[An epidemiological study of head injury in Hualien County, Taiwan].
An epidemiological study of head injuries in Hualien County, Taiwan, was undertaken from July 1, 1987 to June 30, 1988. Clinical records, including emergency room (ER) charts, inpatient charts from the four major hospitals and coroner or medical examiner reports in this county, were reviewed. A formulated definition was used in identifying patients with head injury. A total of 1,183 cases were identified. They included 975 hospital inpatients and 208 nonhospital deaths. The age-adjusted incidence rate for head injuries was 333/100,000 for all, 450/100,000 for males and 194/100,000 for females, with a male-to-female ratio of 2.32. The cumulative incidence rate from 0 to 69 years of age was 27.6% for males and 13.7% for females. The highest incidence rate was observed in the elderly group, whereas in other published reports the highest occurrence has been noted in the young adult group. An extraordinary 82% of the head injuries were associated with traffic accidents, 71% of which directly involved motorcycle riders. The age-adjusted mortality rate was 89/100,000 per year, 127/100,000 for males and 44/100,000 for females. The cumulative mortality rate was 8.7% for males and 3.2% for females. These are the highest rates ever reported. Sixty percent of the 1,183 patients had a moderate to severe injury or were dead. In the remaining 40%, the injury was considered mild. The elderly group presented with the highest percentage of moderate to severe degrees of injury, as well as mortality. Among traffic accident victims, those from motorcycle accidents and pedestrians had the highest percentage of severe head injuries.(ABSTRACT TRUNCATED AT 250 WORDS)


Assessing the effect of public health information by incentivised risk estimation: An example on Swedish snus.
The provision of accurate information on health damaging behaviours and products is a widely accepted and widespread governmental task. It is easily mismanaged. This study demonstrates a simple method which can help to evaluate whether such information corrects recipient risk beliefs. Participants assess risks numerically, before and after being exposed to a relevant risk communication. Accuracy is incentivised by awarding financial prizes to answers closest to a pursued risk belief. To illustrate this method, 228 students from the University of Oslo, Norway, were asked to estimate the mortality risk of Swedish snus and cigarettes twice, before and after being exposed to one of three risk communications with information on the health dangers of snus. The data allow us to measure how participants updated their risk beliefs after being exposed to different risk communications. Risk information from the government strongly distorted risk perceptions for snus. A newspaper article discussing the relative risks of cigarettes and snus reduced belief errors regarding snus risks, but increased belief errors regarding smoking. The perceived quality of the risk communication was not associated with decreased belief errors. Public health information can potentially make the public less informed on risks about harmful products or behaviours. This risk can be reduced by targeting identified, measurable belief errors and empirically assessing how alternative communications affect these. The proposed method of incentivised risk estimation might be helpful in future assessments of risk communications.


Statins and their potential targets in multiple sclerosis therapy.
Multiple sclerosis (MS) is a CNS-demyelinating disease characterised by relapsing and chronic neurological impairment. While traditionally CNS autoantigen-specific CD4(+) T cells have been considered the culprits in the initial phase of the disease, recent observations have altered this concept. It is now recognised that other T lymphocyte subclasses can initiate CNS demyelination. In addition, other cell types and molecules may play an important role in MS pathogenesis. There is overwhelming evidence that MS is a dynamic process, in which recurrent episodes of blood-brain barrier disruption and CNS inflammation play a crucial role in early disease stages, leading eventually to the largely irreversible changes of demyelination, gliosis and axonal degeneration. These observations may have important therapeutic implications. Within the last ten years, several medications have been approved for MS treatment. These agents, all of which are given parenterally, are only partially effective and are often associated with adverse effects and potential toxicities. The number and different types of medications used for MS are likely to increase in the near future, as several novel therapies are currently tested in clinical trials. 3-hydroxy-3-methyglutaryl coenzyme A reductase inhibitors, 'statins', are cholesterol-lowering drugs that are given orally, are safe and have biological effects independent of their cholesterol-reducing properties. Recent reports have shown that statins have anti-inflammatory and neuroprotective properties that may be beneficial in the treatment of MS. This article will outline experimental evidence that suggests potential clinical benefits of statins for MS patients.


PPARγ suppression inhibits adipogenesis but does not promote osteogenesis of human mesenchymal stem cells.
Mesenchymal stem cells (MSCs) are the common progenitors of osteoblasts and adipocytes. A reciprocal relationship exists between osteogenesis and adipogenesis in the bone marrow, and the identification of signaling pathways that stimulate MSC osteogenesis at the expense of adipogenesis is of great importance from the viewpoint of developing new therapeutic treatments for bone loss. The adipogenic transcription factor peroxisome proliferator-activated receptor γ (PPARγ) has been reported to play a vital role in modulating mesenchymal lineage allocation within the bone marrow compartment, stimulating adipocyte development at the expense of osteoblast differentiation. Hence, PPARγ may be a valuable target for drugs intended to enhance bone mass. However, little direct evidence is available for the role played by PPARγ in human mesenchymal lineage allocation. In this study, using human MSCs as an in vitro model, we showed that the two isoforms of PPARγ, PPARγ1 and PPARγ2, were differentially induced during hMSC adipogenesis, whereas only PPARγ1 was detected during osteogenesis. BADGE and GW9662, two potential antagonists of PPARγ, as well as lentivirus-mediated knockdown of PPARγ, inhibited hMSC adipogenesis but did not significantly affect osteogenesis. PPARγ knockdown did not significantly influence the expression level of the osteogenic transcription factor Runx2. Together, these results suggest that PPARγ is not the master factor regulating mesenchymal lineage determination in human bone marrow.


