady flows particle motion is described by path lines which generally gives different swirling patterns than stream lines. We introduce a novel mathematical characterization of swirling motion cores in unsteady flows by generalizing the approach of Sujudi/Haimes to path lines. The cores of swirling particle motion are lines sweeping over time, i.e., surfaces in the space-time domain. They occur at locations where three derived 4D vectors become coplanar. To extract them, we show how to re-formulate the problem using the Parallel Vectors operator. We apply our method to a number of unsteady flow fields.


Reflex increase in blood pressure during the intracoronary administration of adenosine in man.
Infusion of adenosine (0.022-2.2 mg/min) into the left anterior descending (LAD) coronary artery of 26 patients produced a dose-dependent increase in blood pressure without a change in heart rate. At adenosine 2.2 mg/min, systolic pressure rose by 21.0 +/- 2.2 mmHg from 134 +/- 4.3 mmHg (P less than 0.001) and diastolic pressure increased by 10.4 +/- 1.1 mmHg from 76 +/- 1.9 mmHg (P less than 0.001). The rise in arterial pressure was associated with a 22 +/- 3.4% increase in systemic vascular resistance (P less than 0.01) and no change in cardiac output (-2.8 +/- 4.3%, P = NS). Plasma norepinephrine levels rose by 40 +/- 14% from 105 +/- 9 pg/ml (P less than 0.05) and epinephrine levels by 119 +/- 31% from 37 +/- 9 pg/ml (P less than 0.01). Right atrial infusion of adenosine produced insignificant hemodynamic effects, suggesting that systemic spillover of adenosine was not responsible for the observed effects. In 20 cardiac transplant patients with denervated hearts, LAD infusion of adenosine (2.2 mg/min) produced no change in systolic pressure (-0.1 +/- 1.6 mmHg from 139 +/- 3.4 mmHg, P = NS) and a decrement in diastolic pressure (-4.7 +/- 1.2 mmHg from 98 +/- 2.5 mmHg, P less than 0.01). Thus, infusion of adenosine into the LAD coronary artery causes a reflex increase in arterial pressure due to a rise in systemic vascular resistance, probably as a result of increased sympathetic discharge. This reflex pathway may be of importance in disease states such as myocardial ischemia, in which myocardial adenosine levels are elevated.


Chromatin accessibility maps of chronic lymphocytic leukaemia identify subtype-specific epigenome signatures and transcription regulatory networks.
Chronic lymphocytic leukaemia (CLL) is characterized by substantial clinical heterogeneity, despite relatively few genetic alterations. To provide a basis for studying epigenome deregulation in CLL, here we present genome-wide chromatin accessibility maps for 88 CLL samples from 55 patients measured by the ATAC-seq assay. We also performed ChIPmentation and RNA-seq profiling for ten representative samples. Based on the resulting data set, we devised and applied a bioinformatic method that links chromatin profiles to clinical annotations. Our analysis identified sample-specific variation on top of a shared core of CLL regulatory regions. IGHV mutation status-which distinguishes the two major subtypes of CLL-was accurately predicted by the chromatin profiles and gene regulatory networks inferred for IGHV-mutated versus IGHV-unmutated samples identified characteristic differences between these two disease subtypes. In summary, we discovered widespread heterogeneity in the chromatin landscape of CLL, established a community resource for studying epigenome deregulation in leukaemia and demonstrated the feasibility of large-scale chromatin accessibility mapping in cancer cohorts and clinical research.


Elevated levels of peritumoral chondroitin sulfate are predictive of poor prognosis in patients treated by radical prostatectomy for early-stage prostate cancer.
The disease course of localized prostate cancer is highly variable, and patients potentially curable by aggressive management are not readily identified by current clinical practice. Chondroitin sulfate (CS) glycosaminoglycan is a candidate biomarker as elevated levels of CS in peritumoral stroma of prostate cancer have been associated with prostate-specific antigen (PSA) failure. Immunoreactive CS was measured using image analysis of archived radical prostatectomy tissues, obtained from 157 men with a median of 47 months (range, 16-111 months) clinical follow-up. CS level, Gleason score, and preoperative serum PSA levels were independent predictors of PSA failure by Cox's multivariate analysis. Patients with low CS levels had significantly fewer PSA failures after radical prostatectomy than patients with high levels of CS (Kaplan-Meier plot; 32% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 50% for CS > or = 7.0, P = 0.0001). In the subgroup of patients with preoperative serum PSA levels < 10 ng/ml, CS was particularly useful in discriminating retrospectively those patients most suited for surgery (Kaplan-Meier plot; 14% PSA failures at 5 years for CS mean integrated absorbance cut point < 7.0 versus 47% for CS > or = 7.0, P = 0.0001). We conclude that measurements of CS level can assist in predicting patient outcome after surgery. Additionally, our data suggest that the combination of CS and PSA measurements may improve outcome prediction for patients with intermediate Gleason scores.


Limitations in daily activities are the major determinant of reduced health-related quality of life in patients with hand osteoarthritis.
To determine the impact of limitations in daily activities and pain on quality of life (QoL) in patients with osteoarthritis (OA) visiting a rheumatologist. Patients diagnosed by the rheumatologist with primary hand, knee or hip OA were consecutively included from August 2005 to April 2009. QoL was assessed by Short Form-36, with the physical component summary score (PCS), calculated using data from a norm-based population. Self-reported pain and function in patients with hand OA was assessed by the Australian/Canadian OA hand index (AUSCAN) pain (range 0-20) and AUSCAN function (range 0-36). Linear regression analyses were performed to investigate associations between PCS and demographic characteristics, and between PCS and pain and function in patients with OA. Hand OA was diagnosed in 95% of 460 included patients (89% women, mean age 61 years). PCS was lowered in patients with OA. Patients with hand OA reported a considerable amount of pain (mean 9.5 (SD 4.3)) and disability (mean 16.5 (SD 8.6)). AUSCAN function was associated with PCS (adjusted β=-0.3, 95% CI -0.4 to -0.2), but AUSCAN pain was not. Hand OA was the most common OA subtype in secondary care. Health-related QoL is decreased in patients with OA and is associated with limitations in daily activities.


