Exploring Social Dominance in Wild Diademed Sifakas (Propithecus diadema): Females Are Dominant, but It Is Subtle and the Benefits Are Not Clear.
Rarely observed in mammals, female dominance is documented in several of Madagascar's lemurs. Although dominance affects many aspects of primates' lives, studies have largely focused on dyadic agonistic interactions to characterise relationships. We explored the power structure of three diademed sifaka groups (Propithecus diadema) at Tsinjoarivo during the lean season (July-August, 325 h) using social behaviours, group leadership, displacements and feeding outcomes. Two groups had a hierarchy dominated by the breeding female, while the highest rank was held by the breeding male in the third; in dyadic interactions, breeding females dominated males in all groups. Inconsistencies in hierarchies suggest that groups vary, with rank related to kinship ties of breeders. Aggression and grooming were rare; adult females received aggression at lower frequencies than males. Group movements were led more by females and followed more by males, and female feeding priority was evident in displacements during feeding. However, males and females did not differ in feeding outcomes, as expected (particularly in the lean season) if female dominance (and/or male deference) serves to ensure better access for females. This unexpected pattern (female dominance despite rare aggression, clear female leadership and displacement, yet no observable benefit in grooming or feeding outcomes) defies easy explanation, and reinforces the fact that studies examining female power in lemurs should take a multifaceted approach. Further study is needed to understand this pattern, the physiological and reproductive consequences of female dominance (e.g. detecting subtler variation in food quality or intake rates) and exactly how (and when) the benefits of female dominance are manifested.


Saccadic eye movements in the dark while performing an automatized sequential high-speed sensorimotor task.
Saccades during object-related everyday tasks select visual information to guide hand movements. Nevertheless, humans can perform such a task in the dark provided it was automatized beforehand. It is largely unknown whether and how saccades are executed in this case. Recently, a long-term memory (LTM)-based direct control mode of attention during the execution of well-learned sensorimotor tasks, which predicts task-relevant saccades in the dark, was proposed (R. M. Foerster, E. Carbone, H. Koesling, & W. X. Schneider, 2011). In the present study, participants performed an automatized speed-stacking task in the dark and in the light while their eye movements were recorded. Speed stacking is a sequential high-speed sensorimotor object manipulation task. Results demonstrated that participants indeed made systematic eye movements in the dark. Saccadic scan paths and the number of fixations were highly similar across illumination conditions, while fixation rates were lower and fixation durations were longer in the dark. Importantly, the eye reached a location ahead of the hands even in the dark. Finally, neither eye-hand dynamics nor saccade accuracy correlated with hand movement durations in the dark. Results support the hypothesis of an LTM-based mode of attention selection during the execution of automatized sequential high-speed sensorimotor tasks.


Interfaces detection after corneal refractive surgery by low coherence optical interferometry.
The detection of refractive corneal surgery by LASIK, during the storage of corneas in Eye Banks will become a challenge when the numerous operated patients will arrive at the age of cornea donation. The subtle changes of corneal structure and refraction are highly suspected to negatively influence clinical results in recipients of such corneas. In order to detect LASIK cornea interfaces we developed a low coherence interferometry technique using a broadband continuum source. Real time signal recording, without moving any optical elements and without need of a Fourier Transform operation, combined with good measurement resolution is the main asset of this interferometer. The associated numerical processing is based on a method initially used in astronomy and offers an optimal correlation signal without the necessity to image the whole cornea that is time consuming. The detection of corneal interfaces - both outer and inner surface and the buried interface corresponding to the surgical wound - is then achieved directly by the innovative combination of interferometry and this original numerical process.


Regression of electrocardiographic left ventricular hypertrophy is associated with less hospitalization for heart failure in hypertensive patients.
Reduction of electrocardiographic left ventricular hypertrophy (LVH) has been associated with decreased cardiovascular death, stroke, myocardial infarction, and atrial fibrillation. However, whether reduction of electrocardiographic LVH is associated with decreased heart failure is unclear. To examine the relation of reduction of electrocardiographic LVH to incident heart failure. Multicenter cohort study derived from a randomized, controlled trial. Losartan Intervention For Endpoint reduction in hypertension study. 8479 hypertensive patients without history of heart failure who were randomly assigned to losartan or atenolol treatment. Change in Cornell product electrocardiographic LVH between baseline and in-study electrocardiograms, examined as both a continuous variable and a dichotomous variable (above or below the median decrease of 236 mm x msec) to predict heart failure hospitalization occurring after the 6-month follow-up visit. During mean follow-up of 4.7 years (SD, 1.1 years), 214 patients were hospitalized for heart failure (2.5%): 77 patients with an in-treatment decrease of 236 mm x msec or more (4.4 per 1000 patient-years) and 137 patients with a reduction less than 236 mm x msec during treatment (6.8 per 1000 patient-years). In a univariate Cox analysis in which change in Cornell product was treated as a time-varying continuous variable, decrease in Cornell product during treatment was associated with a decreased risk for new-onset heart failure, with a 24% lower risk for heart failure for every 817-mm x msec (1 SD of the mean) lower Cornell product (hazard ratio, 0.76 [95% CI, 0.72 to 0.80]). In a parallel analysis in which change in Cornell product was entered as a time-varying dichotomous variable, a greater-than-median in-treatment decrease in Cornell product (236 mm x msec) was associated with a 43% lower risk for heart failure (hazard ratio, 0.57 [CI, 0.44 to 0.76]). After adjustment for treatment, baseline risk factors for heart failure, baseline and in-treatment blood pressure, and baseline severity of electrocardiographic LVH, in-treatment decrease of Cornell product LVH in time-varying multivariate Cox models remained strongly associated with new heart failure hospitalization, with a 19% lower risk for every 817-mm . msec lower Cornell product treated as a continuous variable (hazard ratio, 0.81 [CI, 0.77 to 0.85]) or a 36% decreased rate of new heart failure in patients with an in-treatment reduction in Cornell product of 236 mm x msec or more (hazard ratio, 0.64 [CI, 0.47 to 0.89]; P < 0.001 for all comparisons). Use of electrocardiographic LVH to select patients may have increased risk compared with unselected hypertensive patients, and use of hospitalization for heart failure as the end point will underestimate the incidence of new heart failure. Reduction in Cornell product electrocardiographic LVH during antihypertensive therapy is associated with fewer hospitalizations for heart failure, independent of blood pressure lowering, treatment method, and other risk factors for heart failure. ClinicalTrials.gov registration number: NCT00338260.


Therapeutic equivalence of single oral doses of dolasetron mesilate and multiple doses of ondansetron for the prevention of emesis after moderately emetogenic chemotherapy. European Dolasetron Comparative Study Group.
This multicentre, randomised, double-blind study was designed to compare the anti-emetic efficacy and safety of single oral doses of dolasetron mesilate with that of the approved oral, multiple-dose regimen of ondansetron in 399 cancer patients receiving moderately emetogenic chemotherapy. Single oral doses of 25, 50, 100 or 200 mg of dolasetron mesilate were administered 1 h prior to the initiation of moderately emetogenic chemotherapy. Multiple doses of ondansetron (8 mg x 3 or 8 mg x 4) capsules, or matching placebo for patients randomised to dolasetron, were given 1.5 h before and 6.5, 14.5 and 22.5 h after the start of chemotherapy (total dose = 32 mg). Efficacy was evaluated for 24 h after the initiation of chemotherapy. The most frequently used moderately emetogenic chemotherapeutic agents included cyclophosphamide, doxorubicin and carboplatin (28.4, 23.1 and 20.6% of patients, respectively). A statistically significant (P < 0.001) linear dose-response relationship was observed over the entire dolasetron dosage range for all efficacy parameters. Complete response rates were 45.0, 49.4, 60.5 and 76.3% for 25, 50, 100 and 200 mg dolasetron mesilate, respectively, and 72.3% of ondansetron patients. A single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to ondansetron for all efficacy parameters and patient satisfaction was high. Overall, there were no significant differences in the incidence of adverse events between any of the dolasetron mesilate doses, or between dolasetron and ondansetron. Headache was most frequently reported (approximately 15% for each drug). No clinically important changes in vital signs or clinical laboratory parameters were observed with either drug. In conclusion, a single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to multiple-dose ondansetron in the prevention of emesis and nausea following moderately emetogenic chemotherapy.


Protective effects of Atractylodes macrocephala polysaccharide on liver ischemia-reperfusion injury and its possible mechanism in rats.
Atractylodes macrocephala polysaccharide (AMP), a traditional Chinese medicine, is thought to have protective effects against liver injury. Therefore, this study was designed to explore the effects of AMP on hepatic ischemia-reperfusion injury (IRI) and elucidate the possible mechanisms. Ninety-six Sprague-Dawley rats were randomly divided into four groups with 24 rats per group: a normal control group, an IRI group, an AMP-treated group (0.4 g/kg/d) and a bifendate-treated group (100 mg/kg). Rats were treated with AMP or bifendate once daily for seven days by gastric gavage. The normal control group and the IRI model group received an equivalent volume of physiological saline. At 1, 6 and 24 h after surgery, the rats were killed and liver tissue samples were obtained to determine interleukin-1 (IL-1) expression by Western blotting and nuclear factor-κB (NF-κB) expression by immunohistochemistry. Liver morphology was assessed by microscopy and transmission electron microscopy. Blood samples were obtained to measure liver function (alanine aminotransferase, aspartate aminotransferase, total bilirubin and direct bilirubin). AMP significantly reduced the elevated expression of markers of liver dysfunction and the hepatic morphologic changes induced by hepatic IRI in rats. AMP also markedly inhibited IRI-induced lipid peroxidation and altered the activities of the antioxidant enzyme superoxide dismutase and malondialdehyde levels. Moreover, pretreatment with AMP suppressed the expression of interleukin-1β and NF-kB in IRI-treated rats. These results suggest that AMP exerts protective and therapeutic effects against hepatic IRI in rats, which might be associated with its antioxidant properties and inhibition of NF-κB activation. More studies are needed to better understand the mechanisms underlying the protective effects of AMP on hepatic IRI.