Impact of the rpoS genotype for acid resistance patterns of pathogenic and probiotic Escherichia coli.
Enterohemorrhagic E. coli (EHEC), a subgroup of Shiga toxin (Stx) producing E. coli (STEC), may cause severe enteritis and hemolytic uremic syndrome (HUS) and is transmitted orally via contaminated foods or from person to person. The infectious dose is known to be very low, which requires most of the bacteria to survive the gastric acid barrier. Acid resistance therefore is an important mechanism of EHEC virulence. It should also be a relevant characteristic of E. coli strains used for therapeutic purposes such as the probiotic E. coli Nissle 1917 (EcN). In E. coli and related enteric bacteria it has been extensively demonstrated, that the alternative sigma factor sigmaS, encoded by the rpoS gene, acts as a master regulator mediating resistance to various environmental stress factors. Using rpoS deletion mutants of a highly virulent EHEC O26:H11 patient isolate and the sequenced prototype EHEC EDL933 (ATCC 700927) of serotype O157:H7 we investigated the impact of a functional rpoS gene for orchestrating a satisfactory response to acid stress in these strains. We then functionally characterized rpoS of probiotic EcN and five rpoS genes selected from STEC isolates pre-investigated for acid resistance. First, we found out that ATCC isolate 700927 of EHEC EDL933 has a point mutation in rpoS, not present in the published sequence, leading to a premature stop codon. Moreover, to our surprise, one STEC strain as well as EcN was acid sensitive in our test environment, although their cloned rpoS genes could effectively complement acid sensitivity of an rpoS deletion mutant. The attenuation of sequenced EHEC EDL933 might be of importance for anyone planning to do either in vitro or in vivo studies with this prototype strain. Furthermore our data supports recently published observations, that individual E. coli isolates are able to significantly modulate their acid resistance phenotype independent of their rpoS genotype.


A meta-analysis of the risk for psychotic disorders among first- and second-generation immigrants.
There is increasing acceptance of migration as a risk factor for schizophrenia and related disorders; however, the magnitude of the risk among second-generation immigrants (SGIs) remains unclear. Generational differences in the incidence of psychotic disorders among migrants might improve our understanding of the relationship between migration, ethnicity and psychotic disorders. This meta-analysis aimed at determining the risk of psychotic disorders among SGIs in comparison with non-migrants and first-generation immigrants (FGIs). Medline, EMBASE and PsycINFO databases were searched systematically for population-based studies on migration and psychotic disorders published between 1977 and 2008. We also contacted experts, tracked citations and screened bibliographies. All potential publications were screened by two independent reviewers in a threefold process. Studies were included in the meta-analysis if they reported incidence data, differentiated FGIs from SGIs and provided age-adjusted data. Data extraction and quality assessment were conducted for each study. Twenty-one studies met all inclusion criteria. A meta-analysis of 61 effect sizes for FGIs and 28 for SGIs yielded mean-weighted incidence rate ratios (IRRs) of 2.3 [95% confidence interval (CI) 2.0-2.7] for FGIs and 2.1 (95% CI 1.8-2.5) for SGIs. There was no significant risk difference between generations, but there were significant differences according to ethno-racial status and host country. The increased risk of schizophrenia and related disorders among immigrants clearly persists into the second generation, suggesting that post-migration factors play a more important role than pre-migration factors or migration per se. The observed variability suggests that the risk is mediated by the social context.


Secondary rectal linitis plastica as first manifestation of urinary bladder carcinoma.
Secondary rectal linitis plastica is a very rare malignancy with poor prognosis. Diagnosis is difficult because of nonspecific clinical and endoscopic findings and negative biopsies in most cases owing to the fact that the mucosa is frequently unaffected. We herein describe a 68-year-old man who presented with a six-month history of tenesmus and constipation. Endoscopy revealed a narrow distal rectum with an indurated, cobblestone appearance of mucosa. Multiple biopsies and fine-needle aspiration were negative for malignancy. Abdominal MRI and transrectal ultrasonography showed findings compatible with rectal linitis plastica. He underwent rectal extirpation with total cystectomy and lymph nodes dissection. Histology demonstrated secondary rectal linitis plastica due to a poorly differentiated urinary bladder carcinoma. We emphasize the endoscopic and endosonographic features and the difficulty to establish a preoperative diagnosis of secondary rectal linitis plastica.


Pre- and postnatal nutrition in sheep affects β-cell secretion and hypothalamic control.
Maternal undernutrition increases the risk of type 2 diabetes and metabolic syndrome later in life, particularly upon postnatal exposure to a high-energy diet. However, dysfunctions of, for example, the glucose-insulin axis are not readily detectable by conventional tests early in life, making it difficult to identify individuals at risk. Thus, other methods are required. We hypothesised that prenatally undernourished individuals (but not postnatally overnourished ones) are adapted to a life with limited food availability, which would be evident under conditions reflecting starvation, stress and short-term abundance of food. In this study, twin-pregnant sheep were fed diets meeting 100% (NORM) or 50% (LOW) of energy and protein requirements during the last trimester. Twin offspring were fed either a normal moderate (CONV) diet or a high-carbohydrate-high-fat (HCHF) diet from 3 days to 6 months of age (approximately puberty) and the same moderate diet thereafter until 2 years of age (young adulthood; only females), resulting in four groups: NORM-CONV, LOW-CONV, NORM-HCHF and LOW-HCHF. At the age of 6 months and 2 years respectively, they were subjected to fasting and propionate (nutrient abundance) and adrenalin challenges. At 6 months of age, postnatal HCHF diet exposure caused metabolic alterations, reflecting hypertriglyceridaemia and altered pancreatic β-cell secretion. Irrespective of postnatal diet, prenatal undernutrition was found to be associated with unexpected endocrine responses of leptin, IGF1 and cortisol during fasting (lack of or the opposite response compared with the controls) in 2-year-old adults. In conclusion, a HCHF diet interfered with β-cell function, whereas maternal undernutrition did not lead to any changes in the LOW offspring, except to abnormal hormone responses, suggesting that fetal programming interferes with hypothalamic integration of important endocrine axis.


