Acute hospital admissions among nursing home residents: a population-based observational study.
Nursing home residents are prone to acute illness due to their high age, underlying illnesses and immobility. We examined the incidence of acute hospital admissions among nursing home residents versus the age-matched community dwelling population in a geographically defined area during a two years period. The hospital stays of the nursing home population are described according to diagnosis, length of stay and mortality. Similar studies have previously not been reported in Scandinavia. The acute hospitalisations of the nursing home residents were identified through ambulance records. These were linked to hospital patient records for inclusion of demographics, diagnosis at discharge, length of stay and mortality. Incidence of hospitalisation was calculated based on patient-time at risk. The annual hospital admission incidence was 0.62 admissions per person-year among the nursing home residents and 0.26 among the community dwellers. In the nursing home population we found that dominant diagnoses were respiratory diseases, falls-related and circulatory diseases, accounting for 55% of the cases. The median length of stay was 3 days (interquartile range = 4). The in-hospital mortality rate was 16% and 30 day mortality after discharge 30%. Acute hospital admission rate among nursing home residents was high in this Scandinavian setting. The pattern of diagnoses causing the admissions appears to be consistent with previous research. The in-hospital and 30 day mortality rates are high.


Myocardial infarction, patient decision delay and help-seeking behaviour: a thematic analysis.
To explore patient decision delay, the symptom experience and factors that motivated the patient experiencing myocardial infarction to go to the emergency department. Reperfusion for myocardial infarction is more effective if performed as soon as possible after the onset of symptoms. Multiple studies show that prehospital delay is long and can average several hours. A qualitative descriptive design using semi-structured interviews. All consecutive myocardial infarction patients who between July 2013-January 2014 at a single-centre metropolitan tertiary hospital in Western Australia were included. Patient responses to an open-ended question were recorded and transcribed verbatim. Data were analysed using Braun & Clarke (Qual Res Psychol, 3, 2006, 77-101) thematic analysis method. Of the 367 eligible, 255 provided consent. Three themes emerged from the qualitative analyses: (1) onset and response to symptoms, and this included three subthemes: context of the event, diversity of symptom interpretation and response to symptoms; (2) help-seeking behaviour, and this included the patient seeking help from various lay and professional sources; and (3) help-seeking outcomes, which include calling the emergency ambulance, going to emergency department, seeing a general practitioner, seeing a general practitioner who advised them to go home. The context of the event, their symptomatology and the layperson who was the first point of contact influenced the decision for the patient to go to the emergency department. Many patients used private transport or contacted their general practitioner. New knowledge from this study emphasises the importance of the layperson understanding the appropriate response is to seek prompt care through immediate emergency transport by ambulance to emergency department. This study highlights the need to educate both the patient and the wider public, not only to seek prompt care but to also to call the emergency ambulance to arrange transport to the emergency department.


Gold as a Possible Alternative to Platinum-Based Chemotherapy for Colon Cancer Treatment.
Due to the increasing incidence and high mortality associated with colorectal cancer (CRC), novel therapeutic strategies are urgently needed. Classic chemotherapy against CRC is based on oxaliplatin and other cisplatin analogues; however, platinum-based therapy lacks selectivity to cancer cells and leads to deleterious side effects. In addition, tumor resistance to oxaliplatin is related to chemotherapy failure. Gold(I) derivatives are a promising alternative to platinum complexes, since instead of interacting with DNA, they target proteins overexpressed on tumor cells, thus leading to less side effects than, but a comparable antitumor effect to, platinum derivatives. Moreover, given the huge potential of gold nanoparticles, the role of gold in CRC chemotherapy is not limited to gold(I) complexes. Gold nanoparticles have been found to be able to overcome multidrug resistance along with reduced side effects due to a more efficient uptake of classic drugs. Moreover, the use of gold nanoparticles has enhanced the effect of traditional therapies such as radiotherapy, photothermal therapy, or photodynamic therapy, and has displayed a potential role in diagnosis as a consequence of their optic properties. Herein, we have reviewed the most recent advances in the use of gold(I) derivatives and gold nanoparticles in CRC therapy.


Discretization of parametrizable signal manifolds.
Transformation-invariant analysis of signals often requires the computation of the distance from a test pattern to a transformation manifold. In particular, the estimation of the distances between a transformed query signal and several transformation manifolds representing different classes provides essential information for the classification of the signal. In many applications, the computation of the exact distance to the manifold is costly, whereas an efficient practical solution is the approximation of the manifold distance with the aid of a manifold grid. In this paper, we consider a setting with transformation manifolds of known parameterization. We first present an algorithm for the selection of samples from a single manifold that permits to minimize the average error in the manifold distance estimation. Then we propose a method for the joint discretization of multiple manifolds that represent different signal classes, where we optimize the transformation-invariant classification accuracy yielded by the discrete manifold representation. Experimental results show that sampling each manifold individually by minimizing the manifold distance estimation error outperforms baseline sampling solutions with respect to registration and classification accuracy. Performing an additional joint optimization on all samples improves the classification performance further. Moreover, given a fixed total number of samples to be selected from all manifolds, an asymmetric distribution of samples to different manifolds depending on their geometric structures may also increase the classification accuracy in comparison with the equal distribution of samples.


Performance of ceramic laminate veneers with immediate dentine sealing: An 11 year prospective clinical trial.
In this prospective clinical trial the survival, success rate and patient satisfaction of ceramic laminate veneers with special interest on existing restorations, immediate dentin sealing and endodontically treated teeth was evaluated. A total of 104 patients (mean age: 42.1 years old) received 384 feldspathic ceramic laminate veneers on maxillary anterior teeth. Veneer preparations with incisal overlap were performed using a mock up technique. Existing resin composite restorations of acceptable quality were not removed but conditioned using silica coating and silanization. Immediate dentin sealing (IDS) was applied when more than 50% of dentin was exposed during preparation. Endodontically treated teeth were not excluded. After adhesive cementation, restorations were evaluated by calibrated evaluators at baseline and final follow-up using modified USPHS criteria. 225 Laminate veneers were bonded onto teeth without existing restorations, 159 on teeth with pre-existing resin composite restorations, 87 to teeth with more than 50% of exposed dentin surface and 43 to endodontically-treated teeth. In total, 19 failures were observed in form of debonding (n = 3), fracture (n = 15) and extraction due to endodontic complications (n = 1). In teeth with more than 50% of dentin exposure, a significant increase in survival rate was observed when IDS was used (96.4% versus 81.8%). No significant difference was found between teeth with and without pre-existing composite resin restorations (84.6% versus 95.5%) or between vital and non-vital teeth (95.6% versus 88.1%). Laminate veneers luted to endontically-treated teeth had a significant mis-match in color compared to vital teeth. Patients who smoked presented with significantly more marginal discoloration, but no intervention was needed. Patients scored favorably values on the Oral Health Impact Profile questionnaire and were generally satisfied with the treatment. In this clinical trial, the ceramic laminate veneers had a relatively high survival rate. Teeth with more than 50% of dentin exposure significantly benefit from IDS. Pre-existing restorations or endodontic treatments do not have an effect on the survival rate of ceramic laminate veneers. However, smoking habits and previous endodontic treatments negatively affect the success rate due to color changes. NCT03645551.


Aedes albopictus in the United States: ten-year presence and public health implications.
Since its discovery in Houston, Texas, in 1987, the Asian "tiger mosquito" Aedes albopictus has spread to 678 counties in 25 states. This species, which readily colonizes container habitats in the peridomestic environment, was probably introduced into the continental United States in shipments of scrap tires from northern Asia. The early pattern of dispersal followed the interstate highway system, which suggests further dispersal by human activities. The Public Health Service Act of 1988 requires shipments of used tires from countries with Ae. albopictus to be treated to prevent further importations. Given the extensive spread of the mosquito in the United States, it is questionable whether such a requirement is still justified. Ae. albopictus, a major biting pest throughout much of its range, is a competent laboratory vector of at least 22 arboviruses, including many viruses of public health importance. Cache Valley and eastern equine encephalomyelitis viruses are the only human pathogens isolated from U.S. populations of Ae. albopictus. There is no evidence that this mosquito is the vector of human disease in the United States.


Emergency department visits for medical device-associated adverse events among children.
The purposes of this study were to provide national estimates of emergency department (ED) visits for medical device-associated adverse events (MDAEs) in the pediatric population and to characterize these events further. ED medical record reports from the National Electronic Injury Surveillance System All Injury Program database from January 1, 2004, through December 21, 2005, were reviewed. MDAEs among pediatric patients were identified, and data were abstracted. National estimates for pediatric MDAEs were determined according to medical specialty, device category and class, injury diagnosis, and patient characteristics and outcome. The total estimated number of pediatric MDAEs during the 24-month period was 144,799 (95% confidence interval: 113,051-183,903), involving devices from 13 medical specialties. Contact lenses accounted for most MDAEs (23%), followed by hypodermic needles (8%). The distribution of MDAEs according to medical specialty varied according to age subgroup. The most-prevalent types of injuries included contusions/abrasions, foreign-body intrusions, punctures, lacerations, and infections. The most-frequently affected body parts were the eyeball, pubic region, finger, face, and ear. The majority of pediatric MDAEs involved class II (moderate-risk) devices. The incidence of pediatric MDAEs decreased with increasing age from early to late childhood and then spiked after 10 years of age. More girls than boys were affected at older ages (16-21 years) and more boys than girls at younger ages (< or =10 years). Hospitalizations were more likely to involve invasive or implanted devices. This study provides national estimates of pediatric MDAEs resulting in ED visits and highlights the need to develop interventions to prevent pediatric device-related injuries.