Neuronal hypertrophy and mast cells in histologically negative, clinically diagnosed acute appendicitis: a quantitative immunophenotypical analysis.
In about 20-25% of appendicectomies performed for clinically suspected acute appendicitis, definite morphological changes are lacking on histopathological examination. The present study was done to investigate whether any changes in neurons and mast cells could be detected in patients presenting with clinical acute appendicitis but found to have normal appendix at histopathology. A descriptive study was conducted on 50 appendix specimens which were categorized as histology-positive acute appendicitis (HPAA), clinically acute appendicitis but histologically negative (HNAA), appendices resected for other causes and appendices from forensic autopsy. A morphometric and quantitative evaluation of nerve fibers and ganglion plexus and its relation to mast cell density were studied. All sections were subjected to hematoxylin and eosin stain, toluidine blue stain, S 100 protein and neuron specific enolase (NSE) immunostaining and a quantitative image analysis system. Mucosal and submucosal neuronal components highlighted by NSE and S100 immunostaining observed in cases of HNAA were comparable to cases of HPAA. With S 100 immunostaining in HNAA cases, the increase in number and size of myentric neuronal plexus were mild in 40% (10/25) cases, moderate in 40% (10/25) and marked in 20% (5/25) cases as compared to 66.7% (10/15) cases of HPAA showing moderate and 33.3% (5/15) cases showing marked increase (p = 0.018). The mean mast cell count was highest in the HNAA cases (2.74) in all the four layers as compared to the HPAA (1.85) and control group (2.05). There was no difference in the relationship of the size of ganglion cells and the mast cell concentration. Neuronal hypertrophy and mast cells may play a role in the pathogenesis of appendicitis-like pain in patients with histologically normal appendices.


Psychiatric advance directives in Australian mental-health legislation.
Following the recent widespread reform of mental-health legislation in Australia, psychiatric advance directives (PADs) have now been incorporated in four jurisdictions. We contextualise the potential role for PADs within the Australian legal framework and note their varying introduction across jurisdictions, with a focus on progressive legislation in the Australian Capital Territory (ACT). The formal recognition of PADs effectively shifts the trajectory of mental-health law towards a stronger recognition of consumer autonomy, albeit to varying degrees across jurisdictions. The most inspiring of these changes may be seen in the ACT Act, where an innovative framing of PAD provisions creates a safe space for clinicians and patients to engage, build therapeutic alliances and develop appropriate frameworks for further change.


Clinical and histological responses of congenital melanocytic nevi after single treatment with Q-switched lasers.
Laser irradiation of congenital melanocytic nevi is a controversial treatment. Recurrence of lesions after laser treatment appears to be the rule, and the effects of laser irradiation on cellular biological behavior and the possible mutagenic responses of nevomelanocytes that have received nonlethal doses of irradiation are still unclear. Without treatment, there is an increased potential for malignant degeneration over a life-time. The purpose of this study was to examine the effects of Q-switched lasers on congenital nevi and to explain the mechanism(s) behind the response of the nevi to laser treatment. Five congenital nevi were divided into 3 equal parts: 1 part was treated with the Q-switched ruby laser at a wavelength of 694 nm, 1 part was treated with the Q-switched neodymium: YAG laser at a wavelength of 1064 nm, and 1 part was left untreated to serve as control. At intervals ranging from 3 days to 3 months after laser irradiation, the lesions were excised and evaluated by routine staining. This clinical study was conducted entirely at the Massachusetts General Hospital Dermatology Laser Center, Boston, Mass. Both the superficial and the deep portions of the congenital melanocytic nevi were affected by the 2 lasers, as evidenced by macroscopic inspection as well as microscopic evaluation. However, the Q-switched laser treatment did not destroy all nevomelanocytes, particularly in the deeper, less pigmented portions of the lesions. Both the Q-switched ruby laser and the neodymium: YAG laser often removed only the superficial portion of the congenital melanocytic nevi. The Q-switched ruby laser (694 nm) appeared to be more effective in removing nevomelanocytes than the Q-switched neodymium: YAG laser (1064 nm).


Novel mitochondrial protein interactors of immunoglobulin light chains causing heart amyloidosis.
In immunoglobulin (Ig) light-chain (LC) (AL) amyloidosis, AL deposition translates into life-threatening cardiomyopathy. Clinical and experimental evidence indicates that soluble cardiotoxic LCs are themselves harmful for cells, by which they are internalized. Hypothesizing that interaction of soluble cardiotoxic LCs with cellular proteins contributes to damage, we characterized their interactome in cardiac cells. LCs were purified from patients with AL amyloidosis cardiomyopathy or multiple myeloma without amyloidosis (the nonamyloidogenic/noncardiotoxic LCs served as controls) and employed at concentrations in the range observed in AL patients' sera. A functional proteomic approach, based on direct and inverse coimmunoprecipitation and mass spectrometry, allowed identifying LC-protein complexes. Findings were validated by colocalization, fluorescence lifetime imaging microscopy (FLIM)-fluorescence resonance energy transfer (FRET), and ultrastructural studies, using human primary cardiac fibroblasts (hCFs) and stem cell-derived cardiomyocytes. Amyloidogenic cardiotoxic LCs interact in vitro with specific intracellular proteins involved in viability and metabolism. Imaging confirmed that, especially in hCFs, cardiotoxic LCs (not controls) colocalize with mitochondria and spatially associate with selected interactors: mitochondrial optic atrophy 1-like protein and peroxisomal acyl-coenzyme A oxidase 1 (FLIM-FRET efficiencies 11 and 6%, respectively). Cardiotoxic LC-treated hCFs display mitochondrial ultrastructural changes, supporting mitochondrial involvement. We show that cardiotoxic LCs establish nonphysiologic protein-protein contacts in human cardiac cells, offering new clues on the pathogenesis of AL cardiomyopathy.


Differential effects of compartment deacidification on the targeting of membrane and soluble proteins to the vacuole in yeast.
Lysosomal/vacuolar protein targeting is dependent on compartment acidification. In yeast, sorting of soluble vacuolar proteins such as carboxypeptidase Y is sensitive to acute changes in vacuolar pH. In contrast, the vacuolar membrane protein alkaline phosphatase is missorted only under conditions of chronic deacidification. We have undertaken a temporal analysis to define further the relationship between compartment acidification and sorting of soluble and membrane vacuolar proteins. Depletion of either the Vma3p or Vma4p subunits of the yeast vacuolar ATPase over time resulted in loss of vacuolar ATPase activity and vacuolar acidification. A kinetic delay in processing of carboxypeptidase Y occurred concomitant with these physiological changes while transport of alkaline phosphatase remained unaffected. Carboxypeptidase S, another vacuolar hydrolase that transits through the secretory pathway as an integral membrane protein, displayed a pH sensitivity similar to that of soluble vacuolar proteins. These results indicate that compartment acidification is tightly coupled to efficient targeting of proteins to the vacuole and that there may be multiple distinct mechanisms for targeting of vacuolar membrane proteins.