Radial growth rate increases in naturally occurring ponderosa pine trees: a late-20th century CO2 fertilization effect?
The primary objective of this study was to determine if gradually increasing levels of atmospheric CO2, as opposed to 'step' increases commonly employed in controlled studies, have a positive impact on radial growth rates of ponderosa pine (Pinus ponderosa) in natural environments, and to determine the spatial extent and variability of this growth enhancement. We developed a series of tree-ring chronologies from minimally disturbed sites across a spectrum of environmental conditions. A series of difference of means tests were used to compare radial growth post-1950, when the impacts of rising atmospheric CO2 are best expressed, with that pre-1950. Spearman's correlation was used to relate site stress to growth-rate changes. Significant increases in radial growth rates occurred post-1950, especially during drought years, with the greatest increases generally found at the most water-limited sites. Site harshness is positively related to enhanced radial growth rates. Atmospheric CO2 fertilization is probably operative, having a positive effect on radial growth rates of ponderosa pine through increasing water-use efficiency. A CO2-driven growth enhancement may affect ponderosa pine growing under both natural and controlled conditions.


Low-noise, tunable diode laser for ultra-high-resolution spectroscopy.
We demonstrate the excellent spectral properties of a diode laser setup that combines good tunability with superb short-term frequency stability and controllability. It is based on merging two concepts, the diode laser with resonant optical feedback and the grating stabilized diode laser. To characterize the short-term performance we beat two essentially identical diode lasers and find a short-term linewidth of ~11 kHz. Phase locking between these lasers is achieved with a servo bandwidth as small as 46 kHz, although an analog phase detector is used that requires subradian residual phase error. Despite small phase error detection range and small servo bandwidth, cycle-slip-free phase locking is accomplished for typically many 10 min, and the optical power is essentially contained in a spectral window of less than 20 mHz relative to the optical reference. Due to the excellent performance this laser concept is well suited for atomic or molecular coherence experiments, which require phase locking of different lasers to each other, and as part of a flywheel for optical clocks.


Measuring and mapping the effectiveness of the European Air Quality Directive in reducing N and S deposition at the ecosystem level.
To protect human health and the environment (namely ecosystems), international air quality protocols and guidelines, like the Gothenburg protocol (1999) and the 2001 EU Air Quality Directive (NECD), conveyed national emission ceilings for atmospheric pollutants (Directive 2001/81/EC), including the reduction of sulfur (S) and nitrogen (N) emissions by 2010. However, to what degree this expected reduction in emissions had reflections at the ecosystem level (i.e. pollutant levels reaching and impacting ecosystems and their organisms) remains unknown. Here, we used lichens as ecological indicators, together with reported air and precipitation pollutant concentrations, to determine and map the consequences of the S and N atmospheric emission's reduction, during the implementation of the 2001 Directive (in 2002 and 2011), due primarily to the industrial-sector. The study area is a mixed-land-use industrialized Mediterranean agroforest ecosystem, in southwest Europe. The reduction of S emissions (2002-2011) was reflected at the ecosystem level, as the same S-declining trend was observed in atmospheric measurement stations and lichens alike (-70%), indicating that most S deposited to the ecosystem had an industrial origin. However, this was not the case for N with a slight N-reduction near industrial facilities, but mostly N-deposition in lichens increased in areas dominated by agricultural land-uses. Taken together, these results highlight the importance of going beyond emissions estimation and modeling, to assess the success of the implementation of the NECD in lowering pollutant accumulation in living organisms and their environment. This can only be achieved by measuring pollutant deposition at the ecosystem level (e.g. living organisms). By doing so, we were able to show that the 2001 NECD was successful in reducing S concentrations from Industry, whereas N remains a challenge. Despite the small reduction in N-emissions, deposition into ecosystems did not reflect these changes as agriculture and transport sectors must reduce NH3 and NOx emissions.


Spondylolisthesis with spondylolysis in a 17-month-old: a case report.
Spondylolysis is frequently seen in adolescents, typically at the L5 vertebral level. While there may be a congenital predisposition for spondylolysis, it has long been suggested that the defect results from a fatigue or stress fracture of the pars interarticularis. Spondylolisthesis may result from a bilateral spondylolytic defect and is frequently asymptomatic. There is a paucity of literature on infant and toddler spondylolysis, as the focus is primarily on school-aged children, typically those over ten years of age. This case report presents an incidentally discovered L5 spondylolysis with spondylolisthesis in a 17-month-old female. The patient presented to the emergency department with multiple facial abrasions and bruises from reportedly being struck by her 4-year-old sister. Her past medical history included a hospitalization four months prior for a distal radius buckle fracture from a thirty foot fall from a window. A routine non-accidental trauma work-up was performed, including a skeletal survey which demonstrated L5 bilateral pars defect with Myerding grade 2 spondylolisthesis. An MRI of the lumbar spine was performed, again demonstrating the L5 bilateral pars defect with position dependent reduction of the spondylolisthesis. The patient was seen back in the orthopedic office three months later which is her latest follow-up. Dynamic plain films of the lumbar spine were unchanged from previous imaging, without evidence of instability or slip progression. Further progression of her slip should warrant consideration for further treatment, whether it be cast immobilization or surgery.