[Iatrogenic, intrinsic irritation of the oral mucosa].
The behaviour of a 78-year-old, edentulous female resident of a care home, suffering from dementia indicated to her care providers that she was experiencing oral pain. At the left (pre)molar region of the mandibular residual alveolar ridge, an irritated, red-coloured, sharply restricted mucosal area was seen, extending in width from the buccal to the lingual border of the ridge. Eventually it was identified as mucosal irritation, apparently due to hydroxylapatite cones that had previously been inserted to augment the residual alveolar ridge. Preservation and augmentation of an edentulous part of an alveolar ridge or of a fully edentulous alveolar ridge are both possible using alveolar implants and/or several surgical procedures. In the current case, such previous treatment was not known to have taken place. Consequently, the dentist was not able to provide treatment immediately. This case illustrates the need for general dental practitioners to keep an eye on their older patients and to provide all relevant information when the oral health care provision is taken over by another dentist.


Longitudinal clusters of pain and stiffness in polymyalgia rheumatica: 2-year results from the PMR Cohort Study.
To investigate potential subgroups of primary care-diagnosed patients with PMR based on self-reported pain and stiffness severity over time. A total of 652 people with an incident PMR diagnosis were recruited from English general practices and completed a baseline postal questionnaire. They were followed up with a further six questionnaires over a 2 year period. A total of 446 people completed the 2 year follow-up. Pain and stiffness were reported on a 0-10 numerical rating scale. Latent class growth analysis was used to estimate the joint trajectories of pain and stiffness over time. A combination of statistical and clinical considerations was used to choose the number of clusters. Characteristics of the classes were described. Five clusters were identified. One cluster represented the profile of 'classical' PMR symptoms and one represented sustained symptoms that may not be PMR. The other three clusters displayed a partial recovery, a recovery followed by worsening and a slow, but sustained recovery. Those displaying classical PMR symptoms were in better overall health at diagnosis than the other groups. PMR is a heterogeneous condition, with a number of phenotypes. The spectrum of presentation, as well as varying responses to treatment, may be related to underlying health status at diagnosis. Future research should seek to stratify patients at diagnosis to identify those likely to have a poor recovery and in need of an alternative treatment pathway. Clinicians should be aware of the different experiences of patients and monitor symptoms closely, even where there is initial improvement.


The use of multiwell culture plates in the duckweed toxicity test-A case study on Zn nanoparticles.
Extensive production of nanomaterials of various properties needs to be coupled with rapid toxicity testing in order to provide information about their potential risks to the environment and human health. Miniaturization of toxicity tests may accelerate economical testing of nanomaterials, but is not a common practice. We describe a case study to miniaturize a commonly used toxicity test with plant duckweed Lemna minor. 6-well, 12-well and 24-well culture plates were used to assess their potential use for the duckweed toxicity test with potassium chloride as reference material. The results were compared to the standard test design using 100 mL glass beakers. The comparison showed that the best agreement was with the 6-well vessels. This set-up was further used for toxicity testing of zinc oxide nanoparticles (ZnO NP) and zinc chloride. Zinc was not adsorbed onto either glass or plastic walls of the miniaturized system. We assume that in both vessels a fast agglomeration and settling of ZnO NP took place. Linear regression and statistical testing indicated a good correlation between the toxicity results obtained in the standard test and miniaturized 6-well vessels. The miniaturization of the test system for assessing the biological effect of nanomaterials on Lemna minor could become an appropriate alternative to the traditionally used high volume vessels.


Nocardiosis in the Tropical Northern Territory of Australia, 1997-2014.
Nocardia is an opportunistic pathogen that can cause life-threatening disease. We aimed to characterize the epidemiological, microbiological, and clinical features of nocardiosis in the tropical north of Australia. We conducted a retrospective cohort study of nocardiosis diagnosed between 1997 and 2014. Population-based incidences were calculated using district population data. Clinically significant nocardiosis was identified in 61 patients. The unadjusted population-based annual incidence of nocardiosis was 2.02 (95% confidence interval [CI], 1.55-2.60) per 100000 people and was 1.7 (95% CI, .96-2.90) fold higher in Indigenous compared with non-Indigenous persons (P = .027). Of 61 patients, 47 (77%) had chronic lung disease, diabetes, and/or hazardous alcohol consumption; 22 (36%) were immunocompromised; and 8 (13%) had no identified comorbidities. Disease presentations included pulmonary (69%; 42 of 61), cutaneous (13%; 8 of 61), and disseminated nocardiosis (15%; 9 of 61). The most commonly identified species were Nocardia asteroides and Nocardia cyriacigeorgica (each 11%). Linezolid was the only antimicrobial to which isolates were universally susceptible; 89% (48 of 54), 60% (32 of 53), and 48% (26 of 54) of isolates were susceptible to trimethoprim-sulfamethoxazole, ceftriaxone, and imipenem, respectively. Eighteen patients (30%) required intensive care unit (ICU) admission, and 1-year mortality was 31%. The incidence of nocardiosis in tropical Australia is amongst the highest reported globally. Nocardiosis occurs in both immunocompromised and immunocompetent hosts, and it is associated with high rates of ICU admission, 1-year mortality, and resistance to commonly recommended antimicrobials. Diagnosis should be considered in patients with consistent clinical features, particularly if they are Indigenous or have chronic lung disease.


Serial changes during acute cardiac allograft rejection: quantitative ultrasound tissue analysis versus myocardial histologic findings.
The aim of this study was to assess 1) whether quantitative ultrasound tissue analysis by serial measurements of myocardial echo amplitudes can detect and monitor the onset and degree of acute cardiac rejection, as well as its resolution of acute rejection during treatment, and 2) whether changes in myocardial echo amplitudes are modified by repeat additional rejection episodes. Previous experimental studies, all involving heterotopic heart transplantation, have consistently shown reproducible alterations in myocardial echo amplitude during acute rejection episodes untreated by immunosuppressive agents. Two-dimensional echocardiographic long-axis views were obtained daily under strict standardization in 12 dogs after heterotopic cervical heart transplantation (mean survival time 16.1 days) and digitized into a 256 x 256 x 8 matrix. Myocardial echo amplitudes were analyzed by gray level histogram statistics in regions of interest (45 x 12 pixels) within the proximal septum and posterior wall and correlated with the results of daily transmural myocardial biopsies. Maintenance immunosuppressive therapy consisted of cyclosporine, azathioprine and steroids. Additive steroids were given during acute cardiac rejection. All dogs experienced at least one moderate or severe episode of acute cardiac rejection. Successful resolution and repeat acute rejection were observed in three dogs. On 65 days, the left ventricular biopsy specimens showed no evidence of acute rejection. Mild acute rejection was present on 36, moderate on 29 and severe rejection on 40 days. End-diastolic mean (+/- SD) gray level increased progressively from 100.7 +/- 20.4 for no acute cardiac rejection to 113.8 +/- 23.1 for mild rejection (p = NS vs. no rejection) to 126.0 +/- 16.1 for moderate rejection (p < 0.01) and to 136.3 +/- 12.6 for severe rejection (p < 0.01). In each individual dog, a correlation between daily measurements of mean gray levels and histologic cardiac rejection grades was found (rmean = 0.80 +/- 0.14 [range 0.57 to 0.97], n = 12). In three dogs with transient complete histologic resolution of acute cardiac rejection, mean gray level did not return to values before rejection (108.0 +/- 15.4 vs. 87.2 +/- 8.4). The subsequent second episode of rejection was characterized by higher gray level values than those associated with the first rejection episode (141.3 +/- 14.4 vs. 124.3 +/- 20.9). Acute cardiac rejection is associated with a progressive increase in mean gray level. Changes in myocardial echo amplitudes in individuals may thus prove a useful tool for the noninvasive detection and monitoring of acute rejection. Increased mean gray level values after resolution of rejection may indicate persistent structural tissue abnormalities after rejection and demonstrate the need to define new baseline values after histologic resolution of an acute rejection episode.


Pulmonary artery pressure increases during commercial air travel in healthy passengers.
It is not known whether the mild hypoxia experienced by passengers during commercial air travel triggers hypoxic pulmonary vasoconstriction and increases pulmonary artery pressure in flight. Insidious pulmonary hypertensive responses could endanger susceptible passengers who have cardiopulmonary disease or increased hypoxic pulmonary vascular sensitivity. Understanding these effects may improve pre-flight assessment of fitness-to-fly and reduce in-flight morbidity and mortality. Eight healthy volunteers were studied during a scheduled commercial airline flight from London, UK, to Denver, CO. The aircraft was a Boeing 777 and the duration of the flight was 9 h. Systolic pulmonary artery pressure (sPAP) was assessed by portable Doppler echocardiography during the flight and over the following week in Denver, where the altitude (5280 ft/1610 m) simulates a commercial airliner environment. Cruising cabin altitude ranged between 5840 and 7170 ft (1780 to 2185 m), and mean arterial oxygen saturation was 95 +/- 0.6% during the flight. Mean sPAP increased significantly in flight by 6 +/- 1 mmHg to 33 +/- 1 mmHg, an increase of approximately 20%. After landing in Denver, sPAP was still 3 +/- 1 mmHg higher than baseline and remained elevated at 30 +/- 1 mmHg for a further 12 h. Pulmonary artery pressure increases during commercial air travel in healthy passengers, raising the possibility that hypoxic pulmonary hypertension could develop in susceptible individuals. A hypoxia altitude simulation test with simultaneous echocardiography ('HAST-echo') may be beneficial in assessing fitness to fly in vulnerable patients.


Fabrication, Characterization and Application of Biomolecule Micropatterns on Cyclic Olefin Polymer (COP) Surfaces with Adjustable Contrast.
Peptide and protein micropatterns are powerful tools for the investigation of various cellular processes, including protein-protein interactions (PPIs). Within recent years, various approaches for the production of functional surfaces have been developed. Most of these systems use glass as a substrate, which has several drawbacks, including high fragility and costs, especially if implemented for fluorescence microscopy. In addition, conventional fabrication technologies such as microcontact printing (µCP) are frequently used for the transfer of biomolecules to the glass surface. In this case, it is challenging to adjust the biomolecule density. Here, we show that cyclic olefin polymer (COP) foils, with their encouraging properties, including the ease of manufacturing, chemical resistance, biocompatibility, low water absorption, and optical clarity, are a promising alternative to glass substrates for the fabrication of micropatterns. Using a photolithography-based approach, we generated streptavidin/biotinylated antibody patterns on COPs with the possibility of adjusting the pattern contrast by varying plasma activation parameters. Our experimental setup was finally successfully implemented for the analysis of PPIs in the membranes of live cells via total internal reflection fluorescence (TIRF) microscopy.