Clinical profile and prognostic value of low systolic blood pressure in patients hospitalized for heart failure with reduced ejection fraction: insights from the Efficacy of Vasopressin Antagonism in Heart Failure: Outcome Study with Tolvaptan (EVEREST) trial.
Systolic blood pressure (SBP) is related to the pathophysiologic development and progression of heart failure (HF) and is inversely associated with adverse outcomes during hospitalization for HF (HHF). The prognostic value of SBP after initiating inhospital therapy and the mode of death and etiology of cardiovascular readmissions based on SBP have not been well characterized in HHF. A post hoc analysis was performed of the placebo group (n = 2061) of the EVEREST trial, which enrolled patients within 48 hours of admission for worsening HF with an ejection fraction (EF) ≤40% and an SBP ≥90 mm Hg, for a median follow-up of 9.9 months. Systolic blood pressure was measured at baseline, daily during hospitalization, and at discharge/day 7. Patients were divided into the following quartiles by SBP at baseline: ≤105, 106 to 119, 120 to 130, and ≥131 mm Hg. Outcomes were all-cause mortality (ACM) and the composite of cardiovascular mortality or HHF (CVM + HHF). The associations between baseline, discharge, and inhospital change in SBP and ACM and CVM + HHF were assessed using multivariable Cox proportional hazards regression models adjusted for known covariates. Median (25th, 75th) SBP at baseline was 120 (105, 130) mm Hg and ranged from 82 to 202 mm Hg. Patients with a lower SBP were younger and more likely to be male; had a higher prevalence of prior revascularization and ventricular arrhythmias; had a lower EF, worse renal function, higher natriuretic peptide concentrations, and wider QRS durations; and were more likely to require intravenous inotropes during hospitalization. Lower SBP was associated with increased mortality, driven by HF and sudden cardiac death, and cardiovascular hospitalization, primarily caused by HHF. After adjusting for potential confounders, SBP was inversely associated with risk of the coprimary end points both at baseline (ACM: hazard ratio [HR]/10-mm Hg decrease 1.15, 95% CI1.08-1.22; CVM + HHF: HR 1.09/10-mm Hg decrease, 95% CI 1.04-1.14) and at the time of discharge/day 7 (ACM: HR 1.15/10-mm Hg decrease, 95% CI 1.08-1.22; CVM + HHF: HR 1.07/10-mm Hg decrease, 95% CI 1.02-1.13), but the association with inhospital SBP change was not significant. Systolic blood pressure is an independent clinical predictor of morbidity and mortality after initial therapy during HHF with reduced EF.


Effect of immunosuppression on Rickettsia rickettsii infection in guinea pigs.
The role of the immune response in the pathogenesis of Rickettsia rickettsii infection in guinea pigs was investigated by immunosuppression, using antilymphocyte serum. Twenty guinea pigs were inoculated with R. rickettsii, Sheila Smith strain, on day 0. Fifteen animals received antilymphocyte serum on days --1, 0, 2, 4, and 6. Five animals received normal rabbit serum on the same schedule. At necropsy, specimens were collected for histological examination, rickettsial immunofluorescence, rickettsial titration, and antirickettsial antibody titration. All normal rabbit serum recipients and 12 of 15 antilymphocyte serum recipients developed typical disease. Comparison of animals in terminal stages of disease revealed the same clinical course and gross lesions, but differing rickettsial burden and cellular response. Immunosuppressed animals had higher titers of splenic rickettsiae and greater numbers of immunofluorescent rickettsiae. Thus, although antibody was undetectable in both groups, there appeared to be an inhibition of antirickettsial immunity. Microscopic vasculitis was similar quantitatively, but differed qualitatively, with immunocompetent animals having the typical monouclear/lymphocytic inflammation and immunosuppressed animals having neutrophilic predominance. This study demonstrates that immunopathological mechanisms are not necessary for the pathogenesis of experimental Rocky Mountain spotted fever. The rickettsiae themselves seem capable of causing cellular and tissue damage.


Variations of gastric corpus microbiota are associated with early esophageal squamous cell carcinoma and squamous dysplasia.
Observational studies revealed a relationship between changes in gastric mucosa and risk of esophageal squamous cell carcinoma (ESCC) which suggested a possible role for gastric microbiota in ESCC carcinogenesis. In this study we aimed to compare pattern of gastric corpus microbiota in ESCC with normal esophagus. Cases were included subjects with early ESCC (stage I-II) and esophageal squamous dysplasia (ESD) as the cancer precursor. Control groups included age and sex-matched subjects with mid-esophagus esophagitis (diseased-control), and histologically normal esophagus (healthy-control). DNA was extracted from snap-frozen gastric corpus tissues and 16S rRNA was sequenced on GS-FLX Titanium. After noise removal, an average of 3004 reads per sample was obtained from 93 subjects. We applied principal coordinate analysis to ordinate distances from beta diversity data. Pattern of gastric microbiota using Unifrac (p = 0.004) and weighted Unifrac distances (p = 0.018) statistically varied between cases and healthy controls. Sequences were aligned to SILVA database and Clostridiales and Erysipelotrichales orders were more abundant among cases after controling for multiple testing (p = 0.011). No such difference was observed between mid-esophagitis and healthy controls. This study is the first to show that composition of gastric corpus mucosal microbiota differs in early ESCC and ESD from healthy esophagus.