Randomized controlled trial comparing hand-assisted retroperitoneoscopic versus standard laparoscopic donor nephrectomy.
Laparoscopic donor nephrectomy (LDN) has become the gold standard for live-donor nephrectomy, as it results in a short convalescence time and increased quality of life. However, intraoperative safety has been debated, as severe complications occur incidentally. Hand-assisted retroperitoneoscopic donor nephrectomy (HARP) is an alternative approach, combining the safety of hand-guided surgery with the benefits of endoscopic techniques and retroperitoneal access. We assessed the best approach to optimize donors' quality of life and safety. In two tertiary referral centers, donors undergoing left-sided nephrectomy were randomly assigned to HARP or LDN. Primary endpoint was physical function, one of the dimensions of the Short Form-36 questionnaire on quality of life, at 1 month postoperatively. Secondary endpoints included intraoperative events and operation times. Follow-up was 1 year. In total, 190 donors were randomized. Physical function at 1 month follow-up did not significantly differ between groups (estimated difference, 1.79; 95% confidence interval, -4.1 to 7.68; P=0.55). HARP resulted in significantly shorter skin-to-skin time (mean, 159 vs. 188 min; P<0.001), shorter warm ischemia time (2 vs. 5 min; P<0.001) and a lower intraoperative event rate (5% vs. 11%, P=0.117). Length of stay (both 3 days; P=0.135) and postoperative complication rate (8% vs. 8%; P=1.00) were not significantly different. Potential graft-related complications did not significantly differ (6% vs. 13%; P=0.137). Compared with LDN, left-sided HARP leads to similar quality of life, shorter operating time, and warm ischemia time. Therefore, we recommend HARP as a valuable alternative to the laparoscopic approach for left-sided donor nephrectomy.


Process development for the elucidation of mycotoxin formation in Alternaria alternata.
The black mould Alternaria alternata produces a wide diversity of mycotoxins which are of particular health concern. Since no maximum allowable limits are set for Alternaria toxins in food and feed, prevention of Alternaria infestations and mycotoxin spoilage is the only way to avoid health risks. Thus, the understanding of mycotoxin biosynthesis is essential. For that purpose, a reliable batch process in a 2 L bioreactor was established which enables the study of several parameters influencing the production of the mycotoxins alternariol (AOH), alternariol monomethylether (AME) and tenuazonic acid (TA) by A. alternata DSM 12633. Modified Czapek-Dox medium was used with glucose as carbon source and ammonium and nitrate as nitrogen sources. Consumption of carbon and nitrogen sources as well as formation of the three mycotoxins were monitored; the average data of five independent fermentations was plotted and fitted using a logistic equation with four parameters. Maximum mycotoxin concentrations of 3.49 ± 0.12 mg/L AOH, 1.62 ± 0.14 mg/L AME and 38.28 ± 0.1 mg/L TA were obtained.In this system the effect of different aeration rates (0.53 vvm-0.013 vvm) was tested which exerted a great influence on mycotoxin production. The use of the semi-synthetic Czapek-Dox medium allowed the exchange of carbon and nitrogen sources for acetate and aspartic acid. The use of acetate instead of glucose resulted in the sole production of alternariol whereas the exchange of ammonium and nitrate for aspartate enhanced the production of both AOH and AME while TA production was not affected.


Hypothalamic thyroid hormone catabolism acts as a gatekeeper for the seasonal control of body weight and reproduction.
Seasonal adaptations in physiology exhibited by many animals involve an interface between biological timing and specific neuroendocrine systems, but the molecular basis of this interface is unknown. In this study of Siberian hamsters, we show that the availability of thyroid hormone within the hypothalamus is a key determinant of seasonal transitions. The expression of the gene encoding type III deiodinase (Dio3) and Dio3 activity in vivo (catabolism of T(4) and T(3)) is dynamically and temporally regulated by photoperiod, consistent with the loss of hypothalamic T(3) concentrations under short photoperiods. Chronic replacement of T(3) in the hypothalamus of male hamsters exposed to short photoperiods, thus bypassing synthetic or catabolic deiodinase enzymes located in cells of the ependyma of the third ventricle, prevented the onset of short-day physiology: hamsters maintained a long-day body weight phenotype and failed to undergo testicular and epididymal regression. However, pelage moult to a winter coat was not affected. Type II deiodinase gene expression was not regulated by photoperiod in these hamsters. Collectively, these data point to a pivotal role for hypothalamic DIO3 and T(3) catabolism in seasonal cycles of body weight and reproduction in mammals.


Safety and efficacy of a multi-electrode renal sympathetic denervation system in resistant hypertension: the EnligHTN I trial.
Catheter-based renal artery sympathetic denervation has emerged as a novel therapy for treatment of patients with drug-resistant hypertension. Initial studies were performed using a single electrode radiofrequency catheter, but recent advances in catheter design have allowed the development of multi-electrode systems that can deliver lesions with a pre-determined pattern. This study was designed to evaluate the safety and efficacy of the EnligHTN(™) multi-electrode system. We conducted the first-in-human, prospective, multi-centre, non-randomized study in 46 patients (67% male, mean age 60 years, and mean baseline office blood pressure 176/96 mmHg) with drug-resistant hypertension. The primary efficacy objective was change in office blood pressure from baseline to 6 months. Safety measures included all adverse events with a focus on the renal artery and other vascular complications and changes in renal function. Renal artery denervation, using the EnligHTN system significantly reduced the office blood pressure from baseline to 1, 3, and 6 months by -28/10, -27/10 and -26/10 mmHg, respectively (P < 0.0001). No acute renal artery injury or other serious vascular complications occurred. Small, non-clinically relevant, changes in average estimated glomerular filtration rate were reported from baseline (87 ± 19 mL/min/1.73 m2) to 6 months post-procedure (82 ± 20 mL/min/1.73 m2). Renal sympathetic denervation, using the EnligHTN multi-electrode catheter results in a rapid and significant office blood pressure reduction that was sustained through 6 months. The EnligHTN system delivers a promising therapy for the treatment of drug-resistant hypertension.