Reducing the biomechanical stress of lifting by training.
The effectiveness of two methods of training in reducing biomechanical stress during lifting was examined in a sample of 12 men aged 18-40 years. Subjects carried out three 40 min sessions, one session per day, of a simple symmetrical lifting task. No training was given before the first session, which acted as the control condition. before each of the next two sessions training was given in the form of either written guidelines or interactive personal tuition in a crossover design. Interaction of order with method was expected and was of interest. The effectiveness of each training method in relieving the stress of lifting was measured in four ways: by ratings of perceived exertion on the Borg scale; by video analysis of adherence to guideline kinematics; by chronic spinal compression measured by precision stadiometry; and by the relative compression force at L5/S1 calculated using Chaffin's model. Although the differences in the results of the four assessment methods make reservations necessary it is suggested that while brief personal tuition may demonstrably reduce lifting stress even in a simple lifting task, written guidelines for the untrained may be counterproductive and may interfere with habitual skills. It is recommended that the efficiency of lifting training methods be estimated objectively, such as by the methods employed here, before being adopted.


Poor overall diet quality as a possible contributor to calculus formation.
An association between diet and calculus deposits was suggested by animal studies. The objective of the present analysis was to examine whether or not there is an association between overall diet quality, as measured by the healthy eating index, and extent of dental calculus deposits using a subset of the third National Health and Nutrition Examination Survey (NHANES III) data. NHANES III participants 18-years of age or older who had data on dental calculus and diet quality were selected (n = 12405). The healthy eating index (HEI), used as an indicator of overall diet quality, has a minimum score of zero (poorest) and a maximum score of 100 (best) and was divided into three categories, poor (HEI < 51), fair (HEI, between 51 - 80) and good (HEI > 80). Ordinal logistic regression models were used to examine the association between the HEI and the percentage of sites with calculus deposits. Overall diet quality was found to be significantly associated with calculus deposits controlling for: age, gender, race, education, poverty income ratio, smoking, diabetes, history of vitamin and mineral use, body mass index, time elapsed since last dental visit and gingival bleeding. The adjusted odds ratios for having a greater percentage of sites with calculus were 1.54 (1.19 - 1.98), 1.30 (1.02 - 1.60) and 1.00 (reference) for subjects with poor, fair, and good diet quality respectively. Poor diet quality is significantly associated with more calculus deposits. Further studies are needed to examine if poor diet quality is a predisposing factor for calculus formation and/or a risk factor for periodontal diseases.


Health on the web: randomised controlled trial of online screening and brief alcohol intervention delivered in a workplace setting.
Alcohol misuse in England costs around £7.3 billion (US$12.2 billion) annually from lost productivity and absenteeism. Delivering brief alcohol interventions to employees as part of a health check may be acceptable, particularly with online delivery which can provide privacy for this stigmatised behaviour. Research to support this approach is limited and methodologically weak. The aim was to determine the effectiveness of online screening and personalised feedback on alcohol consumption, delivered in a workplace as part of a health check. This two-group online individually randomised controlled trial recruited employees from a UK-based private sector organisation (approx. 100,000 employees). 3,375 employees completed the online health check in the three week recruitment period. Of these, 1,330 (39%) scored five or more on the AUDIT-C (indicating alcohol misuse) and were randomised to receive personalised feedback on their alcohol intake, alongside feedback on other health behaviours (n = 659), or to receive feedback on all health behaviours except alcohol intake (n = 671). Participants were mostly male (75%), with a median age of 48 years and half were in managerial positions (55%). Median Body Mass Index was 26, 12% were smokers, median time undertaking moderate/vigorous physical activity a week was 173 minutes and median fruit and vegetable consumption was three portions a day. Eighty percent (n = 1,066) of participants completed follow-up questionnaires at three months. An intention to treat analysis found no difference between experimental groups for past week drinking (primary outcome) (5.6% increase associated with the intervention (95% CI -4.7% to 16.9%; p = .30)), AUDIT (measure of alcohol-related harm) and health utility (EQ-5D). There was no evidence to support the use of personalised feedback within an online health check for reducing alcohol consumption among employees in this organisation. Further research is needed on how to engage a larger proportion of employees in screening. International Standard Randomised Controlled Trial Number Register ISRCTN50658915.


Molecular mechanism of ubiquitin recognition by GGA3 GAT domain.
GGA (Golgi-localizing, gamma-adaptin ear domain homology, ARF-binding) proteins, which constitute a family of clathrin coat adaptor proteins, have recently been shown to be involved in the ubiquitin-dependent sorting of receptors, through the interaction between the C-terminal three-helix-bundle of the GAT (GGA and Tom1) domain (C-GAT) and ubiquitin. We report here the crystal structure of human GGA3 C-GAT in complex with ubiquitin. A hydrophobic patch on C-GAT helices alpha1 and alpha2 forms a binding site for the hydrophobic Ile44 surface of ubiquitin. Two distinct orientations of ubiquitin Arg42 determine the shape and the charge distribution of ubiquitin Ile44 surface, leading to two different binding modes. Biochemical and NMR data strongly suggest another hydrophobic binding site on C-GAT helices alpha2 and alpha3, opposite to the first binding site, also binds ubiquitin although weakly. The double-sided ubiquitin binding provides the GAT domain with higher efficiency in recognizing ubiquitinated receptors for lysosomal receptor degradation.


Rationale for and design of the TRUE-AHF trial: the effects of ularitide on the short-term clinical course and long-term mortality of patients with acute heart failure.
The TRUE-AHF is a randomized, double-blind, parallel-group, placebo-controlled trial which is evaluating the effects of a 48-h infusion of ularitide (15 ng/kg/min) on the short- and long-term clinical course of patients with acute heart failure. Noteworthy features of the study include the early enrolment of patients following their initial clinical presentation (within 12 h), and entry blood pressure criteria and thresholds for the adjustment of drug infusion rates, which aim to minimize the risk of hypotension. The trial has two primary endpoints: (i) cardiovascular mortality during long-term follow-up; and (ii) the clinical course of patients during their index hospitalization. Cardiovascular mortality is evaluated in this event-driven trial by following all randomized patients for the occurrence of death until the end of the entire study without truncation at an arbitrarily determined early time point. The clinical course during the index hospitalization is evaluated using the hierarchical clinical composite endpoint, which combines information regarding changes in symptoms and the occurrence of in-hospital worsening heart failure events and death into a single ranked metric that captures interval clinical events and minimizes the likelihood of missing data and confounding due to intensification of background therapy. The design of the TRUE-AHF trial capitalizes on lessons learned from earlier trials and aims to evaluate definitively the potential benefit of ularitide in patients with acute heart failure. NCT01661634.


[Is homeopathy a false doctrine?].
We realize that it is virtually impossible to persuade the convinced practitioners of any of the pseudo-scientific beliefs. Therefore, it is our aim to support those fellow workers and interested laymen, intimidated by the contentions of homeopaths by providing them with relevant facts to counter the mostly absurd claims put forward by practitioners of alternative medicine. 1. The rule of "similarity" is based on incorrect assumptions. 2. Dilution = Dilution A dilution is neither a "potentization" nor a "dynamization" nor an "energyzation". All these expressions are not based on carefully defined notions or concepts but are merely literal creations of homeopaths. It is well known that the "Urtinktur" in addition to producing desired effects possesses a substantial number of undesired side effects. The reader might wonder why only the beneficial effects would be amplified ("potentiated") while all other side effects would happen to be attenuated ("diluted"). 3. The only evidence all practitioners of pseudo-medicine can muster to prove the efficacy of their methods are occasional healings following pseudo-medical treatment.


Beyond intervention into daily life: A systematic review of generalisation following social communication interventions for young children with autism.
Researchers have generally considered autistic individuals to have difficulties generalising learned skills across novel contexts. Successful generalisation is necessary for an intervention to have benefits in everyday life beyond the original learning environment. We conducted a systematic review of randomised controlled trials of early social communication interventions for children with autism in order to explore generalisation and its measurement. We identified nine RCTs that provided evidence of initial target learning and measured generalisation, of which eight demonstrated at least some successful generalisation across people, settings, and/or activities. The findings did not support the widely reported generalisation 'difficulties' associated with autism. However, generalisation was not consistent across all skills within studies, and one study found no generalisation despite evidence for initial target learning within the intervention context. In general, there are few methodologically sound social communication intervention studies exploring generalisation in autism and no consensus on how it should be measured. In particular, failure to demonstrate initial learning of target skills within the intervention setting and an absence of formal mediation analyses of the hypothesised mechanisms limit current research. We outline a framework within which measurement of generalisation can be considered for use in future trials. To maximise the effectiveness of interventions, the field needs to gain a better understanding of the nature of generalisation among autistic individuals and what additional strategies may further enhance learning. Autism Res 2020, 13: 506-522. © 2020 The Authors. Autism Research published by International Society for Autism Research published by Wiley Periodicals, Inc. LAY SUMMARY: It is generally considered that autistic individuals experience difficulties applying things they have learned in one context into different settings (e.g. from school to home). This is important to consider for intervention studies. Our review does not support a complete lack of generalisation but instead suggests that after early social communication intervention, autistic children can transfer some skills to new contexts. Overall, there is limited research in this area and further work is needed.


Rectal biopsy in the diagnosis of systemic vasculitis.
Vasculitis has been seen in rectal biopsies from 22 patients over a six year period. The most common finding was a necrotising vasculitis of small arteries, indistinguishable from that seen in polyarteritis nodosa (PAN). Sub-acute, chronic ("burnt out") and leucocytoclastic changes were also seen. Sixteen patients had vasculitis complicating rheumatoid arthritis (RA), 3 PAN and 3 overlap syndromes. Patients with RA and rectal vasculitis had a higher mortality, and a greater incidence of neuropathy than those with negative biopsies. An adequate biopsy is positive in 40% of patients with clinical vasculitis and RA but was only positive in one of a control series of 46 RA patients with no clinical vasculitis. Rectal biopsy in experienced hands is a safe, and repeatable procedure. It is useful as a "blind" biopsy site in the diagnosis of systemic vasculitis, especially that complicating RA. It can also be used for serial studies of the evolution of vasculitis. Serial sections of the entire biopsy may be required to reveal the vasculitis which is often focal in nature.