Does the surgical approach for treating mandibular condylar fractures affect the rate of seventh cranial nerve injuries? A systematic review and meta-analysis based on a new classification for surgical approaches.
The purpose of this study was to determine the rate of facial nerve injury (FNI) when performing (ORIF) of mandibular condylar fractures by different surgical approaches. A systematic review and meta-analysis were performed that included several databases with specific keywords, a reference search, and a manual search for suitable articles. The inclusion criteria were all clinical trials, with the aim of assessing the rate of facial nerve injuries when (ORIF) of mandibular condylar fractures was performed using different surgical approaches. The main outcome variable was transient facial nerve injury (TFNI) and permanent facial nerve injury (PFNI) according to the fracture levels, namely: condylar head fractures (CHFs), condylar neck fractures (CNFs), and condylar base fractures (CBFs). For studies where there was no delineation between CNFs and CBFs, the fractures were defined as CNFs/CBFs. The dependent variables were the surgical approaches. A total of 3873 patients enrolled in 96 studies were included in this analysis. TFNI rates reported in the literature were as follows: A) For the transoral approach: a) for strictly intraoral 0.72% (1.3 in CNFs and 0% for CBFs); b) for the transbuccal trocar instrumentation 2.7% (4.2% in CNFs and 0% for CBFs); and c) for endoscopically assisted ORIF 4.2% (5% in CNFs, and 4% in CBFs). B) For low submandibular approach 15.3% (26.1% for CNFs, 11.8% for CBFs, and 13.7% for CNFs/CBFs). C) For the high submandibular/angular subparotid approach with masseter transection 0% in CBFs. D) For the high submandibular/angular transmassetric anteroparotid approach 0% (CNFs and CBFs). E) For the transparotid retromandibular approach a) with nerve facial preparation 14.4% (23.9% in CNFs, 11.8% in CBFs and 13.7% for CNFs/CBFs); b) without facial nerve preparation 19% (24.3% for CNFs and 10.5% for CBFs). F) For retromandibular transmassetric anteroparotid approach 3.4% in CNFs/CBFs. G) For retromandibular transmassetric anteroparotid approach with preauricular extension 2.3% for CNFs/CBFs. H) For preauricular approach a) deep subfascial dissection plane 0% in CHFs b) for subfascial approach using traditional preauricular incision 10% (8.5% in CHFs and 11.5% in CNFs). I) For retroauricular approach 3% for CHFs. PFNI rates reported in the literature were as follows: A) for low submandibular approach 2.2%, B) for retromandibular transparotid approach 1.4%; C) for preauricular approach 0.33%; D) for high submandibular approach 0.3%; E) for deep retroparotid approach 1.5%. According to published data for CHFs, a retroauricular approach or deep subfascial preauricular approach was the safest to protect the facial nerve. For CNFs, a transmassetric anteroparotid approach with retromandibular and preauricular extension was the safest approach to decrease risk of FNI. For CBFs, high submandibular incisions with either transmassetric anteroparotid approach with retromandibular or transmassetric subparotid approach, followed by intraoral (with or without endoscopic/transbuccal trocar) were the safest approaches with respect to decreased risk of FNI.


Apparent hyperkalaemia from blood sampled from an arterial cannula.
Blood samples were obtained from a radial artery cannula in a 60-yr-old man during coronary artery surgery. Serum potassium concentrations of 9.3, 8.4, and 7.4 mmol litre(-1) were obtained. A simultaneous venous blood sample gave a serum potassium concentration of 4.4 mmol litre(-1). The ECG was unchanged. After the arterial cannula was repositioned, subsequent blood samples gave expected ranges of serum potassium concentration. We suggest that the initial arterial cannula position caused a high shear rate in the blood when samples were withdrawn, causing haemolysis and hyperkalaemia.


Gender Differences in Complex Posttraumatic Stress Symptoms, and Their Relationship to Mental Health and Substance Abuse Outcomes in Incarcerated Adults.
Complex trauma (CT; for example, childhood abuse) has been associated with significant behavioral health problems (i.e., mental health and substance use disorders) and symptoms that are consistent with complex posttraumatic stress disorder (C-PTSD). CT is prevalent in adult forensic populations, and particularly important for women as they tend to report more adverse consequences of exposure to traumatic stressors and are entering the criminal justice system at a heightened rate compared with men. However, no studies have empirically tested the relationship among CT, C-PTSD, and behavioral health problems with gender among incarcerated adults. The present study examined the relationship between gender and childhood abuse history, C-PTSD symptom severity, and behavioral health problems in 497 incarcerated adults. Findings indicate that women were more likely to report a history of childhood abuse, and more severe C-PTSD symptoms and behavioral health problems than men. Childhood abuse history significantly accounted for the gender difference observed in C-PTSD symptom severity. C-PTSD partially mediated the gender difference in psychiatric morbidity and in risk of hard drug use. Implications for trauma-informed and gender-responsive services and research in the adult criminal justice system are discussed.


Cdc42 is required for cytoskeletal support of endothelial cell adhesion during blood vessel formation in mice.
The Rho family of small GTPases has been shown to be required in endothelial cells (ECs) during blood vessel formation. However, the underlying cellular events controlled by different GTPases remain unclear. Here, we assess the cellular mechanisms by which Cdc42 regulates mammalian vascular morphogenesis and maintenance. In vivo deletion of Cdc42 in embryonic ECs (Cdc42(Tie2KO)) results in blocked lumen formation and endothelial tearing, leading to lethality of mutant embryos by E9-10 due to failed blood circulation. Similarly, inducible deletion of Cdc42 (Cdc42(Cad5KO)) at mid-gestation blocks angiogenic tubulogenesis. By contrast, deletion of Cdc42 in postnatal retinal vessels leads to aberrant vascular remodeling and sprouting, as well as markedly reduced filopodia formation. We find that Cdc42 is essential for organization of EC adhesion, as its loss results in disorganized cell-cell junctions and reduced focal adhesions. Endothelial polarity is also rapidly lost upon Cdc42 deletion, as seen by failed localization of apical podocalyxin (PODXL) and basal actin. We link observed failures to a defect in F-actin organization, both in vitro and in vivo, which secondarily impairs EC adhesion and polarity. We also identify Cdc42 effectors Pak2/4 and N-WASP, as well as the actomyosin machinery, to be crucial for EC actin organization. This work supports the notion of Cdc42 as a central regulator of the cellular machinery in ECs that drives blood vessel formation.


RNA-binding proteins implicated in neurodegenerative diseases.
Gene expression is regulated at many levels, including after generation of the primary RNA transcript from DNA but before translation into protein. Such post-translational gene regulation occurs via the action of a multitude of RNA binding proteins and include varied actions from splicing to regulation of association with the translational machinery. Primary evidence that such processes might contribute to disease mechanisms in neurodegenerative disorders comes from the observation of mutations in RNA binding proteins, particularly in diseases in the amyotrophic lateral sclerosis-frontotemporal dementia spectrum and in some forms of ataxia and tremor. The bulk of evidence from recent surveys of the types of RNA species that are affected in these disorders suggests a global deregulation of control rather than a very small number of RNA species, although why some groups of neurons are sensitive to these changes is not well understood. Overall, these data suggest that neurodegeneration can be initiated by mutations in RNA binding proteins and, as a corollary, that neurons are particularly sensitive to loss of control of gene expression at the post-transcriptional level. Such observations have implications not only for understanding the nature of neurodegenerative disorders but also how we might intervene therapeutically in these diseases. WIREs RNA 2017, 8:e1397. doi: 10.1002/wrna.1397 For further resources related to this article, please visit the WIREs website.