Rating general practitioner consultation performance in cancer care: does the specialty of assessors matter? A simulated patient study.
Patients treated for prostate cancer may present to general practitioners (GPs) for treatment follow up, but may be reticent to have their consultations recorded. Therefore the use of simulated patients allows practitioner consultations to be rated. The aim of this study was to determine whether the speciality of the assessor has an impact on how GP consultation performance is rated. Six pairs of scenarios were developed for professional actors in two series of consultations by GPs. The scenarios included: chronic radiation proctitis, Prostate Specific Antigen (PSA) 'bounce', recurrence of cancer, urethral stricture, erectile dysfunction and depression or anxiety. Participating GPs were furnished with the patient's past medical history, current medication, prostate cancer details and treatment, details of physical examinations. Consultations were video recorded and assessed for quality by two sets of assessors- a team of two GPs and two Radiation Oncologists deploying the Leicester Assessment Package (LAP). LAP scores by the GPs and Radiation Oncologists were compared. Eight GPs participated. In Series 1 the range of LAP scores by GP assessors was 61%-80%, and 67%-86% for Radiation Oncologist assessors. The range for GP LAP scores in Series 2 was 51%- 82%, and 56%-89% for Radiation Oncologist assessors. Within GP assessor correlations for LAP scores were 0.31 and 0.87 in Series 1 and 2 respectively. Within Radiation Oncologist assessor correlations were 0.50 and 0.72 in Series 1 and 2 respectively. Radiation Oncologist and GP assessor scores were significantly different for 4 doctors and for some scenarios. Anticipatory care was the only domain where GPs scored participants higher than Radiation Oncologist assessors. The assessment of GP consultation performance is not consistent across assessors from different disciplines even when they deploy the same assessment tool.


Cortical auditory evoked potentials and hemispheric specialization of speech in individuals with learning disability and healthy controls: A preliminary study.
Background: Dichotic listening (DL) technique is a behavioral non-invasive tool which is used in studying hemispheric lateralization. Previous studies using behavioral DL have hypothesized that individuals with learning disabilities (LD) exhibit a lack of cortical specialization for processing speech stimulus. However, there is no event related potential (ERP) evidence, hence the main objective of the study is to explore hemispheric asymmetry using cortical auditory evoked potential (CAEPs) in normal hearing adults and also to compare the same in children with LD and healthy controls. Methods: CAEPs were recorded in 16 normal hearing young adults, eight right-handed children with LD and their age matched controls. Two stop constants (/Pa/ - voiceless, bilabial, stop: /Ta/ - voiceless, alveolar, stop) were chosen for this experiment and presented in each ear and dichotically in two different orders (/pa-ta/, /ta-pa/). ERPs were processed using a standard pipeline, and electrodes readings over the left and right hemispheres were averaged to create left and right regions of interest (ROI). The CAEPs were analyzed for mean amplitude and peak latency of P1-N1-P2 components. Results: The current study results suggest no statistically significant difference between the two stimulus in monaural condition and absence of order effect in dichotic condition. In healthy controls the CAEP latencies were shorter over the left hemisphere in both monaural and dichotic conditions in adults and control children. However, it was very evident that such a difference was lacking in children with LD. Conclusions: Hemispheric asymmetry can be detected using CAEPs for speech stimulus. The measures are consistent and void of stimulus or order effect. Taken together, the findings of current study, both monaural and dichotic condition illustrates the hemispheric differences in processing speech stimuli in normal hearers. Absence of latency differences between hemispheres in children with LD indicate a lack of hemispheric asymmetry.


Empowerment in critical care - a concept analysis.
The purpose of this paper was to analyse how the concept of empowerment is defined in the scientific literature in relation to critical care. As empowerment is a mutual process affecting all individuals involved, the perspectives of not only patients and next of kin but also staff were sought. A literature review and a concept analysis based on Walker and Avant's analysis procedure were used to identify the basic elements of empowerment in critical care. Twenty-two articles with a focus on critical care were discovered and included in the investigation. A mutual and supportive relationship, knowledge, skills, power within oneself and self-determination were found to be the common attributes of empowerment in critical care. The results could be adapted and used for all parties involved in critical care - whether patients, next of kin or staff - as these defining attributes are assumed to be universal to all three groups, even if the more specific content of each attribute varies between groups and individuals. Even if empowerment is only sparsely used in relation to critical care, it appears to be a very useful concept in this context. The benefits of improving empowerment are extensive: decreased levels of distress and strain, increased sense of coherence and control over situation, and personal and/or professional development and growth, together with increased comfort and inner satisfaction.


EDD inhibits ATM-mediated phosphorylation of p53.
The EDD (E3 identified by differential display) gene, first identified as a progestin-induced gene in T-47D breast cancer cells, encodes an E3 ubiquitin ligase with a HECT domain. It was reported that EDD is involved in the G(2)/M progression through ubiquitination of phospho-katanin p60. Previous study has also shown that EDD can act as a transcription cofactor independently of its E3 ligase activity. In this study, we uncover a new role for EDD during cell cycle progression in an E3 ligase-independent manner. We demonstrate that EDD can physically interact with p53 and that this interaction blocks the phosphorylation of p53 by ataxia telangiectasia mutated (ATM). Silencing of EDD induces phosphorylation of p53 at Ser(15) and activates p53 target genes in fibroblasts and some transformed cells without activation of DNA damage response. The G(1)/S arrest induced by EDD depletion depends on p53. On the other hand, overexpression of EDD inhibits p53-Ser(15) phosphorylation and suppresses the induction of p53 target genes during DNA damage, and this effect does not require its E3 ligase activity. Thus, through binding to p53, EDD actively inhibits p53 phosphorylation by ATM and plays a role in ensuring smooth G(1)/S progression.