Acute health effects of the Tasman Spirit oil spill on residents of Karachi, Pakistan.
On July 27 2003, a ship carrying crude oil ran aground near Karachi and after two weeks released 37,000 tons of its cargo into the sea. Oil on the coastal areas and fumes in air raised health concerns among people. We assessed the immediate health impact of oil spill from the tanker Tasman Spirit on residents of the affected coastline in Karachi, Pakistan. We conducted a study consisting of an exposed group including adults living in houses on the affected shoreline and two control groups (A and B) who lived at the distance of 2 km and 20 km away from the sea, respectively. We selected households through systematic sampling and interviewed an adult male and female in each household about symptoms relating to eyes, respiratory tract, skin and nervous system, smoking, allergies, beliefs about the effect on their health and anxiety about the health effects. We used logistic regression procedures to model each symptom as an outcome and the exposure status as an independent variable while adjusting for confounders. We also used linear regression procedure to assess the relationship exposure status with symptoms score; calculated by summation of all symptoms. Overall 400 subjects were interviewed (exposed, n = 216; group A, n = 83; and group B, n = 101). The exposed group reported a higher occurrence of one or more symptoms compared to either of the control groups (exposed, 96% vs. group A, 70%, group B 85%; P < 0.001). Mean summary symptom scores were higher among the exposed group (14.5) than control group A (4.5) and control group B (3.8, P < 0.001). Logistic regression models indicated that there were statistically significant, moderate-to-strong associations (Prevalence ORs (POR) ranging from 2.3 to 37.0) between the exposed group and the symptoms. There was a trend of decreasing symptom-specific PORs with increase in distance from the spill site. Multiple linear regression model revealed strong relationship of exposure status with the symptoms score (beta = 8.24, 95% CI: 6.37-10.12). Results suggest that the occurrence of increased symptoms among the exposed group is more likely to be due to exposure to the crude oil spill.


A novel gene expression system strongly enhances the anticancer effects of a REIC/Dkk-3-encoding adenoviral vector.
Gene expression systems with various promoters, including the cytomegalovirus (CMV) promoter, have been developed to increase the gene expression in a variety of normal and cancer cells. In particular, in the clinical trials of cancer gene therapy, a more efficient and robust gene expression system is required to achieve sufficient therapeutic outcomes. By inserting the triple translational enhancer sequences of human telomerase reverse transcriptase (hTERT), Simian virus 40 (SV40) and CMV downstream of the sequence of the BGH polyA, we were able to develop a novel gene expression system that significantly enhances the expression of the genes of interest. We termed this novel gene expression cassette the super gene expression (SGE) system, and herein verify the utility of the SGE cassette for a replication-deficient adenoviral vector. We newly developed an adenoviral vector expressing the tumor suppressor, reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), based on the CMV promoter-driven SGE system (Ad-SGE-REIC) and compared the therapeutic utility of Ad-SGE-REIC with that of the conventional adenoviral vectors (Ad-CMV-REIC or Ad-CAG-REIC). The results demonstrated that the CMV promoter-SGE system allows for more potent gene expression, and that the Ad-SGE-REIC is superior to conventional adenoviral systems in terms of the REIC protein expression and therapeutic effects. Since the SGE cassette can be applied for the expression of various therapeutic genes using various vector systems, we believe that this novel system will become an innovative tool in the field of gene expression and gene therapy.


Irrelevant auditory and tactile signals, but not visual signals, interact with the target onset and modulate saccade latencies.
Saccadic eye movements bring events of interest to the center of the retina, enabling detailed visual analysis. This study explored whether irrelevant auditory (experiments A, B & F), visual (C & D) or tactile signals (E & F) delivered around the onset of a visual target modulates saccade latency. Participants were instructed to execute a quick saccade toward a target stepping left or right from a fixation position. We observed an interaction between auditory beeps or tactile vibrations and the oculomotor reaction that included two components: a warning effect resulting in faster saccades when the signal and the target were presented simultaneously; and a modulation effect with shorter-or longer-latencies when auditory and tactile signals were delivered before-or after-the target onset. Combining both modalities only increased the modulation effect to a limited extent, pointing to a saturation of the multisensory interaction with the motor control. Interestingly, irrelevant visual stimuli (black background or isoluminant noise strips in peripheral vision, flashed for 10 ms) increased saccade latency whether they were presented just before or after target onset. The lack of latency reduction with visual signals suggests that the modulation observed in the auditory and tactile experiments was not related to priming effects but rather to low-level audio- and tactile-visual integration. The increase in saccade latency observed with irrelevant visual stimuli is discussed in relation to saccadic inhibition. Our results demonstrate that signals conveying no information regarding where and when a visual target would appear modulate saccadic reactivity, much like in multisensory temporal binding, but only when these signals come from a different modality.


The neurofibromatosis type 1 tumor suppressor controls cell growth by regulating signal transducer and activator of transcription-3 activity in vitro and in vivo.
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome in which affected individuals develop benign and malignant nerve tumors. The NF1 gene product neurofibromin negatively regulates Ras and mammalian target of rapamycin (mTOR) signaling, prompting clinical trials to evaluate the ability of Ras and mTOR pathway inhibitors to arrest NF1-associated tumor growth. To discover other downstream targets of neurofibromin, we performed an unbiased cell-based high-throughput chemical library screen using NF1-deficient malignant peripheral nerve sheath tumor (MPNST) cells. We identified the natural product, cucurbitacin-I (JSI-124), which inhibited NF1-deficient cell growth by inducing apoptosis. We further showed that signal transducer and activator of transcription-3 (STAT3), the target of cucurbitacin-I inhibition, was hyperactivated in NF1-deficient primary astrocytes and neural stem cells, mouse glioma cells, and human MPNST cells through Ser(727) phosphorylation, leading to increased cyclin D1 expression. STAT3 was regulated in NF1-deficient cells of murine and human origin in a TORC1- and Rac1-dependent manner. Finally, cucurbitacin-I inhibited the growth of NF1-deficient MPNST cells in vivo. In summary, we used a chemical genetics approach to reveal STAT3 as a novel neurofibromin/mTOR pathway signaling molecule, define its action and regulation, and establish STAT3 as a tractable target for future NF1-associated cancer therapy studies.


The thyroid and the heart.
Cardiovascular manifestations are a frequent finding in hyperthyroid and hypothyroid states. In this review, potential mechanisms by which thyroid hormones may exert their cardiovascular effects and pathophysiological consequences of such effects are briefly discussed. Two major concepts have emerged about how thyroid hormones exert their cardiovascular effects. First, there is increasing evidence that thyroid hormones exert direct effects on the myocardium, which are mediated by stimulation of specific nuclear receptors, which in turn leads to specific mRNAs production. Furthermore, there is some evidence that thyroid hormones may also activate extranuclear sites and may directly alter plasma membrane function. Second, thyroid hormones interact with the sympathetic nervous system by altering responsiveness to sympathetic stimulation presumably by modulating adrenergic receptor function and/or density. Pathophysiological consequences of such direct and indirect thyroid hormone effects include increased myocardial contractility and relaxation that may be related to stimulation by T3 of specific myocardial enzymes. However, when left ventricular hypertrophy occurs in association with hyperthyroidism, it may be related to either direct thyroid hormone-induced stimulation of myocardial protein synthesis or to thyrotoxicosis-induced increases in cardiac work load. Although hyperthyroidism generally has little or no effect on mean arterial blood pressure, hypothyroidism is often associated with increases in diastolic blood pressure that are reversible after hormone substitution and may be mediated in part by sympathetic activation. Moreover, there is increasing evidence that thyroid hormones have direct chronotropic effect on the heart that are independent of the sympathetic nervous system.(ABSTRACT TRUNCATED AT 250 WORDS)


Experience of self-management of medications among older people with multimorbidity.
To explore the experience of self-managing medication among older people with multimorbidity. Older people with multimorbidity are now more likely to live at home and to self-medicate. Reduced assistance from professional caregivers is associated with medical errors. Face-to-face interviews were conducted with older people with multimorbidity. Participants aged ≥75 years with ≥2 medical diagnoses and living at home or in special accommodation were interviewed. Twenty-eight men and women (mean age 84 years) participated. Interviews lasted from 45 minutes-2 hours and were transcribed verbatim. A lifeworld-based phenomenological method was used for analysis. Uncertainty among the participants increased with their experience of side effects and concern that the medication might be harmful. These uncertainties were reinforced by a fear of malpractice when several physicians were involved. This meant living with ambivalence when taking the medication, which required a trade-off between symptom relief and reducing side effects. A lack of continuity with physicians and nurses led to uncertainty in maintaining an overview of the medications. By contrast, when the relationships were supportive and caring, the uncertainties diminished. Four concepts were used to describe the various meanings of this experience: adapting to a new lifestyle; ambivalence towards medicine; experience of side effects and concerns about medical errors; and relationships as sources of feeling secure. Medications can cause side effects, and unclear benefits increase the uncertainty for older people with multimorbidity. Health care professionals need to develop an understanding of each patient's experience of such uncertainty. Health care professionals can give support and show understanding for older people's existential uncertainty by creating good relationships and continuity in care, and offering appropriate information. Regular visits should be scheduled to manage any problems patients might have when self-medicating.