Sequential super-stereotypy of an instinctive fixed action pattern in hyper-dopaminergic mutant mice: a model of obsessive compulsive disorder and Tourette's.
Excessive sequential stereotypy of behavioral patterns (sequential super-stereotypy) in Tourette's syndrome and obsessive compulsive disorder (OCD) is thought to involve dysfunction in nigrostriatal dopamine systems. In sequential super-stereotypy, patients become trapped in overly rigid sequential patterns of action, language, or thought. Some instinctive behavioral patterns of animals, such as the syntactic grooming chain pattern of rodents, have sufficiently complex and stereotyped serial structure to detect potential production of overly-rigid sequential patterns. A syntactic grooming chain is a fixed action pattern that serially links up to 25 grooming movements into 4 predictable phases that follow 1 syntactic rule. New mutant mouse models allow gene-based manipulation of brain function relevant to sequential patterns, but no current animal model of spontaneous OCD-like behaviors has so far been reported to exhibit sequential super-stereotypy in the sense of a whole complex serial pattern that becomes stronger and excessively rigid. Here we used a hyper-dopaminergic mutant mouse to examine whether an OCD-like behavioral sequence in animals shows sequential super-stereotypy. Knockdown mutation of the dopamine transporter gene (DAT) causes extracellular dopamine levels in the neostriatum of these adult mutant mice to rise to 170% of wild-type control levels. We found that the serial pattern of this instinctive behavioral sequence becomes strengthened as an entire entity in hyper-dopaminergic mutants, and more resistant to interruption. Hyper-dopaminergic mutant mice have stronger and more rigid syntactic grooming chain patterns than wild-type control mice. Mutants showed sequential super-stereotypy in the sense of having more stereotyped and predictable syntactic grooming sequences, and were also more likely to resist disruption of the pattern en route, by returning after a disruption to complete the pattern from the appropriate point in the sequence. By contrast, wild-type mice exhibited weaker forms of the fixed action pattern, and often failed to complete the full sequence. Sequential super-stereotypy occurs in the complex fixed action patterns of hyper-dopaminergic mutant mice. Elucidation of the basis for sequential super-stereotypy of instinctive behavior in DAT knockdown mutant mice may offer insights into neural mechanisms of overly-rigid sequences of action or thought in human patients with disorders such as Tourette's or OCD.


Management of Respiratory Syncytial Virus Bronchiolitis: 2015 Survey of Members of the European Society for Paediatric Infectious Diseases.
In 1995, the European Society for Paediatric Infectious Diseases (ESPID) carried out a survey of its members to assess the variation in management of respiratory syncytial virus (RSV) bronchiolitis. The aim of the current study was to carry out a similar survey 20 years later to assess how the management had changed. An electronic, structured, English language survey, based on the United Kingdom National Institute for Health and Care Excellence (NICE) bronchiolitis draft guideline, was sent to ESPID members in March 2015. Questions asked included information on treatment practices of infants with bronchiolitis and doctor demographics. We received responses from 135 doctors (14% of the ESPID members) who worked in 115 hospitals. 56% of the doctors used a written guideline to manage bronchiolitic infants. All doctors stated that they isolated individually or in cohorts all hospitalised bronchiolitis infants. The level of oxygen saturation suggested as an indication to administer supplemental oxygen varied between <89% and <95%. We found significant reductions in the use of ribavirin, bronchodilators, and corticosteroids from 1995 to 2015 (ribavirin 57% to 13%, P < 0.0001; bronchodilators 95% to 82%, P = 0.0024; corticosteroids 81% to 45%, P < 0.0001). Although variability in management remains high, encouragingly significantly fewer doctors are prescribing ribavirin, bronchodilators, and corticosteroids compared to 20 years ago.


Muscle length changes during swimming in scup: sonomicrometry verifies the anatomical high-speed cine technique.
Recent attempts to determine how fish muscles are used to power swimming have employed the work loop technique (driving isolated muscles using their in vivo strain and stimulation pattern). These muscle strains have in turn been determined from the anatomical high-speed cine technique. In this study, we used an independent technique, sonomicrometry, to attempt to verify these strain measurements and the conclusions based on them. We found that the strain records measured from sonomicrometry and the anatomical-cine techniques were very similar. The ratio of the strain measured from sonomicrometry to that from the anatomical-cine technique was remarkably close to unity (1.046 +/- 0.013, mean +/- S.E.M., N = 15, for transducers placed on the muscle surface and corrected for muscle depth, and 0.921 +/- 0.028, N = 8, in cases where the transducers were inserted to the average depth of the red muscle). These measurements also showed that red muscle shortening occurs simultaneously with local backbone curvature, unlike previous results which suggested that white muscle shortening during the escape response occurs prior to the change in local backbone curvature.


Reciprocal regulation of carbon monoxide metabolism and the circadian clock.
Circadian clocks are cell-autonomous oscillators regulating daily rhythms in a wide range of physiological, metabolic and behavioral processes. Feedback of metabolic signals, such as redox state, NAD+/NADH and AMP/ADP ratios, or heme, modulate circadian rhythms and thereby optimize energy utilization across the 24-h cycle. We show that rhythmic heme degradation, which generates the signaling molecule carbon monoxide (CO), is required for normal circadian rhythms as well as circadian metabolic outputs. CO suppresses circadian transcription by attenuating CLOCK-BMAL1 binding to target promoters. Pharmacological inhibition or genetic depletion of CO-producing heme oxygenases abrogates normal daily cycles in mammalian cells and Drosophila. In mouse hepatocytes, suppression of CO production leads to a global upregulation of CLOCK-BMAL1-dependent circadian gene expression and dysregulated glucose metabolism. Together, our findings show that CO metabolism is an important link between the basic circadian-clock machinery, metabolism and behavior.


Isolating Populations to Control Pandemic Spread in an Austere Military Environment.
The COVID-19 pandemic has been a struggle for medical systems throughout the world. In austere locations in which testing, resupply, and evacuation have been limited or impossible, unique challenges exist. This case series demonstrates the importance of population isolation in preventing disease from overwhelming medical assets. This is a case series describing the outbreak of COVID-19 in an isolated population in Africa. The population consists of a main population with a Role 2 capability, with several supported satellite populations with a Role 1 capability. Outbreaks in five satellite population centers occurred over the course of the COVID-19 pandemic from its start on approximately 1 March 2020 until 28 April 2020, when a more robust medical asset became available at the central evacuation hub within the main population. Population movement controls and the use of telehealth prevented the spread within the main population at risk and enabled the setup of medical assets to prepare for anticipated widespread disease. Isolation of disease in the satellite populations and treating in place, rather than immediately moving to the larger population center's medical facilities, prevented widespread exposure. Isolation also protected critical patient transport capabilities for use for high-risk patients. In addition, this strategy provided time and resources to develop infrastructure to handle anticipated larger outbreaks.


"I'm a storyteller!": Exploring the benefits of TimeSlips creative expression program at a nursing home.
TimeSlips creative storytelling program is beneficial for persons with dementia and caregivers, but no studies have qualitatively explored participant experience. Ten residents in a skilled nursing care unit participated in 2-hour-long TimeSlips sessions per week, for 6 weeks. Semistructured interviews of participants and staff members were conducted to elicit perceptions of TimeSlips. Thematic analysis was used to evaluate qualitative data. There were specific benefits for residents (increased creativity, improved quality of life, positively altered behavior, and involvement in meaningful activity), staff members (learning new practices, developing a deeper understanding of residents, involvement in meaningful activity, and thinking creatively around programmatic challenges), and the nursing home community (nurturing relationships and improved atmosphere). Involvement in TimeSlips can engender benefits for residents, staff, and nursing home communities. Future research is needed to quantitatively assess whether the benefits noted in this study can longitudinally improve quality and lower cost of long-term care.


Comparing visual representations across human fMRI and computational vision.
Feedforward visual object perception recruits a cortical network that is assumed to be hierarchical, progressing from basic visual features to complete object representations. However, the nature of the intermediate features related to this transformation remains poorly understood. Here, we explore how well different computer vision recognition models account for neural object encoding across the human cortical visual pathway as measured using fMRI. These neural data, collected during the viewing of 60 images of real-world objects, were analyzed with a searchlight procedure as in Kriegeskorte, Goebel, and Bandettini (2006): Within each searchlight sphere, the obtained patterns of neural activity for all 60 objects were compared to model responses for each computer recognition algorithm using representational dissimilarity analysis (Kriegeskorte et al., 2008). Although each of the computer vision methods significantly accounted for some of the neural data, among the different models, the scale invariant feature transform (Lowe, 2004), encoding local visual properties gathered from "interest points," was best able to accurately and consistently account for stimulus representations within the ventral pathway. More generally, when present, significance was observed in regions of the ventral-temporal cortex associated with intermediate-level object perception. Differences in model effectiveness and the neural location of significant matches may be attributable to the fact that each model implements a different featural basis for representing objects (e.g., more holistic or more parts-based). Overall, we conclude that well-known computer vision recognition systems may serve as viable proxies for theories of intermediate visual object representation.


Hong Kong Hospital Authority resource efficiency evaluation: Via a novel DEA-Malmquist model and Tobit regression model.
The Hospital Authority (HA) is a statutory body managing all the public hospitals and institutes in Hong Kong (HK). In recent decades, Hong Kong Hospital Authority (HKHA) has been making efforts to improve the healthcare services, but there still exist some problems like unfair resource allocation and poor management, as reported by the Hong Kong medical legislative committee. One critical consequence of these problems is low healthcare efficiency of hospitals, leading to low satisfaction among patients. Moreover, HKHA also suffers from the conflict between limited resource and growing demand. An effective evaluation of HA is important for resource planning and healthcare decision making. In this paper, we propose a two-phase method to evaluate HA efficiency for reducing healthcare expenditure and improving healthcare service. Specifically, in Phase I, we measure the HKHA efficiency changes from 2000 to 2013 by applying a novel DEA-Malmquist index with undesirable factors. In Phase II, we further explore the impact of some exogenous factors (e.g., population density) on HKHA efficiency by Tobit regression model. Empirical results show that there are significant differences between the efficiencies of different hospitals and clusters. In particular, it is found that the public hospital serving in a richer district has a relatively lower efficiency. To a certain extent, this reflects the socioeconomic reality in HK that people with better economic condition prefers receiving higher quality service from the private hospitals.