Mosquitocidal and repellent activity of the leaf extract of Citrullus vulgaris (cucurbitaceae) against the malarial vector, Anopheles stephensi liston (diptera culicidae).
The efficacy of the Cucurbitaceous plant Citrullus vulgaris against the Anopheles stephensi was assessed in the present study. The leaf extract of Citrullus vulgaris with different solvents viz, benzene, petroleum ether, ethyl acetate and methanol were tested for larvicidial, ovicidal, repellent and insect growth regulatory activities against Anopheles stephensi. The larval mortality was observed after 24 h exposure. The LC50 values are 18.56, 48.51, 49.57 and 50.32 ppm respectively. The mean percent hatchability of the egg of Anopheles stephensi were observed after 48 h. 100 per cent mortality was exerted at 250 ppm with benzene extract and the other extracts exerted 100 percent mortality at 300 ppm. Skin repellent test at 1.0, 2.5 and 5.0 mg per cm2 concentration gave the mean complete protection time ranged from 119.17 to 387.83 minutes with the four different extracts tested. The Citrullus vulgaris plant extract have shown insect growth regulatory activity against Anopheles stephensi at five different test concentrations ranging from 10 to 150 ppm with different solvents and they exhibit the following EI50 values 28.99, 70.02, 106.33 and 84.25 ppm respectively.


Survey of the Routine Practice Limits for Physiologic and Technical Parameters Managed by Clinical Perfusionists during Adult Cardiopulmonary Bypass.
Cardiopulmonary bypass (CPB) is a highly technical clinical discipline with a recognized variability in practice. Professional standards and guidelines documents help direct clinical practice and reduce variability, but these guidelines are necessarily vague and fall short of providing specific objective recommendations of clinical practice metrics. If clinical practice metrics were known, they would be informative when writing departmental policy manuals, structuring quality improvement initiatives, describing product R&D specifications, and designing educational assessment rubrics. Therefore, to address this gap, we conducted a national survey of clinical practice with the purpose of producing a benchmark of the typical variability of specific technical parameters that are commonly managed during adult CPB procedures. A pool of expert clinical perfusionists collaborated to compile a data set of normal ranges for 41 individual physiologic and technical parameters (pressures, flows, saturation, times, solutions, and temperatures) that are commonly managed during adult CPB procedures. Results were collected using an online survey application. Respondent demographics and measures of central tendency with descriptive quartile statistics and confidence intervals for each parameter are presented. Of the 335 people who participated in the survey, 315 met the inclusion criteria. The geographic demographics of the respondents were representative of the American Board of Cardiovascular Perfusion's distribution of certified clinical perfusionists. Of the 41 parameters investigated, there were 13 hemodynamic parameters, 13 normal flow rates and technical circuit parameters, 10 blood gasses and hematocrit parameters, and five parameters of patient temperatures. The data presented here are informative and provide a consensus-based objective assessment of the standard practice for adult CPB as reported by practicing clinical perfusionists. Based on these survey data, we have identified the typical clinical limits for the 41 parameters that are managed during adult CPB. This information may be incorporated into guiding documents to support the work of clinicians, researchers, and educators.


Severe thrombocytopenia in hantavirus-induced nephropathia epidemica.
Nephropathia epidemica is a milder form of hemorrhagic fever with renal syndrome, caused by Puumala virus. The clinical picture is characterized by a rapid loss of renal function (acute kidney injury) and thrombocytopenia. The purpose of the current analysis was to compare the clinical course of patients presenting with or without severe thrombocytopenia. In 47 out of 456 patients with acute nephropathia epidemica, the nadir count of thrombocytes was available for the acute course of the disease. The clinical course of these patients was further analyzed. No major bleeding (e.g., intracranial bleeding or gastrointestinal bleeding) occurred in either group. Creatinine peak levels were higher and proteinuria was more frequently present in the severely thrombocytopenic group. In conclusion, severe thrombocytopenia is common in nephropathia epidemica and is associated with a more severe course of the disease; however, bleeding complications are rare.