More than Just a Meal: Breakfast Club Attendance and Children's Social Relationships.
The health benefits of school food have been widely promoted in recent years while the social opportunities that surround eating occasions at school have received little attention. Breakfast clubs (BCs), which take place at the start of the school day, offer a unique opportunity for children to consume a breakfast meal on their school premises in the company of their peers. Alternatively, after-school clubs (ASCs), which take place on school premises at the end of the school day, whilst also providing children with social opportunities tend to focus on sports engagement and skill development. The aim of the current paper is to investigate whether attendance at BCs and ASCs has an impact on children's friendship quality and experiences of peer victimization. BC attendees, ASC attendees, and non-attendees completed the Friendship Qualities Scale and the Multidimensional Peer Victimization Scale (MPVS) at two time points. Time-1 data were collected 2 months after the introduction of school clubs. Time-2 data were then collected on the same measures again 6 months later. Results of the analyses of Time-1 data showed no significant differences between groups on any of the measures at Time-1. However, at Time-2, BC attendees showed improved levels of friendship quality compared to the other two groups. Moreover, analysis of the MPVS data at Time-2 showed that children who attended BC or ASC experienced a decline in victimization across time. The current findings suggest that BC attendance facilitates the quality of children's relationships with their best friend over time. Additionally, attendance at a breakfast or ASC was associated with a reduction in victimization over time. The results have implications for utilization of breakfast and ASCs to aid children's social relationships in school over time.


An "accidental" acute psychosis with ecstasy use.
Over the last 10 years, Europe has witnessed the development of the ecstasy phenomenon; this term is used to describe several products sharing more or less the same effects. The most widely used and hence the most well known is 3,4 MDMA, but MDA, MDEA, MBDB and even 2CB or nexus are available. The psychopathological consequences of MDMA use in man are relatively poorly understood. The case reported here involves an acute psychotic episode with residual symptoms after six months, with a sudden onset at least 12 hours after taking alcohol and ecstasy without realising it, in an individual with no previous psychopathology other than a moderate anxiety disorder. Twelve cases of acute psychotic episodes after taking ecstasy have been reported in the literature; two after taking the drug on two occasions and one after a single use. No authors have examined the previous mental state or possible previous psychopathology with any precision. The present subject had not displayed any previous psychotic behavior when tested with a proven standardized interview technique; this was confirmed by his peers and his family. He did, however, show signs of social phobia. Although the personality of an individual is a factor in taking a drug, and probably in the quality of the psychotropic effects experienced, a host of arguments favor the appearance of psychotic symptoms de novo, which were probably related to direct toxicity by MDMA and/or its metabolites on the serotoninergic neurons.


Constant-flow ventilation of apneic dogs.
The adequacy of constant airway gas flow sustenance of arterial blood gas tensions was investigated in anesthetized-paralyzed mongrel dogs. Gas delivery was achieved via a main-stem bronchi cannulation system constructed of two polyethylene tubes bifurcating at the carina, which rested on the posterior surface of the trachea outside of an endotracheal tube positioned in the upper third of the trachea. Equal flows (total flow = Vin) of humidified air were delivered through each limb of the cannulation system at constant flow rates with Vin ranging from 8 to 28 l/min. Intratracheal pressures at these flows characteristically ranged from 0.1 to 1 cmH2O. Arterial O2 tension varied directly (PaO2 = 0.72 Vin + 74.6), and arterial CO2 tension varied inversely (PaCO2 = -0.73 Vin + 51.2) with Vin during ambient gas, constant-flow ventilation (CFV). During prolonged CFV (greater than 2 h), no evidence of CO2 accumulation or deterioration of PaO2, was observed. This study demonstrates that in apneic dogs normal blood gases can be achieved and maintained over prolonged periods with constant airway flow at low intratracheal pressures.


Buckwheat Secondary Metabolites: Potential Antifungal Agents.
Research groups have put significant emphasis on the evaluation of nutritional, health-promoting, and other biological activities of secondary metabolites from buckwheat. Among these phytochemicals, phenolic and lipophilic antioxidants, particularly, phenolic acids, flavonoids, and tocopherols, have been the focus of the latest studies since antioxidant activity has recently been associated with the possibility of inhibiting fungal growth and mycotoxin biosynthesis. The mycotoxin contamination of cereal and pseudocereal grains caused primarily by Fusarium, Penicillium, and Aspergillus species poses a significant hazard to human health. Therefore, efforts to examine the involvement of plant antioxidants in the biosynthesis of mycotoxins at the transcriptional level have emerged. In addition, hydrophobic interactions of buckwheat phenolics with cell membranes could also explain their capacity to reduce fungal development. Eventually, possibilities of enhancing the biological activity of cereal and pseudocereal phytochemicals have been studied, and sourdough fermentation has been proposed as an efficient method to increase antioxidant activities. This effect could result in an increased antifungal effects of sourdough and bakery products. This review reports the main advances in research on buckwheat phenolics and other antioxidant phytochemicals, highlighting possible mechanisms of action and processes that could improve their biological activities.


Occurrence of pharmaceuticals and personal care products in German fish tissue: a national study.
German Environment Specimen Bank (GESB) fish tissue samples, collected from 14 different GESB locations, were analyzed for 15 pharmaceuticals, 2 pharmaceutical metabolites, and 12 personal care products. Only 2 pharmaceuticals, diphenhydramine and desmethylsertraline, were measured above MDL. Diphenhydramine (0.04-0.07 ng g(-1) ww) and desmethylsertraline (1.65-3.28 ng g(-1) ww) were measured at 4 and 2 locations, respectively. The maximum concentrations of galaxolide (HHCB) (447 ng g(-1) ww) and tonalide (AHTN) (15 ng g(-1) ww) were measured at the Rehlingen sampling site in the Saar River. A significant decrease in HHCB and AHTN fish tissue concentrations was observed from 1995 to 2008 at select GESB sampling sites (r(2) = 0.69-0.89 for galaxolide and 0.89-0.97 for tonalide with p < 0.003). Galaxolide and tonalide fish tissue concentrations in Germany were ∼19× and ∼28× lower, respectively, as compared to fish tissue concentrations measured in a United States nationwide PPCP study conducted in 2006. Proximity of the sampling locations to the upstream wastewater treatment plant discharging point and mean annual flow at the sampling location were found to significantly predict galaxolide and tonalide fish tissue concentrations (HHCB: r(2) = 0.79, p = 0.021 and AHTN: r(2) = 0.81, p = 0.037) in Germany.


Receiving an alcohol enquiry from a physician in routine health care in Sweden: a population-based study of gender differences and predictors.
Research has shown that the provision of brief interventions in the health care system is effective for reducing hazardous drinking. Using a telephone-administered questionnaire, this study provides a population-based investigation on the extent to which physicians address patients' alcohol habits in the Swedish health care system, whether there are gender differences in the extent to which patients receive questions about alcohol, and predictors for receiving such questions. Data were obtained from monthly telephone surveys with around 72,000 people in 2006-2009. Having received an alcohol enquiry was defined as having been asked about one's drinking habits by a physician in any health care visit in the last 12 months. Fourteen percent of the total population had received an alcohol enquiry, but there were considerable gender differences: for hazardous drinkers, 13% of the women and 17% of the men had received an alcohol enquiry; among those with sensible alcohol consumption, 10% of women and 15% of men had received an alcohol enquiry. Patients were more likely to have received an alcohol enquiry if they had self-reported alcohol-related problems, were hazardous drinkers and/or daily smokers. Some of the alcohol enquiry predictors differed by gender; social class was an important predictor for women but not for men.


HLA-D/DR expression on epithelial cells: the finger on the trigger?
The findings we have described here show a clear association between epithelial HLA-D/DR expression and autoimmunity. Furthermore, the ability of class II+ thyrocytes to present both exogenous antigens and autoantigens indicates an active role for these HLA-D/DR molecules in autoimmune pathogenesis. IFN-gamma is capable of inducing HLA-D/DR expression by thyroid epithelium, but a number of observations suggest the involvement of other inducers as well. Overall, we conclude that epithelial class II expression very probably plays a key role in the propagation and also in possibly the initiation of autoimmune attack. This is in accord with the proposal of a more general relationship between inappropriate or excessive class II expression and pathogenesis.


PKA microdomain organisation and cAMP handling in healthy and dystrophic muscle in vivo.
Signalling through protein kinase A (PKA) triggers a multitude of intracellular effects in response to a variety of extracellular stimuli. To guarantee signal specificity, different PKA isoforms are compartmentalised by Akinase anchoring proteins (AKAPs) into functional microdomains. By using genetically encoded fluorescent reporters of cAMP concentration that are targeted to the intracellular sites where PKA type I and PKA type II isoforms normally reside, we directly show for the first time spatially and functionally separate PKA microdomains in mouse skeletal muscle in vivo. The reporters localised into clearly distinct patterns within sarcomers, from where they could be displaced by means of AKAP disruptor peptides indicating the presence of disparate PKA type I and PKA type II anchor sites within skeletal muscle fibres. The functional relevance of such differential localisation was underscored by the finding of mutually exclusive and AKAP-dependent increases in [cAMP] in the PKA type I and PKA type II microdomains upon application of different cAMP agonists. Specifically, the sensors targeted to the PKA type II compartment responded only to norepinephrine, whereas those targeted to the PKA type I compartment responded only to alpha-calcitonin gene-related peptide. Notably, in dystrophic mdx mice the localisation pattern of the reporters was altered and the functional separation of the cAMP microdomains was abolished. In summary, our data indicate that an efficient organisation in microdomains of the cAMP/PKA pathway exists in the healthy skeletal muscle and that such organisation is subverted in dystrophic skeletal muscle.