Antagonism of the neuropeptide S receptor with RTI-118 decreases cocaine self-administration and cocaine-seeking behavior in rats.
Neuropeptide S (NPS) is a neuromodulatory peptide, acting via a G-protein-coupled receptor to regulate sleep, anxiety and behavioral arousal. Recent research has found that intracerebroventricular NPS can increase cocaine and alcohol self-administration in rodents, suggesting a key role in reward-related neurocircuitry. It is hypothesized that antagonism of the NPS system might represent a novel strategy for the pharmacological treatment of cocaine abuse. To this end, a small-molecule NPSR antagonist (RTI-118) was developed and tested in animal models of cocaine seeking and cocaine taking. Male Wistar rats (n=54) trained to self-administer cocaine and food under a concurrent alternating FR4 schedule exhibited specific dose-dependent decreases in cocaine intake when administered RTI-118. RTI-118 also decreased the reinstatement of extinguished cocaine-seeking behavior induced by conditioned cues, yohimbine and a priming dose of cocaine. These data support the hypothesis that antagonism of the neuropeptide S receptor may ultimately show efficacy in reducing cocaine use and relapse.


Effects of nitric oxide synthase inhibitors on timing and short-term memory in rats.
Nitric oxide synthase (NOS) inhibitors have been shown to affect the development of long-term potentiation and the acquisition of new learning. In the present study, we investigated the effects of NOS inhibitors in two animal models in which aspects of cognition are measured in well-learned operant tasks - a delayed non-match-to-position (DNMTP) task and a multiple signalled-unsignalled differential reinforcement of low rates (DRL) 15 s schedule - models of short-term memory and behavioral inhibition/timing, respectively. Since an overlap in the behavioral effects of NOS inhibitors and phencyclidine (PCP)-like N-methyl-D-aspartate (NMDA) antagonists has been observed previously, we compared our results with NOS inhibitors to those obtained with PCP. Whereas PCP produced a delay-independent decrease in the DNMTP task and increased burst responding (consecutive responses with inter-response intervals of < 3 s) in both the signalled and unsignalled components of the DRL procedure, 7-nitroindazole did not affect accuracy in the DNMTP task nor did it alter the pattern of responding in either component of the DRL schedule. Similarly, NG-nitro-L-arginine (L-NOARG) and NG-nitro-L-arginine-methyl-ester (L-NAME) did not affect accuracy in the DNMTP task. These results suggest that NOS inhibitors do not produce PCP-like disruption of behavioral inhibition or timing, nor do they decrease accuracy in a conditional discrimination task, as has been observed with PCP. The present results lend further support to the hypothesis that nitric oxide modulation does not affect retention of well-learned tasks, although it may affect acquisition of novel behavior.


Chlamydial infection of the urethra in men.
Chlamydia trachomatis was isolated from the uretha of 125 (52%) of 238 men with non-gonococcal urethritis (NGU). Repeat isolation attempts in 155 of these patients were successful in eight men in whom results had been negative on the initial visit, but they were unsuccessful in eight men who initially had had positive cultures. We must assume that with our present isolation techniques we are missing, at any single visit, at least 9% of chlamydial infections. C. trachomatis was also found in 32 (23%) of 139 men with gonorrhoea. Positive cultures were obtained from 15 (79%) of 19 men, who later developed post-gonococcal urethritis (PGU). Thiamphenicol, used for the treatment of gonorrhoea, was shown to have very little effect on C. trachomatis, which could still be recovered after treatment in 76% of the patients who initially had had a combined infection. The typing of 35 genital isolates by micro-immunofluorescence confirms the previously reported distribution of chlamydial serotypes. In this study a social profile is given of our patients with urethritis and a comparison is made of the duration of symptoms and the nature of discharge in men with gonococcal, chlamydial, and non-specific urethritis. We were able to show a clear difference in clinical symptoms in men with gonorrhoea and NGU, taken as a whole, but found only a slight difference between men with chlamydial and non-specific urethritis.


Hepatic microsomal metabolism of sulfamethoxazole to the hydroxylamine.
Sulfonamides are oxidized to protein reactive cytotoxic metabolites by murine hepatic microsomes. Mononuclear leukocytes from patients with idiosyncratic reactions to sulfonamides were more susceptible to toxicity from these metabolites than were leukocytes from a control population, suggesting that these metabolites play a role in the pathogenesis of such reactions. Here we have shown that murine hepatic microsomes oxidize sulfamethoxazole at the N4-position to form the hydroxylamine. Formation of the hydroxylamine was dependent on the presence of microsomes, NADPH, and oxygen. The addition of SKF 525-A, cimetidine, or gassing with carbon monoxide inhibited formation. The enzymic activity was stable at 37 degrees C in the absence of NADPH. Ascorbic acid, N-acetylcysteine, and reduced glutathione significantly increased the yield of hydroxylamine, presumably by decreasing further oxidation and covalent binding. Microsomes prepared from mice treated with phenobarbital or beta-naphthoflavone catalyzed the formation of the hydroxylamine more readily than did microsomes from untreated mice. These results demonstrate that cytochrome P-450-mediated oxidation of sulfamethoxazole results in the formation of hydroxylamines, which can be further oxidized to more reactive intermediates. These metabolites are likely involved in the pathogenesis of idiosyncratic reactions.


'Not Always a Baker's Cyst' - An Unusual Presentation of a Central Voluminous Postero-Medial Meniscal Cyst.
Meniscal cysts are rare and often are a result of extrusion of synovial fluid through a tear of the meniscus, resulting in a one-way valve effect of the tear. Arthroscopic partial meniscectomy of the meniscus with intra-articular cyst drainage has become the standard of care. We report a case of an unusually large symptomatic medial meniscal cyst, situated postero-medially and pressing on the posterior cruciate ligament, which was initially clinically misdiagnosed as a Baker's cyst. The patient had difficulty and pain on squatting. He was successfully treated with arthroscopic debridement and needle decompression; a rarity in literature for such a voluminous perilabral cyst tenting the posterior cruciate ligament. This procedure has the advantage of being able to obtain the cystic fluid for histological and cytological analysis before debridement. This case also highlights the importance of the use of Magnetic Resonance Imaging (MRI) to accurately diagnose a central, posterior knee swelling.


The distribution of mycotoxins in a heterogeneous wheat field in relation to microclimate, fungal and bacterial abundance.
To observe the variation in accumulation of Fusarium and Alternaria mycotoxins across a topographically heterogeneous field and tested biotic (fungal and bacterial abundance) and abiotic (microclimate) parameters as explanatory variables. We selected a wheat field characterized by a diversified topography, to be responsible for variations in productivity and in canopy-driven microclimate. Fusarium and Alternaria mycotoxins where quantified in wheat ears at three sampling dates between flowering and harvest at 40 points. Tenuazonic acid (TeA), alternariol (AOH), alternariol monomethyl ether (AME), tentoxin (TEN), deoxynivalenol (DON), zearalenone (ZEN) and deoxynivalenol-3-Glucoside (DON.3G) were quantified. In canopy temperature, air and soil humidity were recorded for each point with data-loggers. Fusarium spp. as trichothecene producers, Alternaria spp. and fungal abundances were assessed using qPCR. Pseudomonas fluorescens bacteria were quantified with a culture based method. We only found DON, DON.3G, TeA and TEN to be ubiquitous across the whole field, while AME, AOH and ZEN were only occasionally detected. Fusarium was more abundant in spots with high soil humidity, while Alternaria in warmer and drier spots. Mycotoxins correlated differently to the observed explanatory variables: positive correlations between DON accumulation, tri 5 gene and Fusarium abundance were clearly detected. The correlations among the others observed variables, such as microclimatic conditions, varied among the sampling dates. The results of statistical model identification do not exclude that species coexistence could influence mycotoxin production. Fusarium and Alternaria mycotoxins accumulation varies heavily across the field and the sampling dates, providing the realism of landscape-scale studies. Mycotoxin concentrations appear to be partially explained by biotic and abiotic variables. We provide a useful experimental design and useful data for understanding the dynamics of mycotoxin biosynthesis in wheat.


Rectal application of a highly osmolar personal lubricant in a macaque model induces acute cytotoxicity but does not increase risk of SHIV infection.
Personal lubricant use is common during anal intercourse. Some water-based products with high osmolality and low pH can damage genital and rectal tissues, and the polymer polyquaternium 15 (PQ15) can enhance HIV replication in vitro. This has raised concerns that lubricants with such properties may increase STD/HIV infection risk, although in vivo evidence is scarce. We use a macaque model to evaluate rectal cytotoxicity and SHIV infection risk after use of a highly osmolar (>8,000 mOsm/kg) water-based lubricant with pH of 4.4, and containing PQ15. Cytotoxicity was documented by measuring inflammatory cytokines and epithelial tissue sloughing during six weeks of repeated, non-traumatic lubricant or control buffer applications to rectum and anus. We measured susceptibility to SHIVSF162P3 infection by comparing virus doses needed for rectal infection in twenty-one macaques treated with lubricant or control buffer 30 minutes prior to virus exposure. Lubricant increased pro-inflammatory cytokines and tissue sloughing while control buffer (phosphate buffered saline; PBS) did not. However, the estimated AID50 (50% animal infectious dose) was not different in lubricant- and control buffer-treated macaques (p = 0.4467; logistic regression models). Although the test lubricant caused acute cytotoxicity in rectal tissues, it did not increase susceptibility to infection in this macaque model. Thus neither the lubricant-induced type/extent of inflammation nor the presence of PQ15 affected infection risk. This study constitutes a first step in the in vivo evaluation of lubricants with regards to HIV transmission.


Identifying Basal Ganglia divisions in individuals using resting-state functional connectivity MRI.
Studies in non-human primates and humans reveal that discrete regions (henceforth, "divisions") in the basal ganglia are intricately interconnected with regions in the cerebral cortex. However, divisions within basal ganglia nuclei (e.g., within the caudate) are difficult to identify using structural MRI. Resting-state functional connectivity MRI (rs-fcMRI) can be used to identify putative cerebral cortical functional areas in humans (Cohen et al., 2008). Here, we determine whether rs-fcMRI can be used to identify divisions in individual human adult basal ganglia. Putative basal ganglia divisions were generated by assigning basal ganglia voxels to groups based on the similarity of whole-brain functional connectivity correlation maps using modularity optimization, a network analysis tool. We assessed the validity of this approach by examining the spatial contiguity and location of putative divisions and whether divisions' correlation maps were consistent with previously reported patterns of anatomical and functional connectivity. Spatially constrained divisions consistent with the dorsal caudate, ventral striatum, and dorsal caudal putamen could be identified in each subject. Further, correlation maps associated with putative divisions were consistent with their presumed connectivity. These findings suggest that, as in the cerebral cortex, subcortical divisions can be identified in individuals using rs-fcMRI. Developing and validating these methods should improve the study of brain structure and function, both typical and atypical, by allowing for more precise comparison across individuals.