Release of somatostatin-like immunoreactivity from the perfused canine thyroid. Selective stimulatory effect of calcium ions.
It is well accepted that the C cells of the thyroid contain somatostatin, but the role in local endocrine function has not yet been firmly established in this organ, and it has not been proved that thyroidal somatostatin is released into the circulation. We have measured the contents of somatostatin-like immunoreactivity in the effluent of canine thyroid glands perfused without recirculation with a synthetic buffer medium. During basal conditions a definite release was consistently found in the order of 10 pg/ml corresponding to 12 pg/min. The somatostatin-like immunoreactivity was studied in dilution experiments and by gel-filtration chromatography, and found to have properties identical to those of synthetic cyclic somatostatin, which was also recovered quantitatively when added to sampling tubes. Various compounds were infused in concentrations that are highly active in pancreas perfusion experiments. 14-min infusion of arginine, 5 and 11.5 mmol/liter; isoproterenol, 10 and 23.7 nmol/liter and 68.7 mumol/liter; acetylcholine, 5 mumol/liter, carbamylcholine, 10 and 100 mumol/liter; glucagon, 1 and 30 nmol/liter; and porcine calcitonin, 1 and 100 ng/ml did not affect the basal release of somatostatin-like immunoreactivity significantly. Neither did an increase from the control level of 4 mmol/liter glucose of 10 or 20 mmol/liter, nor an increase in the control level of 4.4 mmol/liter K+ to 7.5 or 14.4 mmol/liter. Each of these compounds were tested in three or four dogs. The effect of an increase in Ca++ from the control level of 1.5 mmol/liter to 2.25, 3.0, and 4.5 mmol/liter was tested in random order in five thyroid lobes. All three doses elicited an immediate increase in effluent somatostatin-like immunoreactivity. In most experiments the response was biphasic with an early spike, followed by a stable level that was maintained during prolonged Ca++ infusion. The secretory response was not diminished through a series of repeated short pulses of calcium infusion. The response to 3.0 mmol/liter Ca++ (control period 8.4 +/- 1.5, test period 337 +/- 110 pg/ml, mean +/- SE) and 4.5 mmol/liter Ca++ (control period 9.5 +/- 1.4, test period 386 +/- 125) were significantly higher than 2.25 mmol/liter Ca++ (control period 7.2 +/- 1.0 test period 140 +/- 39), while there was no significant difference between responses to the two high doses. Infusion of salmon calcitonin, 10 ng/ml and 1 microgram/ml; or porcine calcitonin, 1 microgram/ml during calcium stimulation (2.25 mmol/liter of Ca++) did not induce alterations in the release of somatostatin-like immunoreactivity. The results demonstrate that thyroidal somatostatin is mobilizable, and it appears to be selectively sensitive to calcium stimulation, indicating a possible role in calcitonin release control.


Partitioned fluid-solid coupling for cardiovascular blood flow: validation study of pressure-driven fluid-domain deformation.
The Karlsruhe Heart Model (KaHMo) is a patient-specific simulation tool for a three-dimensional blood flow evaluation inside the human heart. Whereas KaHMo MRT is based on geometry movement identified from MRT data, KaHMo FSI allows the consideration of structural properties and the analysis of FSI. Previous investigations by Oertel et al. have shown the ability of KaHMo to gain insight into different intra-ventricular fluid mechanics of both healthy and diseased hearts. However, the in vivo validation of the highly dynamic cavity flow pattern has been a challenging task in recent years. As a first step, the focus of this study is on an artificial ventricular experiment, derived from real heart anatomy. Fluid domain deformation and intra-ventricular flow dynamics are enforced by an outer surface pressure distribution. The pure geometrical representation of KaHMo MRT can now be complemented by constitutive properties, pressure forces, and interaction effects using KaHMo FSI's partitioned code-coupling approach. For the first time, fluid domain deformation and intra-ventricular flow of KaHMo FSI has been compared with experimental data. With a good overall agreement, the proof of KaHMo's validity represents an important step from feasibility study toward patient-specific analysis.


Combined zebrafish-yeast chemical-genetic screens reveal gene-copper-nutrition interactions that modulate melanocyte pigmentation.
Hypopigmentation is a feature of copper deficiency in humans, as caused by mutation of the copper (Cu(2+)) transporter ATP7A in Menkes disease, or an inability to absorb copper after gastric surgery. However, many causes of copper deficiency are unknown, and genetic polymorphisms might underlie sensitivity to suboptimal environmental copper conditions. Here, we combined phenotypic screens in zebrafish for compounds that affect copper metabolism with yeast chemical-genetic profiles to identify pathways that are sensitive to copper depletion. Yeast chemical-genetic interactions revealed that defects in intracellular trafficking pathways cause sensitivity to low-copper conditions; partial knockdown of the analogous Ap3s1 and Ap1s1 trafficking components in zebrafish sensitized developing melanocytes to hypopigmentation in low-copper environmental conditions. Because trafficking pathways are essential for copper loading into cuproproteins, our results suggest that hypomorphic alleles of trafficking components might underlie sensitivity to reduced-copper nutrient conditions. In addition, we used zebrafish-yeast screening to identify a novel target pathway in copper metabolism for the small-molecule MEK kinase inhibitor U0126. The zebrafish-yeast screening method combines the power of zebrafish as a disease model with facile genome-scale identification of chemical-genetic interactions in yeast to enable the discovery and dissection of complex multigenic interactions in disease-gene networks.


Alterations in ethanol-induced behaviors and consumption in knock-in mice expressing ethanol-resistant NMDA receptors.
Ethanol's action on the brain likely reflects altered function of key ion channels such as glutamatergic N-methyl-D-aspartate receptors (NMDARs). In this study, we determined how expression of a mutant GluN1 subunit (F639A) that reduces ethanol inhibition of NMDARs affects ethanol-induced behaviors in mice. Mice homozygous for the F639A allele died prematurely while heterozygous knock-in mice grew and bred normally. Ethanol (44 mM; ∼0.2 g/dl) significantly inhibited NMDA-mediated EPSCs in wild-type mice but had little effect on responses in knock-in mice. Knock-in mice had normal expression of GluN1 and GluN2B protein across different brain regions and a small reduction in levels of GluN2A in medial prefrontal cortex. Ethanol (0.75-2.0 g/kg; i.p.) increased locomotor activity in wild-type mice but had no effect on knock-in mice while MK-801 enhanced activity to the same extent in both groups. Ethanol (2.0 g/kg) reduced rotarod performance equally in both groups but knock-in mice recovered faster following a higher dose (2.5 g/kg). In the elevated zero maze, knock-in mice had a blunted anxiolytic response to ethanol (1.25 g/kg) as compared to wild-type animals. No differences were noted between wild-type and knock-in mice for ethanol-induced loss of righting reflex, sleep time, hypothermia or ethanol metabolism. Knock-in mice consumed less ethanol than wild-type mice during daily limited-access sessions but drank more in an intermittent 24 h access paradigm with no change in taste reactivity or conditioned taste aversion. Overall, these data support the hypothesis that NMDA receptors are important in regulating a specific constellation of effects following exposure to ethanol.