Alkylaminophenol Induces G1/S Phase Cell Cycle Arrest in Glioblastoma Cells Through p53 and Cyclin-Dependent Kinase Signaling Pathway.
Glioblastoma (GBM) is the most common type of malignant brain tumor in adults. We show here that small molecule 2-[(3,4-dihydroquinolin-1(2H)-yl)(p-tolyl)methyl]phenol (THTMP), a potential anticancer agent, increases the human glioblastoma cell death. Its mechanism of action and the interaction of selective signaling pathways remain elusive. Three structurally related phenolic compounds were tested in multiple glioma cell lines in which the potential activity of the compound, THTMP, was further validated and characterized. Upon prolonged exposer to THTMP, all glioma cell lines undergo p53 and cyclin-dependent kinase mediated cell death with the IC50 concentration of 26.5 and 75.4 μM in LN229 and Snb19, respectively. We found that THTMP strongly inhibited cell growth in a dose and in time dependent manner. THTMP treatment led to G1/S cell cycle arrest and apoptosis induction of glioma cell lines. Furthermore, we identified 3,714 genes with significant changes at the transcriptional level in response to THTMP. Further, a transcriptional analysis (RNA-seq) revealed that THTMP targeted the p53 signaling pathway specific genes causing DNA damage and cell cycle arrest at G1/S phase explained by the decrease of cyclin-dependent kinase 1, cyclin A2, cyclin E1 and E2 in glioma cells. Consistently, THTMP induced the apoptosis by regulating the expression of Bcl-2 family genes and reactive oxygen species while it also changed the expression of several anti-apoptotic genes. These observations suggest that THTMP exerts proliferation activity inhibition and pro-apoptosis effects in glioma through affecting cell cycle arrest and intrinsic apoptosis signaling. Importantly, THTMP has more potential at inhibiting GBM cell proliferation compared to TMZ, the current chemotherapy treatment administered to GBM patients; thus, we propose that THTMP may be an alternative therapeutic option for glioblastoma.


The anti-inflammatory and antioxidant effects of pigmented rice consumption in an obese cohort.
The development of lifestyle diseases in the obese has been attributed to higher levels of inflammation and free radical mediated oxidative stress. The antioxidant and anti-inflammatory properties of polyphenols in pigmented rice varieties could have potential to neutralize oxidative stress and modulate inflammatory responses in the obese. A cross-over dietary intervention human clinical trial was conducted with three pigmented rice varieties chosen from previous chemical and in vitro antioxidant and anti-inflammatory screening. Obese (n = 22, BMI > 30) sedentary participants consumed one cup of pigmented rice (Reiziq (brown), Purple (purple) and Yunlu29 (red)). Blood samples were collected prior consumption (baseline) and at set time points of 30 minutes, 1 hour, 2 hours and 4 hours post rice consumption. The collected blood samples were analysed for antioxidant and inflammatory biomarkers. Total antioxidant activity increased (p < 0.001) at the 1 hour time point by 40.3% post purple rice consumption. The red rice variety, Yunlu29 increased antioxidant activity at the 30 minute (p < 0.001) and 1 hour (p < 0.01) time point by 29.5% and 21.2% respectively. Lipid peroxidation biomarker, malondialdehyde (MDA), decreased (p < 0.05) at the 30 minute time point by 6.8% post purple rice consumption. At the 4 hour time point MDA levels was significantly reduced (p < 0.001) by the red rice variety Yunlu29, by 9.6%. Pro-inflammatory cytokine, interleukin-10 (IL-10), was significantly (p < 0.0001) reduced by 3.1% 30 minutes post purple rice consumption. In contrast, Yunlu29 (red) reduced interleukin-6 levels by 13.6% and 11.0% at the 30 minute and 1 hour time points respectively. Both the purple (p < 0.01) and red (p < 0.001) varieties significantly reduced interleukin-12p70 concentrations at 30 minutes by 8.7% and 10.3% respectively. Reiziq (brown) did not affect any of the biomarkers analysed in this study. The outcomes of this study highlight that polyphenols found in pigmented rice may play a key role in targeting specific therapeutic pathways in obesity-related oxidative stress and inflammation.


Treatment of a multiple sclerosis animal model by a novel nanodrop formulation of a natural antioxidant.
Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and is associated with demyelination, neurodegeneration, and sensitivity to oxidative stress. In this work, we administered a nanodroplet formulation of pomegranate seed oil (PSO), denominated Nano-PSO, to mice induced for experimental autoimmune encephalomyelitis (EAE), an established model of MS. PSO comprises high levels of punicic acid, a unique polyunsaturated fatty acid considered as one of the strongest natural antioxidants. We show here that while EAE-induced mice treated with natural PSO presented some reduction in disease burden, this beneficial effect increased significantly when EAE mice were treated with Nano-PSO of specific size nanodroplets at much lower concentrations of the oil. Pathological examinations revealed that Nano-PSO administration dramatically reduced demyelination and oxidation of lipids in the brains of the affected animals, which are hallmarks of this severe neurological disease. We propose that novel formulations of natural antioxidants such as Nano-PSO may be considered for the treatment of patients suffering from demyelinating diseases. On the mechanistic side, our results demonstrate that lipid oxidation may be a seminal feature in both demyelination and neurodegeneration.


Age-related impairment in a complex object discrimination task that engages perirhinal cortex.
Previous lesion studies have shown compromised complex object discrimination in rats, monkeys, and human patients with damage to the perirhinal cortical region (PRC) of the medial temporal lobe. These findings support the notion that the PRC is involved in object discrimination when pairs of objects have a high degree of overlapping features but not when object discrimination can be resolved on the basis of a single feature (e.g., size or color). Recent studies have demonstrated age-related functional changes to the PRC in animals (rats and monkeys) resulting in impaired complex object discrimination and object recognition. To date, no studies have compared younger and older humans using paradigms previously shown to engage the PRC. To investigate the influence of age on complex object discrimination in humans, the present study used an object matching paradigm for blob-like objects that have previously been shown to recruit the PRC. Difficulty was manipulated by varying the number of overlapping features between objects. Functional MRI data was acquired to determine the involvement of the PRC in the two groups during complex object discrimination. Results indicated that while young and older adults performed similarly on the easy version of the task, most older adults were impaired relative to young participants when the number of overlapping features increased. fMRI results suggest that older adults do not engage bilateral anterior PRC to the same extent as young adults. Specifically, complex object matching performance in older adults was predicted by the degree to which they engage left anterior PRC. These results provide evidence for human age-related changes in PRC function that impact complex object discrimination.


Insulin and phorbol ester stimulate phosphorylation of acetyl-CoA carboxylase at similar sites in isolated adipocytes. Lack of correspondence with sites phosphorylated on the purified enzyme by protein kinase C.
1. The phorbol ester 12-O-tetradecanoyl phorbol 13-acetate (TPA) stimulates fatty acid synthesis from glucose in isolated adipocytes with a half-maximal effect at 0.72 microM. In seven batches of cells, the maximal effects of TPA and insulin were 8.5 +/- 1.1-fold and 27.1 +/- 2.1-fold respectively. Insulin also stimulated fatty acid synthesis from acetate 8.9 +/- 0.5-fold (three experiments), but TPA did not significantly increase fatty acid synthesis from this precursor. 2. In contrast to insulin, TPA treatment of isolated adipocytes did not produce an activation of acetyl-CoA carboxylase which was detectable in crude cell extracts. 3. The total phosphate content of acetyl-CoA carboxylase, isolated from adipocytes in the presence of protein phosphatase inhibitors, was estimated by 32P-labelling experiments to be 2.6 +/- 0.1 (5), 3.4 +/- 0.2 (5), and 3.8 +/- 0.2 (3) mol/mol subunit for enzyme from control, insulin- and TPA-treated cells respectively. Insulin and TPA stimulated phosphorylation within the same two tryptic peptides. 4. Purified acetyl-CoA carboxylase is phosphorylated in vitro by protein kinase C at serine residues which are recovered in three tryptic peptides, i.e. peptide T1, which appears to be identical with the peptide Ser-Ser(P)-Met-Ser-Gly-Leu-His-Leu-Val-Lys phosphorylated by cyclic-AMP-dependent protein kinase, and peptides Ta and Tb, which have the sequences Ile-Asp-Ser(P)-Gln-Arg and Lys-Ile-Asp-Ser(P)-Gln-Arg respectively, and which appear to be derived from a single site by alternative cleavages. None of these correspond to the peptides whose 32P-labelling increase in response to insulin or TPA. Peptides Ta/Tb are not significantly phosphorylated in isolated adipocytes, even after insulin or TPA treatment. Peptide T1 is phosphorylated in isolated adipocytes, but this phosphorylation is not altered by insulin or TPA. 5. These results show that TPA mimics the effect of insulin on phosphorylation, but not activation, of acetyl-CoA carboxylase, i.e. that these two events can be dissociated. In addition, phorbol ester stimulates phosphorylation of acetyl-CoA carboxylase in isolated adipocytes, but this is not catalyzed directly by protein kinase C, and acetyl-CoA carboxylase does not appear to be a physiological substrate for this kinase.


Salt drying: a low-cost, simple and efficient method for storing plants in the field and preserving biological repositories for DNA diversity research.
Although a variety of methods have been optimized for the collection and storage of plant specimens, most of these are not suited for field expeditions for a variety of logistic reasons. Drying specimens with silica gel in polyethylene bags is currently the standard for field-sampling methods that are suitable for subsequent DNA extraction. However, silica-gel repositories are not readily available in remote areas, and its use is not very cost-effective for the long-term storage of collections or in developing countries with limited research budgets. Salting is an ancient and traditional drying process that preserves food samples by dehydrating tissues and inhibiting water-dependent cellular metabolism. We compared salt and silica-gel drying methods with respect to dehydration rates overtime, DNA quality and polymerase chain reaction(PCR) success to assess whether dry salting can be used as an effective plant preservation method for DNA analysis. Specimens from eleven plant species covering a variety of leaf structures, leaf thicknesses and water contents were analysed. Experimental work indicated that (i) levels of dehydration in sodium chloride were usually comparable to those obtained when silica gel was used, (ii) no spoilage, fungal or bacterial growth was observed for any of the species with all drying treatments and (iii) good yields of quality genomic DNA suitable for PCR applications were obtained in the salt-drying treatments. The preservation of plant tissues in commercial table salt appears to be a satisfactory, and versatile method that may be suitable in remote areas where cryogenic resources and silica repositories are not available.


Liquid drops attract or repel by the inverted Cheerios effect.
Solid particles floating at a liquid interface exhibit a long-ranged attraction mediated by surface tension. In the absence of bulk elasticity, this is the dominant lateral interaction of mechanical origin. Here, we show that an analogous long-range interaction occurs between adjacent droplets on solid substrates, which crucially relies on a combination of capillarity and bulk elasticity. We experimentally observe the interaction between droplets on soft gels and provide a theoretical framework that quantitatively predicts the interaction force between the droplets. Remarkably, we find that, although on thick substrates the interaction is purely attractive and leads to drop-drop coalescence, for relatively thin substrates a short-range repulsion occurs, which prevents the two drops from coming into direct contact. This versatile interaction is the liquid-on-solid analog of the "Cheerios effect." The effect will strongly influence the condensation and coarsening of drops on soft polymer films, and has potential implications for colloidal assembly and mechanobiology.