Prevalence of degenerative changes and overlap with spondyloarthritis-associated lesions in the spine of patients from the DESIR cohort.
To describe the prevalence of degenerative changes on MRI and conventional radiographs of the spine in a young population with suspicion of axial spondyloarthritis (axSpA) and assess whether it is possible to discriminate between degenerative changes and lesions associated with axSpA. Whole spine MRI and cervical and lumbar radiographs of patients ≥18 years with chronic back pain (≥3 months, ≤3 years, onset <50 years) were assessed for degeneration by two readers, and for SpA lesions by two other readers, all blinded for clinical information and results of the other readers. Degenerative scores were adjudicated in case of disagreement (by a third reader). Patients fulfilling and not fulfilling the Assessment of SpondyloArthritis international Society axSpA criteria were compared for prevalence of degenerative lesions. Scores for degenerative and SpA lesions were compared, and overlap was defined as the presence of both types of lesions in a single vertebral unit (VU). In 456/648 (70.4%) patients (46.8% men, mean age 33.6), degenerative lesions were found with similar percentages in patients with no axSpA and with axSpA (72.4% and 69.2%, p=0.45). Modic changes were found more often in patients with no axSpA (29/239, 12.1%) versus patients with axSpA (19/409, 4.6%, p=0.01). Other lesions were evenly distributed. Overlap was minimal in 19 patients (3.0%) and 32/14 674 (0.2%) VUs for SpA reader 1 and in 23 patients (3.6%) and 34/14 674 VUs (0.2%) for SpA reader 2. The prevalence of degeneration is high in an early inflammatory back pain cohort. Discrimination between degeneration and axSpA lesions is very well possible with little overlap between degenerative and axSpA readings.


Benefits of recording and reviewing neonatal resuscitation: the providers' perspective.
To assess benefits of recording and reviewing neonatal resuscitation as experienced by neonatal care providers. A qualitative study using semistructured interviews questioning neonatal care providers about their experiences with recording and reviewing neonatal resuscitation. Data were analysed using the qualitative data analysis software Atlas.ti V.7.0. Neonatal care providers working at neonatal intensive care units (NICUs) of the Leiden University Medical Center, the Netherlands, and the University of Pennsylvania School of Medicine, USA, participated in this study. In total, 48 NICU staff members were interviewed. Reported experiences and attitudes are broadly similar for both NICUs. All interviewed providers reported positive experiences and benefits, with special emphasis on educational benefits. Recording and reviewing neonatal resuscitation is used for various learning activities, such as plenary review meetings and as tool for objective feedback. Providers reported to learn from reviewing their own performance during resuscitation, as well as from reviewing performances of others. Improved time perception, reflection on guideline compliance and acting less invasively during resuscitations were often mentioned as learning outcomes. All providers would recommend other NICUs to implement recording and reviewing neonatal resuscitation, as it is a powerful tool for learning and improving. However, they emphasised preconditions for successful implementation, such as providing information, not being punitive and focusing on the benefits for learning and improving. Recording and reviewing neonatal resuscitation is considered highly beneficial for learning and improving resuscitation skills and is recommended by providers participating in it.


Karyotypic changes through dysploidy persist longer over evolutionary time than polyploid changes.
Chromosome evolution has been demonstrated to have profound effects on diversification rates and speciation in angiosperms. While polyploidy has predated some major radiations in plants, it has also been related to decreased diversification rates. There has been comparatively little attention to the evolutionary role of gains and losses of single chromosomes, which may or not entail changes in the DNA content (then called aneuploidy or dysploidy, respectively). In this study we investigate the role of chromosome number transitions and of possible associated genome size changes in angiosperm evolution. We model the tempo and mode of chromosome number evolution and its possible correlation with patterns of cladogenesis in 15 angiosperm clades. Inferred polyploid transitions are distributed more frequently towards recent times than single chromosome gains and losses. This is likely because the latter events do not entail changes in DNA content and are probably due to fission or fusion events (dysploidy), as revealed by an analysis of the relationship between genome size and chromosome number. Our results support the general pattern that recently originated polyploids fail to persist, and suggest that dysploidy may have comparatively longer-term persistence than polyploidy. Changes in chromosome number associated with dysploidy were typically observed across the phylogenies based on a chi-square analysis, consistent with these changes being neutral with respect to diversification.


Tissue mineralization is increased following 1-year treatment with high doses of bisphosphonates in dogs.
Suppression of bone turnover using anti-resorptive agents such as bisphosphonates prevents bone loss but also may increase tissue mineralization. This may make the bone more prone to initiate microcracks. The objective of this study was to determine whether suppression of remodeling caused by treatment of dogs for 1 year with five times the clinical dose of either alendronate or risedronate is associated with increased tissue mineralization and whether it changes the nature of the mineral crystal. Thirty-five dogs were divided into three weight-matched groups and treated daily for 1 year with a subcutaneous injection of saline (CON, n = 12), oral risedronate (RIS, 0.5 mg/kg/day, n = 11), or oral alendronate (ALN, 1.0 mg/kg/day, n = 12). Density fractionation, peripheral quantitative computerized tomography (pQCT), and quantitative backscattered electron microscopy (qBSE) were used to evaluate changes in mineral content of bone tissue from the vertebrae or ribs. Infrared microspectroscopy (IR) and X-ray diffraction were used to assess the quality of the mineral and some aspects of collagen structure in the thoracic vertebrae and iliac crest. Following 12 months of treatment, there was a significant shift toward higher density bone in both ALN (P = 0.04) and RIS (P = 0.002) by density fractionation methods. IR, pQCT, and qBSE did not detect any significant differences in mineralization, probably because of their lower sensitivity and/or because of the smaller region of interest they sample. No significant differences were found in the maturity of the mineral crystals or in their length or size. We conclude that treatment for 1 year with high doses of bisphosphonates which suppress bone remodeling up to 90% increases tissue mineralization, but does not change the nature of the mineral crystal.


Felbamate inhibits [3H]t-butylbicycloorthobenzoate (TBOB) binding and enhances Cl- current at the gamma-aminobutyric AcidA (GABAA) receptor.
We investigated the interaction of felbamate (FBM) with gamma-aminobutyric acid type A receptors using receptor autoradiography with [3H]t-butylbicycloorthobenzoate (TBOB) and whole-cell patch-clamp recordings of cultured mouse cortical neurons. FBM produced dose-dependent inhibition of [3H]T-BOB binding with IC50 values of approximately 250 microM. Saturation analysis in the presence of FBM revealed increased Kd and decreased Bmax. Dissociation initiated by picrotoxin (PTX) was accelerated by FBM. The regional pattern of [3H]TBOB binding inhibition by FBM was different from the regional modulation of [3H]TBOB binding produced by gamma-aminobutyric acid (GABA) agonists, bicuculline, zinc or neurosteroids. With electrophysiological recordings, FBM enhanced GABA-elicited Cl- currents at GABA concentrations of 10 microM but not 3 microM or 100 microM. FBM enhancement was not blocked by the benzodiazepine antagonist flumazenil, and FBM did not affect pentobarbital potentiation of GABA-elicited currents. FBM also had no effect on PTX inhibition of GABA-elicited Cl- currents. These results suggest that FBM potentiates gamma-aminobutyric acid type A receptor function, at least in part, by acting at a site that interacts with the PTX site but is distinct from the PTX, barbiturate, GABA, benzodiazepine, zinc and neurosteroid sites.


The Human Medial Temporal Lobe Is Necessary for Remembering Durations within a Sequence of Events but Not Durations of Individual Events.
Recent interest in the role of the hippocampus in temporal aspects of cognition has been fueled, in part, by the observation of "time" cells in the rodent hippocampus-that is, cells that have differential firing patterns depending on how long ago an event occurred. Such cells are thought to provide an internal representation of elapsed time. Yet, the hippocampus is not needed for processing temporal duration information per se, at least on the order of seconds, as evidenced by intact duration judgments in rodents and humans with hippocampal damage. Rather, it has been proposed that the hippocampus may be essential for coding higher order aspects of temporal mnemonic processing, such as those needed to temporally organize a sequence of events that form an episode. To examine whether (1) the hippocampus uses duration information in the service of establishing temporal relations among events and (2) its role in memory for duration is unique to sequences, we tested amnesic patients with medial-temporal lobe damage (including the hippocampus). We hypothesized that medial-temporal lobe damage should impair the ability to remember sequential duration information but leave intact judgments about duration devoid of a sequential demand. We found that amnesics were impaired in making judgments about durations within a sequence but not in judging single durations. This impairment was not due to higher cognitive load associated with duration judgments about sequences. In convergence with rodent and human fMRI work, these findings shed light on how time coding in the hippocampus may contribute to temporal cognition.


The effect of orientation of the acetabular component on outcome following total hip arthroplasty with small diameter hard-on-soft bearings.
We assessed the orientation of the acetabular component in 1070 primary total hip arthroplasties with hard-on-soft, small diameter bearings, aiming to determine the size and site of the target zone that optimises outcome. Outcome measures included complications, dislocations, revisions and ΔOHS (the difference between the Oxford Hip Scores pre-operatively and five years post-operatively). A wide scatter of orientation was observed (2sd 15°). Placing the component within Lewinnek's zone was not associated withimproved outcome. Of the different zone sizes tested (± 5°, ± 10° and ± 15°), only ± 15° was associated with a decreased rate of dislocation. The dislocation rate with acetabular components inside an inclination/anteversion zone of 40°/15° ± 15° was four times lower than those outside. The only zone size associated with statistically significant and clinically important improvement in OHS was ± 5°. The best outcomes (ΔOHS > 26) were achieved with a 45°/25° ± 5° zone. This study demonstrated that with traditional technology surgeons can only reliably achieve a target zone of ±15°. As the optimal zone to diminish the risk of dislocation is also ±15°, surgeons should be able to achieve this. This is the first study to demonstrate that optimal orientation of the acetabular component improves the functional outcome. However, the target zone is small (± 5°) and cannot, with current technology, be consistently achieved.