The Aquaporin Splice Variant NbXIP1;1α Is Permeable to Boric Acid and Is Phosphorylated in the N-terminal Domain.
Aquaporins (AQPs) are membrane channel proteins that transport water and uncharged solutes across different membranes in organisms in all kingdoms of life. In plants, the AQPs can be divided into seven different subfamilies and five of these are present in higher plants. The most recently characterized of these subfamilies is the XIP subfamily, which is found in most dicots but not in monocots. In this article, we present data on two different splice variants (α and β) of NbXIP1;1 from Nicotiana benthamiana. We describe the heterologous expression of NbXIP1;1α and β in the yeast Pichia pastoris, the subcellular localization of the protein in this system and the purification of the NbXIP1;1α protein. Furthermore, we investigated the functionality and the substrate specificity of the protein by stopped-flow spectrometry in P. pastoris spheroplasts and with the protein reconstituted in proteoliposomes. The phosphorylation status of the protein and localization of the phosphorylated amino acids were verified by mass spectrometry. Our results show that NbXIP1;1α is located in the plasma membrane when expressed in P. pastoris, that it is not permeable to water but to boric acid and that the protein is phosphorylated at several amino acids in the N-terminal cytoplasmic domain of the protein. A growth assay showed that the yeast cells expressing the N-terminally His-tagged NbXIP1;1α were more sensitive to boric acid as compared to the cells expressing the C-terminally His-tagged isoform. This might suggest that the N-terminal His-tag functionally mimics the phosphorylation of the N-terminal domain and that the N-terminal domain is involved in gating of the channel.


The feasibility and efficacy of subcutaneous plerixafor for mobilization of peripheral blood stem cells in allogeneic HLA-identical sibling donors: results of the HOVON-107 study.
Plerixafor (PFX) mobilizes CD34+ cells into circulation by disrupting the CXCR4 binding of the hematopoietic stem cell in its bone marrow niche. in the prospective HOVON-107 study (www.hovon.nl) 23 allogeneic HLA-identical sibling donors received one or two subcutaneous (sc) injections of plerixafor 0.320 mg/kg.The primary endpoint, was defined as feasibility to mobilize a minimum of 2.0 x106 CD34+ cells/kg recipient weight obtained by leukopheresis in at least 90% of the donors. median 3.3 x 106 CD34+ cells/kg (1.9-6.5) were collected after 1 (n=12) or 2 (n=10) sc injections of PFX. Side effects occurred in 15/23 (65%) donors: most were grade 1-2; in 5 donors grade 3 and all resolved. All grafts were directly transplanted. Compared to 10 grafts obtained with G-CSF the number of CD34+ cells was 2.4 fold lower but the percentage of phenotypically most immature CD34+ subset was higher (31% vs 15%). The total number of CD3+ cells in the graft seemed higher after PFX-mobilization, but CD4/CD 8 ratios, and frequencies of Th2, Th17 and regulatory T-cells or NK cells were comparable. All patients engrafted and no increase in incidence or severity of acute or chronic graft versus host disease was observed. stem cell mobilization with sc PFX 0.320 mg/kg in allogeneic sibling donors is feasible with limited toxicity for donors. 14 allogeneic donors were mobilized with PFX 0.320 mg intravenously according to the same protocol. Due to the limited numbers, these results are in the supplementary section.


A comparison of four severity-adjusted models to predict mortality after coronary artery bypass graft surgery.
To assess the validity of four severity-adjusted models to predict mortality following coronary artery bypass graft surgery by using an independent surgical database. A prospective observational study wherein predicted mortality for each patient was obtained by using four different published severity-adjusted models. A university-affiliated teaching community hospital. Eight hundred sixty-eight consecutive patients who underwent coronary artery bypass graft surgery without accompanying valve or aneurysm repair during the period from 1991 to 1993. None. Predicted mortality rates for each model were obtained by averaging individual patient predictions and were compared with actual morality rates. We assessed the accuracy of overall prediction for the total series, as well as compared individual patient predictions created by each model. The discrimination of models was assessed with receiver operating characteristic curves and the Hosmer-Lemeshow goodness-of-fit statistic. The observed crude mortality rate was 3.7%. The predicted mortality rate ranged from 2.8% to 9.2%, despite relatively good discrimination by the models (area under the receiver operating characteristic curve, 0.70 to 0.74). The individual patient mortality predicted by different models varied by as much as a ninefold difference. The currently used coronary artery bypass graft predictive models, although generally accurate, have significant shortcomings and should be used with caution. The predicted mortality rate following coronary artery bypass graft surgery varied by a factor of 3.3 from lowest to highest, making the choice of model a critical factor when assessing outcome. The use of these models for individual patient risk estimations is risky because of the marked discrepancies in individual predictions created by each model.


The membrane-bound quinohemoprotein alcohol dehydrogenase from Gluconacetobacter diazotrophicus PAL5 carries a [2Fe-2S] cluster.
Gluconacetobacter diazotrophicus stands out among the acetic acid bacteria as it fixes dinitrogen and is a true endophyte. It has a set of constitutive enzymes to oxidize ethanol and acetaldehyde which is upregulated during N(2)-dependent growth. The membrane-bound alcohol dehydrogenase (ADH) is a heterodimer (subunit I approximately 72 kDa, subunit II approximately 44 kDa) and constitutes an important component of this organism. ADH of Ga. diazotrophicus is a typical quinohemoprotein with one pyrroloquinoline quinone (PQQ) and four c-type cytochromes. For the first time, a [2Fe-2S] cluster has been identified by EPR spectroscopy in this type of enzyme. This finding is supported by quantitative chemical analysis, revealing 5.90 +/- 0.15 Fe and 2.06 +/- 0.10 acid-labile sulfurs per ADH heterodimer. The X-band EPR spectrum of ADH (as isolated in the presence of dioxygen, 20 K) showed three broad resonances at g 2.007, 1.941, and 1.920 (g(av) 1.956), as well as an intense narrow line centered at g = 2.0034. The latter signal, which was still detected at 100 K, was attributed to the PQQ semiquinone radical (PQQ(sq)). The broad resonances observed at lower temperature were assigned to the [2Fe-2S] cluster in the one-electron reduced state. The oxidation-reduction potentials E(m) (pH 6.0 vs SHE) of the four c-type cytochromes were estimated to E(m1) = -64 (+/-2) mV, E(m2) = -8 (+/-2) mV, E(m3) = +185 (+/-15) mV, and E(m4) = +210 (+/-10) mV (spectroelectrochemistry), E(mFeS) = -250 (+/-5) mV for the [2Fe-2S] cluster, and E(mPQQ) = -210 (+/-5) mV for the PQQ/PQQH(2) couple (EPR spectroscopy). We propose a model for the membrane-bound ADH of Ga. diazotrophicus showing hypothetical intra- and intermolecular electron pathways. Subunit I binds the PQQ cofactor, the [2Fe-2S] cluster, and one c-type cytochrome. Subunit II harbors three c-type cytochromes, thus providing an efficient electron transfer route to quinones located in the cytoplasmic membrane.