The wheat powdery mildew genome shows the unique evolution of an obligate biotroph.
Wheat powdery mildew, Blumeria graminis forma specialis tritici, is a devastating fungal pathogen with a poorly understood evolutionary history. Here we report the draft genome sequence of wheat powdery mildew, the resequencing of three additional isolates from different geographic regions and comparative analyses with the barley powdery mildew genome. Our comparative genomic analyses identified 602 candidate effector genes, with many showing evidence of positive selection. We characterize patterns of genetic diversity and suggest that mildew genomes are mosaics of ancient haplogroups that existed before wheat domestication. The patterns of diversity in modern isolates suggest that there was no pronounced loss of genetic diversity upon formation of the new host bread wheat 10,000 years ago. We conclude that the ready adaptation of B. graminis f.sp. tritici to the new host species was based on a diverse haplotype pool that provided great genetic potential for pathogen variation.


Trinucleotide repeat expansion and neuropsychiatric disease.
Trinucleotide, or triplet, repeats consist of 3 nucleotides consecutively repeated (e.g., CCG CCG CCG CCG CCG) within a region of DNA, a not uncommon motif in the genome of humans and other species. In 1991, a new type of genetic mutation was discovered, known as a dynamic or expansion mutation, in which the number of triplets in a repeat increases and the length becomes unstable. During the past decade, nearly 20 diseases-including Huntington disease, 2 forms of the fragile X syndrome, and myotonic dystrophy-caused by trinucleotide repeat expansions have been identified. The unstable nature of the expanded repeat leads to remarkable patterns of inheritance in these diseases, distinctly at odds with traditional notions of mendelian genetics. We review the clinical and genetic features of these disorders, with a particular emphasis on their psychiatric manifestations. We also critically examine the hypothesis that expansion mutations may have an etiologic role in psychiatric diseases such as bipolar disorder, schizophrenia, and autism.


Hematopoietic stem cell transplantation in children and young adults with secondary myelodysplastic syndrome and acute myelogenous leukemia after aplastic anemia.
Secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/sAML) are the most serious secondary events occurring after immunosuppressive therapy in patients with aplastic anemia. Here we evaluate the outcome of hematopoietic stem cell transplantation (HSCT) in 17 children and young adults with sMDS/sAML after childhood aplastic anemia. The median interval between the diagnosis of aplastic anemia and the development of sMDS/sAML was 2.9 years (range, 1.2 to 13.0 years). At a median age of 13.1 years (range, 4.4 to 26.7 years), patients underwent HSCT with bone marrow (n = 6) or peripheral blood stem cell (n = 11) grafts from HLA-matched sibling donors (n = 2), mismatched family donors (n = 2), or unrelated donors (n = 13). Monosomy 7 was detected in 13 patients. The preparative regimen consisted of busulfan, cyclophosphamide, and melphalan in 11 patients and other agents in 6 patients. All patients achieved neutrophil engraftment. The cumulative incidence of grade II-IV acute graft-versus-host disease (GVHD) was 47%, and that of chronic GVHD was 70%. Relapse occurred in 1 patient. The major cause of death was transplant-related complication (n = 9). Overall survival and event-free survival at 5 years after HSCT were both 41%. In summary, this study indicates that HSCT is a curative therapy for some patients with sMDS/sAML after aplastic anemia. Future efforts should focus on reducing transplantation-related mortality.


Genome-wide profiling reveals stimulus-specific functions of p53 during differentiation and DNA damage of human embryonic stem cells.
How tumor suppressor p53 selectively responds to specific signals, especially in normal cells, is poorly understood. We performed genome-wide profiling of p53 chromatin interactions and target gene expression in human embryonic stem cells (hESCs) in response to early differentiation, induced by retinoic acid, versus DNA damage, caused by adriamycin. Most p53-binding sites are unique to each state and define stimulus-specific p53 responses in hESCs. Differentiation-activated p53 targets include many developmental transcription factors and, in pluripotent hESCs, are bound by OCT4 and NANOG at chromatin enriched in both H3K27me3 and H3K4me3. Activation of these genes occurs with recruitment of p53 and H3K27me3-specific demethylases, UTX and JMJD3, to chromatin. In contrast, genes associated with cell migration and motility are bound by p53 specifically after DNA damage. Surveillance functions of p53 in cell death and cell cycle regulation are conserved in both DNA damage and differentiation. Comparative genomic analysis of p53-targets in mouse and human ESCs supports an inter-species divergence in p53 regulatory functions during evolution. Our findings expand the registry of p53-regulated genes to define p53-regulated opposition to pluripotency during early differentiation, a process highly distinct from stress-induced p53 response in hESCs.


Molecular imaging using contrast-enhanced ultrasound: evaluation of angiogenesis and cell therapy.
The field of regenerative medicine and its applications for cardiovascular diseases continues to grow rapidly, fuelled by the increasing numbers of symptomatic patients who are not candidates for conventional revascularization procedures and remain refractory to maximal medical therapy. Therapeutic angiogenesis, initially in the form of the administration of growth factor protein or gene therapy and, more recently, in the form of adult progenitor cell therapy, has emerged as a promising new method of treatment for patients with ischaemic heart disease and peripheral arterial disease. There is a growing interest in non-invasive imaging techniques to evaluate the response to angiogenic gene-and cell-based therapies. Contrast-enhanced ultrasound (CEU) techniques using site-specific microbubbles have recently been developed for the molecular imaging of the vascular phenotype that characterizes angiogenesis. These methods have now been modified to allow the imaging of progenitor cell engraftment into neovessels. These molecular imaging techniques using contrast ultrasound and targeted microbubbles have the potential to further characterize the angiogenic response, aid in the optimization of gene- and cell-based strategies of therapeutic neovascularization, and ultimately serve to monitor the therapeutic effects in patients enrolled in clinical trials of regenerative therapies. This review will focus specifically on CEU molecular imaging techniques for the evaluation of angiogenesis and cell therapies in cardiovascular diseases, including: (i) an overview of the techniques and results of pre-clinical studies; (ii) a comparison of CEU molecular imaging techniques with other available molecular imaging modalities; and (iii) a discussion of the future role of CEU molecular imaging in the field of regenerative medicine.


Antileishmanial and cytotoxic effects of essential oil and methanolic extract of Myrtus communis L.
Plants used for traditional medicine contain a wide range of substances that can be used to treat various diseases such as infectious diseases. The present study was designed to evaluate the antileishmanial effects of the essential oil and methanolic extract of Myrtus communis against Leishmania tropica on an in vitro model. Antileishmanial effects of essential oil and methanolic extract of M. communis on promastigote forms and their cytotoxic activities against J774 cells were evaluated using MTT assay for 72 hr. In addition, their leishmanicidal activity against amastigote forms was determined in a macrophage model, for 72 hr. Findings showed that the main components of essential oil were α-pinene (24.7%), 1,8-cineole (19.6%), and linalool (12.6%). Findings demonstrated that M. communis, particularly its essential oil, significantly (P<0.05) inhibited the growth rate of promastigote and amastigote forms of L. tropica based on a dose-dependent response. The IC50 values for essential oil and methanolic extract was 8.4 and 28.9 μg/ml against promastigotes, respectively. These values were 11.6 and 40.8 μg/ml against amastigote forms, respectively. Glucantime as control drug also revealed IC50 values of 88.3 and 44.6 μg/ml for promastigotes and amastigotes of L. tropica, respectively. The in vitro assay demonstrated no significant cytotoxicity in J774 cells. However, essential oil indicated a more cytotoxic effect as compared with the methanolic extract of M. communis. The findings of the present study demonstrated that M. communis might be a natural source for production of a new leishmanicidal agent.


Sex-specific trans-regulatory variation on the Drosophila melanogaster X chromosome.
The X chromosome constitutes a unique genomic environment because it is present in one copy in males, but two copies in females. This simple fact has motivated several theoretical predictions with respect to how standing genetic variation on the X chromosome should differ from the autosomes. Unmasked expression of deleterious mutations in males and a lower census size are expected to reduce variation, while allelic variants with sexually antagonistic effects, and potentially those with a sex-specific effect, could accumulate on the X chromosome and contribute to increased genetic variation. In addition, incomplete dosage compensation of the X chromosome could potentially dampen the male-specific effects of random mutations, and promote the accumulation of X-linked alleles with sexually dimorphic phenotypic effects. Here we test both the amount and the type of genetic variation on the X chromosome within a population of Drosophila melanogaster, by comparing the proportion of X linked and autosomal trans-regulatory SNPs with a sexually concordant and discordant effect on gene expression. We find that the X chromosome is depleted for SNPs with a sexually concordant effect, but hosts comparatively more SNPs with a sexually discordant effect. Interestingly, the contrasting results for SNPs with sexually concordant and discordant effects are driven by SNPs with a larger influence on expression in females than expression in males. Furthermore, the distribution of these SNPs is shifted towards regions where dosage compensation is predicted to be less complete. These results suggest that intrinsic properties of dosage compensation influence either the accumulation of different types of trans-factors and/or their propensity to accumulate mutations. Our findings document a potential mechanistic basis for sex-specific genetic variation, and identify the X as a reservoir for sexually dimorphic phenotypic variation. These results have general implications for X chromosome evolution, as well as the genetic basis of sex-specific evolutionary change.