Neotropical Monogenoidea. 58. Three new species of Gyrodactylus (Gyrodactylidae) from Scleromystax spp. (Callichthyidae) and the proposal of COII gene as an additional fragment for barcoding gyrodactylids.
Based on molecular markers (COII and ITS1-ITS2) and morphological data, we describe three new Neotropical species of Gyrodactylus von Nordmann, 1832 from Scleromystax barbatus (Quoy et Gaimard) and Scleromystax macropterus (Regan) from southern Brazil. The three new species can be distinguished from each other by sequences of both molecular markers and morphology of hooks and anchors. Gyrodactylus bueni sp. n. is characterised by having hook with shaft curved, heel straight, shelf straight, toe pointed, anchor with superficial root slender, elongate and male copulatory organ armed with two rows of spinelets. Gyrodactylus major sp. n. presents hook with shaft, point curved, proximal shaft straight, heel convex, shelf convex, toe concave, anchor with superficial root robust and male copulatory organ armed with two rows of spinelets. Gyrodactylus scleromystaci sp. n. presents hook with shaft, point recurved, heel convex, shelf convex, toe pointed, anchor with superficial root curved and male copulatory organ armed with two rows of spinelets. These species appear to be closely related to other species of Gyrodactylus known from other species of Callichthyidae. These new species, however, differ by the comparative morphology of the haptoral hard structures and molecular data. Comparative analysis of sequences from these species of Gyrodactylus suggests that the COII gene may represent an important marker for the taxonomy of species of Gyrodactylidae and, perhaps, for species of other lineages of Monogenoidea.


Has the Standard Cognitive Reflection Test Become a Victim of Its Own Success?
The Cognitive Reflection Test (CRT) is a hugely influential problem solving task that measures individual differences in the propensity to reflect on and override intuitive (but incorrect) solutions. The validity of this three-item measure depends on participants being naïve to its materials and objectives. Evidence from 142 volunteers recruited online suggests this is often not the case. Over half of the sample had previously seen at least one of the problems, predominantly through research participation or the media. These participants produced substantially higher CRT scores than those without prior exposure (2.36 vs. 1.48), with the majority scoring at ceiling level. Participants that had previously seen a specific problem (e.g., the bat and ball problem) nearly always solved that problem correctly. These data suggest the CRT may have been widely invalidated. As a minimum, researchers must control for prior exposure to the three problems and begin to consider alternative, extended measures of cognitive reflection.


Coordinated epithelial NHE3 inhibition and barrier dysfunction are required for TNF-mediated diarrhea in vivo.
Acute T cell-mediated diarrhea is associated with increased mucosal expression of proinflammatory cytokines, including the TNF superfamily members TNF and LIGHT. While we have previously shown that epithelial barrier dysfunction induced by myosin light chain kinase (MLCK) is required for the development of diarrhea, MLCK inhibition does not completely restore water absorption. In contrast, although TNF-neutralizing antibodies completely restore water absorption after systemic T cell activation, barrier function is only partially corrected. This suggests that, while barrier dysfunction is critical, other processes must be involved in T cell-mediated diarrhea. To define these processes in vivo, we asked whether individual cytokines might regulate different events in T cell-mediated diarrhea. Both TNF and LIGHT caused MLCK-dependent barrier dysfunction. However, while TNF caused diarrhea, LIGHT enhanced intestinal water absorption. Moreover, TNF, but not LIGHT, inhibited Na+ absorption due to TNF-induced internalization of the brush border Na+/H+ exchanger NHE3. LIGHT did not cause NHE3 internalization. PKCalpha activation by TNF was responsible for NHE3 internalization, and pharmacological or genetic PKCalpha inhibition prevented NHE3 internalization, Na+ malabsorption, and diarrhea despite continued barrier dysfunction. These data demonstrate the necessity of coordinated Na+ malabsorption and barrier dysfunction in TNF-induced diarrhea and provide insight into mechanisms of intestinal water transport.


Low-back pain after lumbar discectomy for disc herniation: what can you tell your patient?
Lumbar discectomy (LD) is frequently performed to alleviate radicular pain resulting from disc herniation. While this goal is achieved in most patients, improvement in low-back pain (LBP) has been reported inconsistently. The goal of this study was to characterize how LBP evolves following discectomy. The authors performed a retrospective analysis of prospectively collected patient data from the Canadian Spine Outcomes and Research Network (CSORN) registry. Patients who underwent surgery for lumbar disc herniation were eligible for inclusion. The primary outcome was a clinically significant reduction in the back pain numerical rating scale (BPNRS) assessed at 12 months. Binary logistic regression was used to model the relationship between the primary outcome and potential predictors. There were 557 patients included in the analysis. The chief complaint was radiculopathy in 85%; 55% of patients underwent a minimally invasive procedure. BPNRS improved at 3 months by 48% and this improvement was sustained at all follow-ups. LBP and leg pain improvement were correlated. Clinically significant improvement in BPNRS at 12 months was reported by 64% of patients. Six factors predicted a lack of LBP improvement: female sex, low education level, marriage, not working, low expectations with regard to LBP improvement, and a low BPNRS preoperatively. Clinically significant improvement in LBP is observed in the majority of patients after LD. These data should be used to better counsel patients and provide accurate expectations about back pain improvement.


Atezolizumab (in Combination with Nab-Paclitaxel): A Review in Advanced Triple-Negative Breast Cancer.
Atezolizumab (Tecentriq®), an immune checkpoint inhibitor against programmed death ligand 1 (PD-L1), is the first immunotherapy agent to be approved (for use in combination with nab-paclitaxel) in the USA, the EU (as first-line) and Japan for the treatment of advanced triple-negative breast cancer (TNBC). Approval was based on the results of the phase III IMpassion130 trial in patients with unresectable locally advanced or metastatic TNBC, in which atezolizumab plus nab-paclitaxel significantly prolonged progression-free survival (PFS) when compared to placebo plus nab-paclitaxel in the intent-to-treat (ITT) population and the PD-L1+ subgroup. Statistically significant overall survival (OS) benefits were not seen in two interim analyses and final OS data are awaited. The tolerability and safety profile of atezolizumab plus nab-paclitaxel was consistent with those of each individual drug. The most common treatment-related adverse events included neutropenia, peripheral neuropathy and reduced neutrophil count. Adverse events of special interest occurred with higher frequency in patients who received atezolizumab plus nab-paclitaxel than placebo plus nab-paclitaxel, and were mostly immune-related (e.g. immune-related rash, hypothyroidism and hepatitis). Health-related quality of life was not significantly impacted by the addition of atezolizumab to nab-paclitaxel therapy. Thus, atezolizumab plus nab-paclitaxel is a useful immunochemotherapy option for patients with unresectable locally advanced or metastatic TNBC, including those whose tumours have PD-L1 expression ≥ 1%.


Cardiovascular emergency hospital visits and hourly changes in air pollution.
Few studies have examined the effect of hourly changes in air pollution on cardiovascular disease morbidity. We evaluated the associations between hourly changes in air pollution and the risks of several types of cardiovascular disease. We used a time-stratified case-crossover design. Study participants were 10,949 residents of the city of Okayama, Japan, aged≥65 years who were taken to hospital emergency rooms between January 2006 and December 2010 for onset of cardiovascular disease. We calculated city representative hourly average concentrations of air pollutants from several monitoring stations and examined the associations between air pollution exposure before the case event, focusing mainly on suspended particulate matter, and disease onset. Suspended particulate matter exposure 0 to <6 hours before the case events was associated with risks of onset of cardiovascular and cerebrovascular disease; odds ratios after 1 interquartile range increase in suspended particulate matter exposure were 1.04 (95% confidence interval, 1.01-1.06) for cardiovascular disease and 1.04 (95% confidence interval, 1.00-1.08) for cerebrovascular disease. We observed an elevated risk of hemorrhagic as well as ischemic stroke, but the risk was slightly higher for hemorrhagic stroke, and this elevation was persistent. Women tended to have higher effect estimates. This study provides further evidence that particulate matter exposure increases the risks of onset of cardiovascular and cerebrovascular disease (including hemorrhagic stroke) shortly after exposure.


Machine learning-based model for predicting 1 year mortality of hospitalized patients with heart failure.
Individual risk stratification is a fundamental strategy in managing patients with heart failure (HF). Artificial intelligence, particularly machine learning (ML), can develop superior models for predicting the prognosis of HF patients, and administrative claim data (ACD) are suitable for ML analysis because ACD is a structured database. The objective of this study was to analyse ACD using an ML algorithm, predict the 1 year mortality of patients with HF, and finally develop an easy-to-use prediction model with high accuracy using the top predictors identified by the ML algorithm. Machine learning-based prognostic prediction models were developed from the ACD on 10 175 HF patients from the Japanese Registry of Acute Decompensated Heart Failure with 17% mortality during 1 year follow-up. The top predictors for prognosis in HF were identified by the permutation feature importance technique, and an easy-to-use prediction model was developed based on these predictors. The c-statistics and Brier scores of the developed ML-based models were compared with those of conventional risk models: Seattle Heart Failure Model (SHFM) and Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC). A voting classifier algorithm (ACD-VC) achieved the highest c-statistics among the six ML algorithms. The permutation feature importance technique enabled identification of the top predictors such as Barthel index, age, body mass index, duration of hospitalization, last hospitalization, renal disease, and non-loop diuretics use (feature importance values were 0.054, 0.025, 0.010, 0.005, 0.005, 0.004, and 0.004, respectively). Upon combination of some of the predictors that can be assessed from a brief interview, the Simple Model by ARTificial intelligence for HF risk stratification (SMART-HF) was established as an easy-to-use prediction model. Compared with the conventional models, SMART-HF achieved a higher c-statistic {ACD-VC: 0.777 [95% confidence interval (CI) 0.751-0.803], SMART-HF: 0.765 [95% CI 0.739-0.791], SHFM: 0.713 [95% CI 0.684-0.742], MAGGIC: 0.726 [95% CI 0.698-0.753]} and better Brier scores (ACD-VC: 0.121, SMART-HF: 0.124, SHFM: 0.139, MAGGIC: 0.130). The ML model based on ACD predicted the 1 year mortality of HF patients with high accuracy, and SMART-HF along with the ML model achieved superior performance to that of the conventional risk models. The SMART-HF model has the clear merit of easy operability even by non-healthcare providers with a user-friendly online interface (https://hfriskcalculator.herokuapp.com/). Risk models developed using SMART-HF may provide a novel modality for risk stratification of patients with HF.