Maternal gut bacteria drive intestinal inflammation in offspring with neurodevelopmental disorders by altering the chromatin landscape of CD4+ T cells.
Children with autism spectrum disorders often display dysregulated immune responses and related gastrointestinal symptoms. However, the underlying mechanisms leading to the development of both phenotypes have not been elucidated. Here, we show that mouse offspring exhibiting autism-like phenotypes due to prenatal exposure to maternal inflammation were more susceptible to developing intestinal inflammation following challenges later in life. In contrast to its prenatal role in neurodevelopmental phenotypes, interleukin-17A (IL-17A) generated immune-primed phenotypes in offspring through changes in the maternal gut microbiota that led to postnatal alterations in the chromatin landscape of naive CD4+ T cells. The transfer of stool samples from pregnant mice with enhanced IL-17A responses into germ-free dams produced immune-primed phenotypes in offspring. Our study provides mechanistic insights into why children exposed to heightened inflammation in the womb might have an increased risk of developing inflammatory diseases in addition to neurodevelopmental disorders.


Analyzing regional variation in health care utilization using (rich) household microdata.
This paper exploits rich SOEP microdata to analyze state-level variation in health care utilization in Germany. Unlike most studies in the field of the Small Area Variation (SAV) literature, our approach allows us to net out a large array of individual-level and state-level factors that may contribute to the geographic variation in health care utilization. The raw data suggest that state-level hospitalization rates vary from 65 to 165 percent of the national mean. Ambulatory doctor visits range from 90 to 120 percent of the national mean. Interestingly, in the former GDR states, doctor visit rates are significantly below the national mean, while hospitalization rates lie above the national mean. The significant state-level differences vanish once we control for individual-level socio-economic characteristics, the respondents' health status, their health behavior as well as supply-side state-level factors.


What's "quickest and easiest?": parental decision making about school trip mode.
The potential benefits of active school travel (AST) are widely recognized, yet there is consistent evidence of a systematic decline in the use of active modes of transportation to school since the middle part of the 20th century. This study explored parental accounts of the school travel mode choice decision-making process. Thirty-seven parents of children (17 who walked; 20 who were driven) from four elementary schools in Toronto, Canada participated in semi-structured interviews. The schools varied with respect to walkability of the built environment and socio-economic status. Thematic analysis of interview transcripts identified a two-stage decision-making process. An initial decision concerned the issue of escorting or chauffeuring a child to/from school. This decision appeared to be primarily influenced by concerns about traffic, the child's personal safety, and the child's maturity and cognitive ability regarding navigating his/her way to/from school safely. Following the escort decision, parents considered mode choice, typically selecting what they perceived to be the easiest and most convenient way to travel. The ascription of convenience to the various modes of transportation was influenced by perceptions of travel time and/or distance to/from school. Convenience became a particularly salient theme for parents who found it necessary to complete multi-activity trip chains. The school travel mode choice decision process is complex. Future research and practice should continue to address safety concerns that are typically the focus of active school transport initiatives while addressing more explicitly the behavioural cost of competing mode choices.


An isoform of Arabidopsis myosin XI interacts with small GTPases in its C-terminal tail region.
Myosin XI, a class of myosins expressed in plants is believed to be responsible for cytoplasmic streaming and the translocation of organelles and vesicles. To gain further insight into the translocation of organelles and vesicles by myosin XI, an isoform of Arabidopsis myosin XI, MYA2, was chosen and its role in peroxisome targeting was examined. Using the yeast two-hybrid screening method, two small GTPases, AtRabD1 and AtRabC2a, were identified as factors that interact with the C-terminal tail region of MYA2. Both recombinant AtRabs tagged with His bound to the recombinant C-terminal tail region of MYA2 tagged with GST in a GTP-dependent manner. Furthermore, AtRabC2a was localized on peroxisomes, when its CFP-tagged form was expressed transiently in protoplasts prepared from Arabidopsis leaf tissue. It is suggested that MYA2 targets the peroxisome through an interaction with AtRabC2a.


13N ammonia myocardial imaging at rest and with exercise in normal volunteers. Quantification of absolute myocardial perfusion with dynamic positron emission tomography.
Positron emission tomography (PET) was applied to the measurement of myocardial perfusion using the perfusion tracer 13N-labeled ammonia. 13N ammonia was delivered intravenously to 13 healthy volunteers both at rest and during supine bicycle exercise. Dynamic PET imaging was obtained in three cross-sectional planes for 10 minutes commencing with each injection. The left ventricle was divided into eight sectors, and a small region of interest was assigned to the left ventricular blood pool to obtain the arterial input function. The net extraction of 13N ammonia was obtained for each sector by dividing the tissue 13N concentration at 10 minutes by the integral of the input function from the time of injection to 10 minutes. With this approach for calculating net extractions, rest and exercise net extractions were not significantly different from each other. To obviate possible overestimation of the true 13N ammonia input function by contamination by 13N-labeled compounds other than 13N ammonia or by spillover from myocardium into blood pool, the net extractions were calculated using only the first 90 seconds of the blood and tissue time-activity curves. This approach for calculating net extractions yielded significant differences between rest and exercise, with an average ratio of exercise to rest of 1.38 +/- 0.34. Nonetheless, the increase was less than predicted from the average 2.7-2.8-fold increase in double product at peak exercise or the 1.7-fold increase in double product at 1 minute after exercise. However, when the first 90 seconds of dynamic data were fit with a two compartment tracer kinetic model, average perfusion rates of 0.75 +/- 0.43 ml/min/g at rest and 1.50 +/- 0.74 ml/min/g with exercise were obtained. This average increase in perfusion of 2.2-fold corresponded to similar average increases in double product. Thus, the noninvasive technique of PET imaging with 13N ammonia shows promise for future applications in determining absolute flows in patients with coronary artery disease.