A high-resolution transcript profile across the wood-forming meristem of poplar identifies potential regulators of cambial stem cell identity.
Plant growth is the result of cell proliferation in meristems, which requires a careful balance between the formation of new tissue and the maintenance of a set of undifferentiated stem cells. Recent studies have provided important information on several genetic networks responsible for stem cell maintenance and regulation of cell differentiation in the apical meristems of shoots and roots. Nothing, however, is known about the regulatory networks in secondary meristems like the vascular cambium of trees. We have made use of the large size and highly regular layered organization of the cambial meristem to create a high-resolution transcriptional map covering 220 microm of the cambial region of aspen (Populus tremula). Clusters of differentially expressed genes revealed substantial differences in the transcriptomes of the six anatomically homogenous cell layers in the meristem zone. Based on transcriptional and anatomical data, we present a model for the position of the stem cells and the proliferating mother cells in the cambial zone. We also provide sets of marker genes for different stages of xylem and phloem differentiation and identify potential regulators of cambial meristem activity. Interestingly, analysis of known regulators of apical meristem development indicates substantial similarity in regulatory networks between primary and secondary meristems.


Trends and protective factors of female genital mutilation in Burkina Faso: 1999 to 2010.
The practice of Female Genital Mutilation (FGM) is common in several African countries and some parts of Asia. This practice is not only a violation of human rights, but also puts women at risk of adverse health outcomes. This paper analysed the trends in the prevalence of FGM in Burkina Faso and investigated factors that are associated with this practice following the enactment of an FGM law in 1996. The study used the Burkina Faso Demographic and Health Survey (DHS) data sets from women aged 15 to 49 years undertaken in 1999, 2003 and 2010. Chi square tests were carried out to investigate whether there has been a change in the levels of FGM in Burkina Faso between 1999 and 2010 and multilevel logistic regression analysis were employed to identify factors that were significantly associated with undergoing FGM. The levels of FGM in Burkina Faso declined significantly from 83.6% in 1999 to 76.1% in 2010. The percentage of women circumcised between the ages of 0 to 5 years increased from 34.2% in 1999 to 69% in 2010. Significantly more women in 2010 than in 1999 were of the opinion that FGM should stop (90.6% versus 75.1%, respectively). In 2010, the odds of getting circumcised were lowest amongst women that were born in the period 1990 to 1995 (immediately before the FGM law was enacted) compared to women born in the period 1960-1965 [OR 0.16 (0.13,0.20)]. There was significant variation of FGM across communities. Other factors that were significantly associated with being circumcised were education level, religion, ethnicity, urban residence and age at marriage. Although the prevalence of FGM has declined in Burkina Faso, the levels are still high. In order to tackle the practice of FGM in Burkina Faso, the government of Burkina Faso and its development partners need to encourage girls' participation in education and target its sensitization campaigns against FGM towards Muslim women, women residing in rural areas and women of Mossi ethnic background.


Neuroimaging studies of autobiographical event memory.
Commonalities and differences in findings across neuroimaging studies of autobiographical event memory are reviewed. In general terms, the overall pattern across studies is of medial and left-lateralized activations associated with retrieval of autobiographical event memories. It seems that the medial frontal cortex and left hippocampus in particular are responsive to such memories. However, there are also inconsistencies across studies, for example in the activation of the hippocampus and dorsolateral prefrontal cortex. It is likely that methodological differences between studies contribute to the disparate findings. Quantifying and assessing autobiographical event memories presents a challenge in many domains, including neuroimaging. Methodological factors that may be pertinent to the interpretation of the neuroimaging data and the design of future experiments are discussed. Consideration is also given to aspects of memory that functional neuroimaging might be uniquely disposed to examine. These include assessing the functionality of damaged tissue in patients and the estimation of inter-regional communication (effective connectivity) between relevant brain regions.


Bioorthogonally surface-edited extracellular vesicles based on metabolic glycoengineering for CD44-mediated targeting of inflammatory diseases.
Extracellular vesicles (EVs) are essential mediators in intercellular communication that have emerged as natural therapeutic nanomedicines for the treatment of intractable diseases. Their therapeutic applications, however, have been limited by unpredictable in vivo biodistribution after systemic administration. To control the in vivo fate of EVs, their surfaces should be properly edited, depending on the target site of action. Herein, based on bioorthogonal copper-free click chemistry (BCC), surface-edited EVs were prepared by using metabolically glycoengineered cells. First, the exogenous azide group was generated on the cellular surface through metabolic glycoengineering (MGE) using the precursor. Next, PEGylated hyaluronic acid, capable of binding specifically to the CD44-expressing cells, was labelled as the representative targeting moiety onto the cell surface by BCC. The surface-edited EVs effectively accumulated into the target tissues of the animal models with rheumatoid arthritis and tumour, primarily owing to prolonged circulation in the bloodstream and the active targeting mechanism. Overall, these results suggest that BCC combined with MGE is highly useful as a simple and safe approach for the surface modification of EVs to modulate their in vivo fate.


Vanishing racial disparities in drowning in Florida.
To examine the change in the racial disparity in drowning in Florida from 1970 to 2015 and to analyse the contextual factors associated with white, black and Hispanic drowning rates in Florida from 2007 to 2015. Our outcome variable is county-level annual drowning rates by race, ethnicity, sex and age group. We computed county-level contextual data, including emergency weather events, temperature, extreme weather, number of pools, quality of pools, coastline, swimming participation rates and prominent black competitive swim teams. Between 1970 and 1990, the disparity in drowning rates between white and black males in Florida decreased dramatically. By 2005, the overall age-adjusted drowning rates converged. This convergence was most striking for those aged 10-34 and 35-64. While the gap has declined dramatically, there remains a racial disparity in drownings among those aged 10-34. Overall, racial disparities in drowning have disappeared in Florida. However, some disparities remain. There is a persistent disparity in drownings among those aged 10-34.


Sleep spindles are related to schizotypal personality traits and thalamic glutamine/glutamate in healthy subjects.
Schizophrenia is a severe mental disorder affecting approximately 1% of the worldwide population. Yet, schizophrenia-like experiences (schizotypy) are very common in the healthy population, indicating a continuum between normal mental functioning and the psychosis found in schizophrenic patients. A continuum between schizotypy and schizophrenia would be supported if they share the same neurobiological origin. Two such neurobiological markers of schizophrenia are: (1) a reduction of sleep spindles (12-15 Hz oscillations during nonrapid eye movement sleep), likely reflecting deficits in thalamo-cortical circuits and (2) increased glutamine and glutamate (Glx) levels in the thalamus. Thus, this study aimed to investigate whether sleep spindles and Glx levels are related to schizotypal personality traits in healthy subjects. Twenty young male subjects underwent 2 all-night sleep electroencephalography recordings (128 electrodes). Sleep spindles were detected automatically. After those 2 nights, thalamic Glx levels were measured by magnetic resonance spectroscopy. Subjects completed a magical ideation scale to assess schizotypy. Sleep spindle density was negatively correlated with magical ideation (r = -.64, P < .01) and thalamic Glx levels (r = -.70, P < .005). No correlation was found between Glx levels in the thalamus and magical ideation (r = .12, P > .1). The common relationship of sleep spindle density with schizotypy and thalamic Glx levels indicates a neurobiological overlap between nonclinical schizotypy and schizophrenia. Thus, sleep spindle density and magical ideation may reflect the anatomy and efficiency of the thalamo-cortical system that shows pronounced impairment in patients with schizophrenia.


The dynamics of decision making in risky choice: an eye-tracking analysis.
In the last years, research on risky choice has moved beyond analyzing choices only. Models have been suggested that aim to describe the underlying cognitive processes and some studies have tested process predictions of these models. Prominent approaches are evidence accumulation models such as decision field theory (DFT), simple serial heuristic models such as the adaptive toolbox, and connectionist approaches such as the parallel constraint satisfaction (PCS) model. In two studies involving measures of attention and pupil dilation, we investigate hypotheses derived from these models in choices between two gambles with two outcomes each. We show that attention to an outcome of a gamble increases with its probability and its value and that attention shifts toward the subsequently favored gamble after about two thirds of the decision process, indicating a gaze-cascade effect. Information search occurs mostly within-gambles, and the direction of search does not change over the course of decision making. Pupil dilation, which reflects both cognitive effort and arousal, increases during the decision process and increases with mean expected value. Overall, the results support aspects of automatic integration models for risky choice such as DFT and PCS, but in their current specification none of them can account for the full pattern of results.


Osteolysis of the tibial plateau after meniscal repair with hybrid suture anchor.
Preservation of the meniscus and consideration for repair is important when treating meniscal tears. Many techniques for repair have been described. At present, all-inside, suture anchor-based meniscal repair systems are widely used. Arthroscopic all-inside hybrid meniscal suturing has been shown to have a low complication rate as the suture anchors remain outside the capsule leaving only the suture material inside the joint. Complications such as chondrolysis or arthrolysis have not been reported with these devices until now. The purpose of our study is to highlight the risks of osteochondral damage if these devices persist intra-articularly. IV.


Death of retinal neurons in streptozotocin-induced diabetic mice.
Neuronal cell death has been reported in retinas of humans with diabetic retinopathy and in diabetic rat models. Little is known about neuronal cell death in mouse models of diabetic retinopathy. This study was designed to determine whether neurons are lost in diabetic mouse retinas and whether the loss involves an apoptotic process. Three-week-old C57Bl/6 mice were made diabetic with streptozotocin. They were studied over the course of 14 weeks after onset of diabetes. Eyes were processed for morphometric analysis and detection of apoptotic cells by TUNEL analysis and activated caspase-3 and were subjected to electron microscopy. Morphometric analysis of retinal cross sections of mice that had been diabetic 14 weeks showed approximately 20% to 25% fewer cells in the ganglion cell layer compared with age-matched control mice. There was a modest, but significant, decrease in the thickness of the whole retina and the inner and outer nuclear layers in mice that had been diabetic for 10 weeks. TUNEL analysis and detection of active caspase-3 revealed that cells of the ganglion cell layer were dying by apoptosis. Electron microscopic analysis detected morphologic features characteristic of apoptosis, including margination of chromatin and crenated nuclei of cells in the ganglion cell layer. The data suggest that in diabetic mouse retinas, neurons in the ganglion cell layer die, and this death occurs through an apoptotic pathway. Diabetic mice may be appropriate and valuable models for studies of neuronal cell death in diabetes.