Microarray and RNAi analysis of P450s in Anopheles gambiae male and female steroidogenic tissues: CYP307A1 is required for ecdysteroid synthesis.
In insects, the steroid hormone 20-hydroxyecdysone (20E) coordinates major developmental transitions. While the first and the final steps of 20E biosynthesis are characterized, the pathway from 7-dehydrocholesterol to 5β-ketodiol, commonly referred as the "black box", remains hypothetical and whether there are still unidentified enzymes is unknown. The black box would include some oxidative steps, which are believed to be mediated by P450 enzymes. To identify new enzyme(s) involved in steroid synthesis, we analyzed by small-scale microarray the expression of all the genes encoding P450 enzymes of the malaria mosquito Anopheles gambiae in active steroidogenic organs of adults, ovaries from blood-fed females and male reproductive tracts, compared to inactive steroidogenic organs, ovaries from non-blood-fed females. Some genes encoding P450 enzymes were specifically overexpressed in female ovaries after a blood-meal or in male reproductive tracts but only three genes were found to be overexpressed in active steroidogenic organs of both females and males: cyp307a1, cyp4g16 and cyp6n1. Among these genes, only cyp307a1 has an expression pattern similar to other mosquito steroidogenic genes. Moreover, loss-of-function by transient RNAi targeting cyp307a1 disrupted ecdysteroid production demonstrating that this gene is required for ecdysteroid biosynthesis in Anopheles gambiae.


A pan-genotype hepatitis C virus viral vector vaccine generates T cells and neutralizing antibodies in mice.
A prophylactic vaccine targeting multiple HCV genotypes (gt) is urgently required to meet World Health Organization elimination targets. Neutralizing antibodies (nAbs) and CD4+ and CD8+ T cells are associated with spontaneous clearance of HCV, and each may contribute to protective immunity. However, current vaccine candidates generate either nAbs or T cells targeting genetically variable epitopes and have failed to show efficacy in human trials. We have previously shown that a simian adenovirus vector (ChAdOx1) encoding conserved sequences across gt1-6 (ChAd-Gt1-6), and separately gt-1a E2 protein with variable regions deleted (E2Δ123HMW ), generates pan-genotypic T cells and nAbs, respectively. We now aim to develop a vaccine to generate both viral-specific B- and T-cell responses concurrently. We show that vaccinating with ChAd-Gt1-6 and E2Δ123HMW sequentially in mice generates T-cell and antibody (Ab) responses comparable to either vaccine given alone. We encoded E2Δ123 in ChAdOx1 (ChAd-E2Δ123) and show that this, given with an E2Δ123HMW protein boost, induces greater CD81-E2 inhibitory and HCV-pseudoparticle nAb titers compared to the E2Δ123HMW prime boost. We developed bivalent viral vector vaccines (ChAdOx1 and modified vaccinia Ankara [MVA]) encoding both Gt1-6 and E2Δ123 immunogens (Gt1-6-E2Δ123) generating polyfunctional CD4+ and CD8+ T cells and nAb titers in prime/boost strategies. This approach generated nAb responses comparable to monovalent E2Δ123 ChAd/MVA vaccines and superior to three doses of recombinant E2Δ123HMW protein, while also generating high-magnitude T-cell responses. These data are an important step forward for the development of a pan-genotype HCV vaccine to elicit T cells and nAbs for future assessment in humans.


Accumulation of Plastic Debris and Associated Contaminants in Aquatic Food Webs.
We present a generic theoretical model (MICROWEB) that simulates the transfer of microplastics and hydrophobic organic chemicals (HOC) in food webs. We implemented the model for an Arctic case comprised of nine species including Atlantic cod and polar bear as top predator. We used the model to examine the effect of plastic ingestion on trophic transfer of microplastics and persistent HOCs (PCBs) and metabolizable HOCs (PAHs), spanning a wide range of hydrophobicities. In a scenario where HOCs in plastic and water are in equilibrium, PCBs biomagnify less when more microplastic is ingested, because PCBs biomagnify less well from ingested plastic than from regular food. In contrast, PAHs biomagnify more when more microplastic is ingested, because plastic reduces the fraction of PAHs available for metabolization. We also explore nonequilibrium scenarios representative of additives that are leaching out, as well as sorbing HOCs, quantitatively showing how the above trends are strengthened and weakened, respectively. The observed patterns were not very sensitive to modifications in the structure of the food web. The model can be used as a tool to assess prospective risks of exposure to microplastics and complex HOC mixtures for any food web, including those with relevance for human health.


[Correlation between ipsi- and contralaterally directed nerve fibers from zone CI in the cerebral cortex of the rat].
On frontal sections of the brain of albino rats, by means of peroxidase technique, studies have been made on peculiarities of distribution of cortical nervous fibers from somatosensory zone CI in fugal and comissural directions. Horseradish peroxidase was administered electrophoretically in the focus of the primary response to electrical stimulation of the distal part of the forelimb of the animal. The data obtained were compared with the results of the distribution of labeled fibers from other, more lateral CI zones. Single retrogradely labeled cells in symmetrical (with respect to peroxidase application zones) CI areas of contralateral hemisphere were found, indicating the existence of single comissural connections between these parts of the brain cortex. It was established that among anterogradely labeled fibers emerging from the label zone in focus of the primary response, comissural ones constitute 26-28%, whereas among fibers from the same zone outside primary response focus their share increases up to 53-68%.


Do international trade and investment agreements generate regulatory chill in public health policymaking? A case study of nutrition and alcohol policy in South Africa.
Trade and health scholars have raised concern that international trade and particularly investment disputes may be used by transnational health harmful commodity corporations (THCCs) to effectively generate public health regulatory chill. The purpose of this study was to contribute to the limited evidence base of trade or investment dispute-related regulatory chill using a case study of nutrition and alcohol policy in South Africa. We conducted 35 semi-structured interviews with 36 key stakeholders involved in nutrition, alcohol and/or trade/investment policymaking in South Africa. Interview transcripts were analyzed using thematic analysis. We used Schram et al's theory on three forms of regulatory chill (anticipatory, response and precedential) to guide the analysis. We report evidence on each form of regulatory chill as well as specific contextual factors that may influence the risk of regulatory chill. Trade obligations were found to generate a significantly greater anticipatory-type chilling effect on nutrition and alcohol regulation than South Africa's investment treaty obligations. Response chill was reported to have occurred in relation to South Africa's proposed tobacco plain packaging regulation while awaiting the outcome of both Australia's investor-state and WTO state-state disputes. No cases were reported of THCCs threatening an investor-state dispute over nutrition or food regulations, but there were reported cases of THCCs using arguments related to South Africa's trade obligations to oppose policy action in these areas. No evidence of nutrition or alcohol policy precedential chill were identified. Factors affecting the risk of policy chill include legitimacy and perceived bias of the dispute system, costs involved in pursuing a regulation/defending a dispute and capacity to pay, social acceptability of the industry, a product's perceived risk to health and confidence in a successful dispute outcome e.g. through cross-border policy learning. Our findings indicate that currently, South Africa's trade obligations have a more prominent role in inhibiting nutrition and alcohol action than investment treaty-related concerns. However, given the potential for wider use of the ISDS mechanism by THCCs in the future, strategies to protect public health policy space in the context of both international trade and investment treaty and dispute settlement contexts remain important.


Neural Correlates of Distorted Self-concept in Individuals With Internet Gaming Disorder: A Functional MRI Study.
Background and aims: Discrepancy between ideal self-guide and actual self-concept evoke dejection-related feeling, and often individuals with internet gaming disorder (IGD) use games as the tool to escape those negative emotions. The aim of this study was to evaluate the pattern of self-discrepancy based on actual and ideal self-images and elucidate the neural correlates underlying the distorted self in individuals with IGD. Methods: Nineteen male individuals with IGD and 20 healthy controls (HCs) underwent functional magnetic resonance imaging where they decided on whether they agreed with the adjectives describing their actual or ideal self on a four-point Likert Scale. Two-sample t-test on the self-discrepancy contrast was conducted for neuroimaging analysis and correlation analysis was performed between the behavioral data and regional activities. Results: The IGD group evaluated both their ideal self and actual self more negatively than the HC group. Actual self-concept was associated with satisfaction with psychological needs as opposed to ideal self-guide. Brain activity in the inferior parietal lobule was significantly decreased in individuals with IGD relative to HCs in the self-discrepancy contrast. In addition, neural activity during evaluating actual self-concept showed a significant group difference. Conclusion: These results provide novel evidence for distorted self-concept of people with IGD. Individuals with IGD had a negative ideal and actual self-image. Neurobiologically, dysfunction in the inferior parietal lobule associated with emotional regulation and negative self-evaluation was found in IGD. Considering the characteristics of IGD that often develop in adolescence, this self-concept problem should be noted and applied with appropriate therapy.


Risperidone as monotherapy for a patient with obsessive compulsive disorder comorbid with schizoaffective disorder: a case report.
Data on the efficacy of antipsychotics as monotherapy for obsessive-compulsive disorder (OCD) are inadequate. This report presents the case of a patient with OCD that was successfully treated with risperidone as monotherapy. Assessments revealed significant reductions in OCD symptoms after risperidone treatment (4 mg/d). This report suggests the beneficial effect of risperidone for a patient with OCD comorbid with schizoaffective disorder.


NOGOB receptor deficiency increases cerebrovascular permeability and hemorrhage via impairing histone acetylation-mediated CCM1/2 expression.
The loss function of cerebral cavernous malformation (CCM) genes leads to most CCM lesions characterized by enlarged leaking vascular lesions in the brain. Although we previously showed that NOGOB receptor (NGBR) knockout in endothelial cells (ECs) results in cerebrovascular lesions in the mouse embryo, the molecular mechanism by which NGBR regulates CCM1/2 expression has not been elucidated. Here, we show that genetic depletion of Ngbr in ECs at both postnatal and adult stages results in CCM1/2 expression deficiency and cerebrovascular lesions such as enlarged vessels, blood-brain-barrier hyperpermeability, and cerebral hemorrhage. To reveal the molecular mechanism, we used RNA-sequencing analysis to examine changes in the transcriptome. Surprisingly, we found that the acetyltransferase HBO1 and histone acetylation were downregulated in NGBR-deficient ECs. The mechanistic studies elucidated that NGBR is required for maintaining the expression of CCM1/2 in ECs via HBO1-mediated histone acetylation. ChIP-qPCR data further demonstrated that loss of NGBR impairs the binding of HBO1 and acetylated histone H4K5 and H4K12 on the promotor of the CCM1 and CCM2 genes. Our findings on epigenetic regulation of CCM1 and CCM2 that is modulated by NGBR and HBO1-mediated histone H4 acetylation provide a perspective on the pathogenesis of sporadic CCMs.