Male fecundity stimulation: conflict and cooperation within and between the sexes: model analyses and coevolutionary dynamics.
Female promiscuity forces the ejaculates of different males to compete for fertilization through sperm competition. In turn, competing ejaculates often influence female promiscuity and fitness, for example, when ejaculate products increase female fecundity. Here we develop theory examining situations where males stimulate female fecundity and compete for fertilization and female remating is influenced by male fecundity stimulation. We consider the fitness consequences that fecundity stimulation has simultaneously for males inseminating the same female and for the female herself, and we show that the way fecundity increases with male stimulation shifts the coevolutionary dynamics of female remating and male ejaculate expenditure from conflict to cooperation among all mating partners. When fecundity stimulation is weak and males "know" their mating roles, the second male to inseminate a female can exploit the fecundity stimulation of the first male, fostering intra- and intersexual conflict over female remating. However, in a diversity of species where fecundity more than doubles with remating, we show that the female and both males can gain from female remating, leading to intra- and intersexual cooperation over female remating. This coevolutionary perspective yields new insights into the connection between promiscuity, fecundity, and sperm competition and the complex interplay between sexual conflict and cooperation.


As₂S₃-silica double-nanospike waveguide for mid-infrared supercontinuum generation.
A double-nanospike As2S3-silica hybrid waveguide structure is reported. The structure comprises nanotapers at input and output ends of a step-index waveguide with a subwavelength core (1 μm in diameter), with the aim of increasing the in-coupling and out-coupling efficiency. The design of the input nanospike is numerically optimized to match both the diameter and divergence of the input beam, resulting in efficient excitation of the fundamental mode of the waveguide. The output nanospike is introduced to reduce the output beam divergence and the strong endface Fresnel reflection. The insertion loss of the waveguide is measured to be ∼2 dB at 1550 nm in the case of free-space in-coupling, which is ∼7 dB lower than the previously reported single-nanospike waveguide. By pumping a 3-mm-long waveguide at 1550 nm using a 60-fs fiber laser, an octave-spanning supercontinuum (from 0.8 to beyond 2.5 μm) is generated at 38 pJ input energy.


Diaphragmatic palsy after cardiac surgical procedures in patients with congenital heart.
Paralysis of diaphragm on one or, exceptionally, both sides is a common cause of delayed recovery and excessive morbidity following pediatric cardiac surgery. The consequences of this complication after all forms of congenital heart surgery in newborns and young infants can be potentially serious. The impact of diaphragmatic palsy on the physiology after single ventricle palliations is particularly significant. It is necessary for all professionals taking care of children with heart disease to be familiar with the etiology, diagnosis, and management of this condition. Early recognition and prompt management of diaphragmatic palsy can potentially reduce the duration of mechanical ventilation and intensive care in those who develop this complication. This review summarizes the anatomy of the phrenic nerves, reasons behind the occurrence of diaphragmatic palsy, and suggests practical guidelines for management.


Septicemia and peritonitis in a colony of common marmosets (Callithrix jacchus) secondary to Klebsiella pneumoniae infection.
Six common marmosets from a colony of 50 died over a period of 3 weeks, with the predominant finding of gram-negative bacterial septicemia. Four of these animals died peracutely; the other two were found when they were moribund, and they subsequently died despite clinical intervention. Gram-negative bacterial rods were present in the blood vessels of stained tissues from five of the six marmosets. Three marmosets also had severe fibrinopurulent peritonitis. In addition, one of the marmosets with peritonitis also had purulent mesenteric lymphadenitis with large colonies of gram-negative bacterial rods within dialated colonic crypts. Klebsiella pneumoniae was isolated from multiple organs in three of the marmosets. Clinical evaluation of the entire colony identified four marmosets with anorexia, nasopharyngeal discharge and diarrhea. These marmosets were treated with enrofloxacin immediately, and they responded well. K. pneumonia could not be cultured from nasal or fecal samples obtained from the colony animals. Because of the peracute nature of the disease, animals often die before exhibiting clinical symptoms, and antibiotics are seldom helpful. In this outbreak we saw both of the major forms of Klebsiella infection in common marmosets: the peracute form with bacteremia and minimal inflammatory reaction around blood vessels, and the chronic form with bacteremia, fibrinopurulent peritonitis, and mesenteric lymphadenitis.


Swept-sine noise-induced damage as a hearing loss model for preclinical assays.
Mouse models are key tools for studying cochlear alterations in noise-induced hearing loss (NIHL) and for evaluating new therapies. Stimuli used to induce deafness in mice are usually white and octave band noises that include very low frequencies, considering the large mouse auditory range. We designed different sound stimuli, enriched in frequencies up to 20 kHz ("violet" noises) to examine their impact on hearing thresholds and cochlear cytoarchitecture after short exposure. In addition, we developed a cytocochleogram to quantitatively assess the ensuing structural degeneration and its functional correlation. Finally, we used this mouse model and cochleogram procedure to evaluate the potential therapeutic effect of transforming growth factor β1 (TGF-β1) inhibitors P17 and P144 on NIHL. CBA mice were exposed to violet swept-sine noise (VS) with different frequency ranges (2-20 or 9-13 kHz) and levels (105 or 120 dB SPL) for 30 min. Mice were evaluated by auditory brainstem response (ABR) and otoacoustic emission tests prior to and 2, 14 and 28 days after noise exposure. Cochlear pathology was assessed with gross histology; hair cell number was estimated by a stereological counting method. Our results indicate that functional and morphological changes induced by VS depend on the sound level and frequency composition. Partial hearing recovery followed the exposure to 105 dB SPL, whereas permanent cochlear damage resulted from the exposure to 120 dB SPL. Exposure to 9-13 kHz noise caused an auditory threshold shift (TS) in those frequencies that correlated with hair cell loss in the corresponding areas of the cochlea that were spotted on the cytocochleogram. In summary, we present mouse models of NIHL, which depending on the sound properties of the noise, cause different degrees of cochlear damage, and could therefore be used to study molecules which are potential players in hearing loss protection and repair.


Autosome and sex chromosome diversity among the African pygmy mice, subgenus Nannomys (Murinae; Mus).
The African pygmy mice, subgenus Nannomys, constitute the most speciose lineage of the genus Mus with 19 recognized species. Although morphologically very similar, they exhibit considerable chromosomal diversity which is here confirmed and extended by the G-banding analysis of 65 mice from West and South Africa. On the basis of their karyotype and distribution area, the specimens were assigned to at least five species. Extensive differentiation both within and between species was observed that involved almost exclusively Robertsonian translocations, 23 of which are newly described. Two of the rearrangements were sex chromosome-autosome translocations, associated in some cases with partial deletions of the X or Y chromosomes. Several authors have predicted that the highly deleterious effect of this rearrangement would be reduced if the sex and autosomal segments were insulated by a block of centromeric heterochromatin. The C-banding analyses performed showed that among the species carrying X-autosome translocations, one followed the expected pattern, while the other did not. In this case, functional isolation of the sex and autosome compartments must involve other repetitive sequences or genomic traits that require further molecular characterization. Such studies will provide insight into the causes and consequences of the high diversity of sex chromosome rearrangements in this subgenus.


Overexpression of histone H2A modulates drug susceptibility in Leishmania parasites.
Resistance to antimonials has emerged as a major hurdle to the treatment and control of visceral leishmaniasis (VL), also know as kala-azar (KA), the disease caused by Leishmania donovani, in India where >60% of KA patients are unresponsive to sodium antimony gluconate (SAG) treatment. Determinants of resistance in laboratory strains are partly known, however the mechanism operating in field isolates is not well understood. In microarray-based expression profiling with RNA isolated from field isolates of drug-resistant and -sensitive L. donovani parasites, genes encoding histone 1 (H1), histone 2A (H2A), histone 4 (H4), mitogen-activated protein kinase 1 (MAPK1) and two hypothetical proteins showed significantly higher expression in antimony-resistant parasites, whilst genes encoding an amino acid transporter showed higher expression in sensitive parasites. The expression level of these genes was validated by semiquantitative polymerase chain reaction (PCR). Furthermore, the higher expression of H1, H2A and MAPK1 was confirmed at the protein level in resistant isolates. Overexpression of H2A in a drug-sensitive laboratory strain as well as a field isolate of L. donovani resulted in conversion of SAG-sensitive Leishmania parasites into a resistant phenotype. Moreover, H2A overexpression resulted in a significant decrease in susceptibility towards other antileishmanial drugs currently in use, i.e. amphotericin B and miltefosine, pointing to its role in drug resistance.


Colorectal cancer screening: a comparison of 35 initiatives in 17 countries.
Although in its infancy, organized screening for colorectal cancer (CRC) in the general population is increasing at regional and national levels. Documenting and describing these initiatives is critical to identifying, sharing and promoting best practice in the delivery of CRC screening. Subsequently, the International Colorectal Cancer Screening Network (ICRCSN) was established in 2003 to promote best practice in the delivery of organized screening programs. The initial aim was to identify and document organized screening initiatives that commenced before May 2004. Each identified initiative was sent 1 questionnaire per screening modality: fecal occult blood test, flexible sigmoidoscopy or total colonoscopy. Information was collected on screening methodology, testing details and initiative status. In total, 35 organized initiatives were identified in 17 countries, including 10 routine population-based screening programs, 9 pilots and 16 research projects. Fecal occult blood tests were the most frequently used screening modality, and total colonoscopy was seldom used as a primary screening test. The eligible age for screening ranged from 40 years old to no upper limit; most initiatives included participants aged 50 to 64. Recruitment was usually done by a mailed invitation or during a visit to a family physician. In conclusion, this is the first investigation describing the delivery of CRC screening protocols to various populations. The work of the ICRCSN is enabling valuable information to be shared and a common nomenclature to be established.


Chromosome hydroxymethylation patterns in human zygotes and cleavage-stage embryos.
We report the sequential changes in 5-hydroxymethylcytosine (5hmC) patterns in the genome of human preimplantation embryos during DNA methylation reprogramming. We have studied chromosome hydroxymethylation and methylation patterns in triploid zygotes and blastomeres of cleavage-stage embryos. Using indirect immunofluorescence, we have analyzed the localization of 5hmC and its co-distribution with 5-methylcytosine (5mC) on the QFH-banded metaphase chromosomes. In zygotes, 5hmC accumulates in both parental chromosome sets, but hydroxymethylation is more intensive in the poorly methylated paternal set. In the maternal set, chromosomes are highly methylated, but contain little 5hmC. Hydroxymethylation is highly region specific in both parental chromosome sets: hydroxymethylated loci correspond to R-bands, but not G-bands, and have well-defined borders, which coincide with the R/G-band boundaries. The centromeric regions and heterochromatin at 1q12, 9q12, 16q11.2, and Yq12 contain little 5mC and no 5hmC. We hypothesize that 5hmC may mark structural/functional genome 'units' corresponding to chromosome bands in the newly formed zygotic genome. In addition, we suggest that the hydroxymethylation of R-bands in zygotes can be treated as a new characteristic distinguishing them from G-bands. At cleavages, chromosomes with asymmetrical hydroxymethylation of sister chromatids appear. They decrease in number during cleavages, whereas totally non-hydroxymethylated chromosomes become numerous. Taken together, our findings suggest that, in the zygotic genome, 5hmC is distributed selectively and its pattern is determined by both parental origin of chromosomes and type of chromosome bands - R, G, or C. At cleavages, chromosome hydroxymethylation pattern is dynamically changed due to passive and non-selective overall loss of 5hmC, which coincides with that of 5mC.


The cacao Criollo genome v2.0: an improved version of the genome for genetic and functional genomic studies.
Theobroma cacao L., native to the Amazonian basin of South America, is an economically important fruit tree crop for tropical countries as a source of chocolate. The first draft genome of the species, from a Criollo cultivar, was published in 2011. Although a useful resource, some improvements are possible, including identifying misassemblies, reducing the number of scaffolds and gaps, and anchoring un-anchored sequences to the 10 chromosomes. We used a NGS-based approach to significantly improve the assembly of the Belizian Criollo B97-61/B2 genome. We combined four Illumina large insert size mate paired libraries with 52x of Pacific Biosciences long reads to correct misassembled regions and reduced the number of scaffolds. We then used genotyping by sequencing (GBS) methods to increase the proportion of the assembly anchored to chromosomes. The scaffold number decreased from 4,792 in assembly V1 to 554 in V2 while the scaffold N50 size has increased from 0.47 Mb in V1 to 6.5 Mb in V2. A total of 96.7% of the assembly was anchored to the 10 chromosomes compared to 66.8% in the previous version. Unknown sites (Ns) were reduced from 10.8% to 5.7%. In addition, we updated the functional annotations and performed a new RefSeq structural annotation based on RNAseq evidence. Theobroma cacao Criollo genome version 2 will be a valuable resource for the investigation of complex traits at the genomic level and for future comparative genomics and genetics studies in cacao tree. New functional tools and annotations are available on the Cocoa Genome Hub ( http://cocoa-genome-hub.southgreen.fr ).