Stereo depth estimation under different camera calibration and alignment errors.
Depth estimation is a fundamental issue in computational stereo. To obtain accurate stereo depth estimation, all mechanical parameters with a high precision need to be measured in order to achieve subpixel accuracy and to match features between two different images. This paper investigates accurate depth estimation with different mechanical parameter errors, such as camera calibration and alignment errors, which mainly result from camera lens distortion, camera translation, rotation, pitch, and yaw. For each source of the errors, a model for the error description is presented, and the accurate depth estimation due to this error is quantitatively analyzed. Depth estimation algorithms under an individual error, and with all the errors, are given. Experimental results show that the proposed models can rectify the errors and calculate the accurate depths effectively.


Protein-ligand pose and affinity prediction: Lessons from D3R Grand Challenge 3.
We report the performance of HADDOCK in the 2018 iteration of the Grand Challenge organised by the D3R consortium. Building on the findings of our participation in last year's challenge, we significantly improved our pose prediction protocol which resulted in a mean RMSD for the top scoring pose of 3.04 and 2.67 Å for the cross-docking and self-docking experiments respectively, which corresponds to an overall success rate of 63% and 71% when considering the top1 and top5 models respectively. This performance ranks HADDOCK as the 6th and 3rd best performing group (excluding multiple submissions from a same group) out of a total of 44 and 47 submissions respectively. Our ligand-based binding affinity predictor is the 3rd best predictor overall, behind only the two leading structure-based implementations, and the best ligand-based one with a Kendall's Tau correlation of 0.36 for the Cathepsin challenge. It also performed well in the classification part of the Kinase challenges, with Matthews Correlation Coefficients of 0.49 (ranked 1st), 0.39 (ranked 4th) and 0.21 (ranked 4th) for the JAK2, vEGFR2 and p38a targets respectively. Through our participation in last year's competition we came to the conclusion that template selection is of critical importance for the successful outcome of the docking. This year we have made improvements in two additional areas of importance: ligand conformer selection and initial positioning, which have been key to our excellent pose prediction performance this year.


Multifocal ERG reveals several patterns of cone degeneration in retinitis pigmentosa with concentric narrowing of the visual field.
To analyze multifocal ERGs (mfERGs) in patients with retinitis pigmentosa (RP), with constricted visual fields and visual acuity satisfactory for steady fixation. The mfERGs of 86 eyes of 43 patients with various forms of inheritance and durations of RP were analyzed. A retinal scanning system with a 20-in. monitor was used to map central cone function. Electrical signals of the retina were detected by using DTL fiber electrodes. The site of the best response density of the mfERGs in the patients with RP was found in a central or eccentric position of the trace array. Depending on the position of the best response density in the two eyes, the patients were categorized into three groups. In the first group, the best response density was recorded from the central hexagon in both eyes, producing a central peak surrounded by very low responses in the three-dimensional presentation. In the second group of patients, the best responses were found to correspond to the central hexagon on only one side. In the fellow eye, however, the best response density appeared to be in an eccentric position. The patients in the third group did not present a central peak in the mfERG on either side. In scattered parts of the trace arrays, several acceptable responses were observed in all three groups that might represent patches of functioning retinal cone receptors. The results suggest highly variable central responses and groups of cones with preserved function in areas previously considered nonresponsive. The high variability of the central responses could be a result of variable foveal cone density, with differences in inheritance- and duration-related cone degeneration at the time of the examination. The authors stress the value of step-by-step analysis of the trace array of the mfERGs, which can reveal the still-functioning groups of cones.


Cognitive control of heart rate in diving harbor porpoises.
Marine mammals have adapted to forage while holding their breath in a suite of aquatic habitats from shallow rivers to deep oceans. The key to tolerate such extensive apnea is the dive response, which comprises bradycardia and peripheral vasoconstriction. Although initially considered an all-or-nothing reflex [1], numerous studies on freely diving marine mammals have revealed substantial dynamics of the dive response to meet the impending dive demands of depth, duration and exercise [2]. Such adjustments are not only autonomic responses, but are under acute cognitive control in pinnipeds [3] living amphibiously on land and in water. The fully aquatic cetaceans would similarly benefit from cognitive cardiovascular control; however, even though they have exercise-modulated diving bradycardia [2] and full voluntary control of their respiratory system to such extent that even mild anesthesia often leads to asphyxiation [4], cognitive cardiovascular control has never been demonstrated for this large group of marine mammals. To address this, we tested the hypothesis that porpoises modulate bradycardia according to anticipated dive duration. Two harbor porpoises, instrumented with ECG recording tags, were trained to perform 20- and 80-second stationary dives, during which they adjusted bradycardia to the anticipated duration, demonstrating cognitive control of their dive response.


Targeting a cross-reactive Gly m 5 soy peptide as responsible for hypersensitivity reactions in a milk allergy mouse model.
Cross-reactivity between soybean allergens and bovine caseins has been previously reported. In this study we aimed to map epitopes of the major soybean allergen Gly m 5 that are co-recognized by casein specific antibodies, and to identify a peptide responsible for the cross-reactivity. Cow's milk protein (CMP)-specific antibodies were used in different immunoassays (immunoblotting, ELISA, ELISA inhibition test) to evaluate the in vitro recognition of soybean proteins (SP). Recombinant Gly m 5 (α), a truncated fragment containing the C-terminal domain (α-T) and peptides of α-T were obtained and epitope mapping was performed with an overlapping peptide assay. Bioinformatics tools were used for epitope prediction by sequence alignment, and for modelling the cross-recognized soy proteins and peptides. The binding of SP to a monoclonal antibody was studied by surface Plasmon resonance (SPR). Finally, the in vivo cross-recognition of SP was assessed in a mouse model of milk allergy. Both α and α-T reacted with the different CMP-specific antibodies. α-T contains IgG and IgE epitopes in several peptides, particularly in the peptide named PA. Besides, we found similar values of association and dissociation constants between the α-casein specific mAb and the different milk and soy components. The food allergy mouse model showed that SP and PA contain the cross-reactive B and T epitopes, which triggered hypersensitivity reactions and a Th2-mediated response on CMP-sensitized mice. Gly m 5 is a cross-reactive soy allergen and the α-T portion of the molecule contains IgG and IgE immunodominant epitopes, confined to PA, a region with enough conformation to be bound by antibodies. These findings contribute to explain the intolerance to SP observed in IgE-mediated CMA patients, primarily not sensitised to SP, as well as it sets the basis to propose a mucosal immunotherapy for milk allergy using this soy peptide.


NTP Toxicology and Carcinogenesis Studies of Methyl Methacrylate (CAS No. 80-62-6) in F344/N Rats and B6C3F1 Mice (Inhalation Studies).
Toxicology and carcinogenesis studies of methyl methacrylate, a liquid chemical intermediate used in the plastics industry in the manufacture of plexiglass and other acrylic products, were conducted by exposing groups of F344/N rats and B6C3F1 mice by inhalation for 14 weeks and 2 years. In the 14-week studies, groups of 10 male and 10 female rats and mice were exposed to methyl methacrylate at concentrations of up to 5,000 ppm. All male and female rats and eight male and eight female mice exposed at 5,000 ppm died, one male and nine female rats and four male and no female mice exposed at 3,000 ppm died, and one male and three female rats and two male and one female mouse exposed at 2,000 ppm died; all rats and mice exposed at 500 or 1,000 ppm survived. Compared with the controls, the body weights of the exposed male and female rats and mice were lower. Compound-related lesions included inflammation associated with necrosis and loss of olfactory epithelium in the nasal turbinates in both male and female rats; malacia and gliosis in female rats; inflammation of the nasal turbinates and nasal epithelium metaplasia in both male and female mice; and renal cortical necrosis, renal cortical tubular degeneration, renal focal mineralization, and liver necrosis in male mice. Based on these results, 2-year inhalation toxicology and carcinogenesis studies were conducted in which groups of 50 male rats were exposed to methyl methacrylate at 0, 500, or 1,000 ppm; female rats at 0, 250, or 500 ppm; and male and female mice at 0, 500, or 1,000 ppm. In the 2-year studies, the body weights of the low dose and high dose male and female rats were within 10% of those of the controls. There was no difference in survival between the dosed male and female rats and the controls. Incidences of inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium were greater in the dosed male and female rats than in the controls, with lesions seen in virtually all high dose animals. An increased incidence of mononuclear cell leukemia was observed in female rats exposed to methyl methacrylate at 500 ppm compared with the controls (control, 11/50; 250 ppm, 13/50; 500 ppm, 20/50). This increase was not significant by life table tests, the method of analysis most appropriate for this fatal neoplasm. The mean body weights of dosed male and female mice were 5%-8% lower than those of the controls at the end of the 2-year studies. However, during most of the second year of the studies, body weights of dosed male mice and high dose female mice were 10%-18% lower than those of the controls. Survival rates of the dosed and control mice were similar. Incidences of inflammation and epithelial hyperplasia of the nasal cavity and degeneration of the olfactory sensory epithelium were significantly greater in all dosed groups of male and female mice compared with those of the controls. Compound-related neoplastic lesions were not found in the dosed mice. Significant dose-related decreases were observed in the incidences of pituitary gland and preputial gland tumors in male rats, alveolar/bronchiolar adenomas or carcinomas (combined) in male mice, hepatocellular adenomas in both male and female mice, and pituitary gland adenomas or adenocarcinomas (combined) and uterine adenocarcinomas in female mice. Methyl methacrylate was not mutagenic in strains TA100, TA1535, TA97, or TA98 of Salmonella typhimurium in the presence or absence of male rat or hamster liver S9 when assayed by a preincubational protocol but gave a positive response in L5178Y/TK+/- mouse lymphoma cells in the presence or absence of male rat liver S9. In cultured Chinese hamster ovary cells, methyl methacrylate produced a reproducible, dose-related increase in the frequency of sister-chromatid exchanges, both with and without rat liver S9. A slight, dose-related increase in chromosomal aberrations was also induced in cultured Chinese hamster ovary cells in the absence of S9; in the presence of S9, an increase in the frequency of aberrations was seen only at the highest, near-lethalas seen only at the highest, near-lethal dose of 5 mg/ml. An audit of the experimental data was conducted for the 2-year carcinogenesis studies on methyl methacrylate. No data discrepancies were found that influenced the final interpretations. Under the conditions of these 2-year inhalation studies, there was no evidence of carcinogenicity of methyl methacrylate for male F344/N rats exposed at 500 or 1,000 ppm, for female F344/N rats exposed at 250 or 500 ppm, or for male and female B6C3F1 mice exposed at 500 or 1,000 ppm. Inhalation of methyl methacrylate was associated with inflammation of the nasal cavity and degeneration of the olfactory sensory epithelium in male and female rats and mice; epithelial hyperplasia of the nasal cavity was also observed in exposed mice. Synonyms: acrylic acid, 2-methyl, methyl ester; methacrylic acid, methyl ester; methyl a-methylacrylate; methyl methylacrylate; methyl-2-methylpropenoate; methyl-2-methyl-2-propenoate; 2-methyl-2-propenoic acid methyl ester; MME


[Non-immunological risk factors associated with chronic allograft nephropathy following kidney transplantation].
Although the precise mechanisms are unclear, not only alloantigen-dependent but also antigen-independent factors are generally thought to influence the development of chronic allograft nephropathy (CAN). Among the non-immunological determinants, there are various factors related with donor, recipient and graft procurement. As donor factors, age and cause of death were demonstrated to be significantly independent in long-term graft survival of cadaveric kidney transplantation. Grafts from aged donors and from donors with athelosclerosis showed poor prognosis on graft survival. Regarding recipient factors, cardiovascular complications, as hypertension and hyperlipidemia, were responsible for graft as well as patient survival. In addition, CMV infection and drug nephrotoxicity were also shown to affect graft survival. For procurement factors, warm ischemia was determined to possess the strongest impact on long-term graft survival in our series of kidney transplant using grafts from non-heart beating donors (NHBDs). Delayed graft function, which correlated well with length of warm ischemia, also influenced long-term graft survival. These results proved that the supply of viable donor nephrons and the physiologic demands of the recipient are important determinants of long-term graft survival. So far there seems to be neither definitive nor specific treatment for CAN. It is basically essential to avoid graft damage before transplant and keep recipients from risk factors after transplant as much as possible. To improve long-term graft survival in cadaveric kidney transplantation, recipient selection is greatly important in terms of not only immunological compatibility but also body to nephron mass imbalance and ischemic time, which might cause fatal damage to grafts before engraftment.


Chronic and intermittent exposure to alcohol vapors: a new model of alcohol-induced osteopenia in the rat.
Different models are used to study the effects of chronic alcohol consumption on bone tissue in the rat. However, the current models take several months to show indices of osteopenia as observed in chronic drinkers. Numerous studies have supported that chronic and intermittent exposure to ethanol vapors has predictive validity as a model of alcohol dependence in humans. However, this model has never been applied to bone research to study its effects on the parameters that define osteopenia. This was the goal of this study in the rat. Male Wistar rats were exposed to ethanol vapor inhalation (n = 6) or air (controls, n = 6). Animals were exposed to chronic (11 weeks) and intermittent (14 hours a day) ethanol vapor reaching stable blood alcohol levels (BALs; 150 to 250 mg/dl) at the end of the third week of inhalation. After the sacrifice, right and left femur and tibia were dissected free of fat and connective tissue and bone mineral density (BMD) was assessed by dual X-ray absorptiometry. The microarchitecture of the femur was studied using microcomputed tomography. The BMD of the left and right femurs and the left tibia was lower in the ethanol group compared with the control group. The bone volume fraction (BV/TV) and the bone surface density (BS/TV) were lower in the ethanol group compared with control animals. The trabecular number (Tb.N) was lower in the ethanol group while the trabecular spacing was higher. The decrease in the BMD, BV/TV, and Tb.N is in the same range as what is observed in human drinkers and what is reported with other animal alcohol models (Lieber-DeCarli liquid diet, ethanol in the tap water). Therefore, this model could be useful to study the effects of chronic alcohol consumption in the bone research field and has the advantage of controlling easily targeted BALs.


Prenatal exposure to amphetamines. Risks and adverse outcomes in pregnancy.
Based on findings in humans and the confirmation of prenatal exposures in animals, amphetamines and methamphetamines increase the risk of an adverse outcome when abused during pregnancy. Clefting, cardiac anomalies, and fetal growth reduction deficits that have been seen in infants exposed to amphetamines during pregnancy have all been reproduced in animal studies involving prenatal exposures to amphetamines. The differential effects of amphetamines between genetic strains of mice and between species demonstrate that pharmacokinetics and the genetic disposition of the mother and developing embryo can have an enormous influence on enhancing or reducing these potential risks. The effects of prenatal exposure to amphetamines in producing altered behavior in humans appear less compelling when one considers other confounding variables of human environment, genetics, and polydrug abuse. In view of the animal data concerning altered behavior and learning tasks in comparison with learning deficits observed in humans, the influence of the confounding variables in humans may serve to increase the sensitivity of the developing embryo/fetus to prenatal exposure to amphetamines. These factors and others may predispose the developing conceptus to the damaging effects of amphetamines by actually lowering the threshold of susceptibility at the sites where damage occurs. Knowledge of the effects of prenatal exposure of the fetus and the mother to designer amphetamines is lacking. Based on the few studies in which designer drugs have been examined in animal models, more questions are raised than answered. Possible reasons why no malformations or significant fetal effects were found in the study by St. Omer include the genetic strain of rat used, the conservative exposure profile, or the fact that the placenta metabolized MDMA before reaching the embryo. These questions underscore the need for further investigations concerning the prenatal exposure effects of designer compounds and the effects of amphetamine and methamphetamine in general.


Variable selection in heterogeneous datasets: A truncated-rank sparse linear mixed model with applications to genome-wide association studies.
A fundamental and important challenge in modern datasets of ever increasing dimensionality is variable selection, which has taken on renewed interest recently due to the growth of biological and medical datasets with complex, non-i.i.d. structures. Naïvely applying classical variable selection methods such as the Lasso to such datasets may lead to a large number of false discoveries. Motivated by genome-wide association studies in genetics, we study the problem of variable selection for datasets arising from multiple subpopulations, when this underlying population structure is unknown to the researcher. We propose a unified framework for sparse variable selection that adaptively corrects for population structure via a low-rank linear mixed model. Most importantly, the proposed method does not require prior knowledge of sample structure in the data and adaptively selects a covariance structure of the correct complexity. Through extensive experiments, we illustrate the effectiveness of this framework over existing methods. Further, we test our method on three different genomic datasets from plants, mice, and human, and discuss the knowledge we discover with our method.


Array based detection of antibiotic resistance genes in Gram negative bacteria isolated from retail poultry meat in the UK and Ireland.
The use of antibiotics in birds and animals intended for human consumption within the European Union (EU) and elsewhere has been subject to regulation prohibiting the use of antimicrobials as growth promoters and the use of last resort antibiotics in an attempt to reduce the spread of multi-resistant Gram negative bacteria. Given the inexorable spread of antibiotic resistance there is an increasing need for improved monitoring of our food. Using selective media, Gram negative bacteria were isolated from retail chicken of UK-Intensively reared (n=27), Irish-Intensively reared (n=19) and UK-Free range (n=30) origin and subjected to an oligonucleotide based array system for the detection of 47 clinically relevant antibiotic resistance genes (ARGs) and two integrase genes. High incidences of β-lactamase genes were noted in all sample types, acc (67%), cmy (80%), fox (55%) and tem (40%) while chloramphenicol resistant determinants were detected in bacteria from the UK poultry portions and were absent in bacteria from the Irish samples. Denaturing Gradient Gel Electrophoresis (DGGE) was used to qualitatively analyse the Gram negative population in the samples and showed the expected diversity based on band stabbing and DNA sequencing. The array system proved to be a quick method for the detection of antibiotic resistance gene (ARG) burden within a mixed Gram negative bacterial population.


Auger radiation targeted into DNA: a therapy perspective.
Auger electron emitters that can be targeted into DNA of tumour cells represent an attractive systemic radiation therapy goal. In the situation of DNA-associated decay, the high linear energy transfer (LET) of Auger electrons gives a high relative biological efficacy similar to that of alpha particles. In contrast to alpha radiation, however, Auger radiation is of low toxicity when decaying outside the cell nucleus, as in cytoplasm or outside cells during blood transport. The challenge for such therapies is the requirement to target a high percentage of all cancer cells. An overview of Auger radiation therapy approaches of the past decade shows several research directions and various targeting vehicles. The latter include hormones, peptides, halogenated nucleotides, oligonucleotides and internalising antibodies. Here, we will discuss the basic principles of Auger electron therapy as compared with vector-guided alpha and beta radiation. We also review some radioprotection issues and briefly present the main advantages and disadvantages of the different targeting modalities that are under investigation.


Cross-Reactivity as a Mechanism Linking Infections to Stroke.
The relevance of infections as risk factor for cerebrovascular disease is being increasingly recognized. Nonetheless, the pathogenic link between the two entities remains poorly understood. Consistent with recent advances in medicine, the present work addresses the hypothesis that infection-induced immune responses may affect human proteins associated with stroke. Applying established procedures in bioinformatics, the pathogen antigens and the human proteins were searched for common sequences using pentapeptides as probes. The resulting data demonstrate massive peptide sharing between infectious pathogens-such as Chlamydia pneumoniae, Streptococcus pneumoniae, Tannerella forsythia, Haemophilus influenzae, Influenza A virus, and Cytomegalovirus-and human proteins related to risk of ischemic and hemorrhagic stroke. Moreover, the shared peptides are also evident in a number of epitopes experimentally proven immunopositive in the human host. The present findings suggest cross-reactivity as a potential mechanistic link between infections and stroke.