Can convict Cichlids (Amatitlania siquia) socially learn the degree of predation risk associated with novel visual cues in their environment?
For many animals, the ability to distinguish cues indicative of predation risk from cues unrelated to predation risk is not entirely innate, but rather is learned and improved with experience. Two pathways to such learning are possible. First, an animal could initially express antipredator behaviour toward a wide range of cues and subsequently learn which of those cues are non-threatening. Alternatively, it could initially express no antipredator behaviour toward a wide range of cues and subsequently learn which of them are threatening. While the learned recognition of threatening cues may occur either through personal interaction with a cue (asocial learning) or through observation of the behaviour of social companions toward a cue (social learning), the learned recognition of non-threatening cues seems to occur exclusively through habituation, a form of asocial learning. Here, we tested whether convict cichlid fish (Amatitlaniasiquia) can socially learn to recognize visual cues in their environment as either threatening or non-threatening. We exposed juvenile convict cichlids simultaneously to a novel visual cue and one of three (visual) social cues: a social cue indicative of non-risk (the sight of conspecifics that had previously been habituated to the novel cue), a social cue indicative of predation risk (the sight of conspecifics trained to fear the novel cue), or a control treatment with no social cue. The subsequent response of focal fish, when presented with the novel cue alone, was not influenced by the social cue that they had previously witnessed. We therefore did not find evidence that convict cichlids in our study could use social learning to recognize novel visual cues as either threatening or non-threatening. We consider alternative explanations for our findings.


Youth Involvement in the Decision to Start CGM Predicts Subsequent CGM Use.
The ability of continuous glucose monitoring (CGM) to improve diabetes outcomes depends upon consistent use. To identify factors that facilitate long-term use of CGM, this study tested the hypothesis that youth involvement in the decision to initiate this therapy would influence subsequent CGM use and that CGM self-efficacy and satisfaction mediate this relationship. Before initiating CGM, parent-youth dyads (i.e., pairs) from an academic endocrinology clinic completed assessments, including a measure of the child's involvement in the decision to start CGM. Two months into CGM use, youth completed measures of CGM self-efficacy and satisfaction. Fidelity of CGM use between weeks 5 and 12 was accessed via a cloud-based data repository. Hypotheses were tested with linear mixed-effects models, accounting for patients clustered within provider and repeated measures within patients. CGM use in 108 dyads (youth mean age 13.4 ± 2.7 years; 73% White) was positively predicted by baseline parent report of youth involvement in the CGM decision (P < 0.0001), and this relationship was mediated by youth's perceptions of CGM self-efficacy (P < 0.0001) and hassle (P = 0.014). So, when the youth shared their opinions about CGM with parents and participated in the decision to start, they perceived higher self-efficacy and lower hassle at 2-month follow-up, which predicted more days of use. This pattern held in models adjusting for youth race and sex and family income. To achieve maximum clinical benefit from CGM use, providers should facilitate youth involvement in the decision to initiate the device.


Endosome-associated CRT1 functions early in resistance gene-mediated defense signaling in Arabidopsis and tobacco.
Resistance gene-mediated immunity confers protection against pathogen infection in a wide range of plants. A genetic screen for Arabidopsis thaliana mutants compromised for recognition of turnip crinkle virus previously identified CRT1, a member of the GHKL ATPase/kinase superfamily. Here, we demonstrate that CRT1 interacts with various resistance proteins from different structural classes, and this interaction is disrupted when these resistance proteins are activated. The Arabidopsis mutant crt1-2 crh1-1, which lacks CRT1 and its closest homolog, displayed compromised resistance to avirulent Pseudomonas syringae and Hyaloperonospora arabidopsidis. Additionally, resistance-associated hypersensitive cell death was suppressed in Nicotiana benthamiana silenced for expression of CRT1 homolog(s). Thus, CRT1 appears to be a general factor for resistance gene-mediated immunity. Since elevation of cytosolic calcium triggered by avirulent P. syringae was compromised in crt1-2 crh1-1 plants, but cell death triggered by Nt MEK2(DD) was unaffected in CRT1-silenced N. benthamiana, CRT1 likely functions at an early step in this pathway. Genome-wide transcriptome analysis led to identification of CRT1-Associated genes, many of which are associated with transport processes, responses to (a)biotic stress, and the endomembrane system. Confocal microscopy and subcellular fractionation revealed that CRT1 localizes to endosome-like vesicles, suggesting a key process in resistance protein activation/signaling occurs in this subcellular compartment.


The social media index: measuring the impact of emergency medicine and critical care websites.
The number of educational resources created for emergency medicine and critical care (EMCC) that incorporate social media has increased dramatically. With no way to assess their impact or quality, it is challenging for educators to receive scholarly credit and for learners to identify respected resources. The Social Media index (SMi) was developed to help address this. We used data from social media platforms (Google PageRanks, Alexa Ranks, Facebook Likes, Twitter Followers, and Google+ Followers) for EMCC blogs and podcasts to derive three normalized (ordinal, logarithmic, and raw) formulas. The most statistically robust formula was assessed for 1) temporal stability using repeated measures and website age, and 2) correlation with impact by applying it to EMCC journals and measuring the correlation with known journal impact metrics. The logarithmic version of the SMi containing four metrics was the most statistically robust. It correlated significantly with website age (Spearman r=0.372; p<0.001) and repeated measures through seven months (r=0.929; p<0.001). When applied to EMCC journals, it correlated significantly with all impact metrics except number of articles published. The strongest correlations were seen with the Immediacy Index (r=0.609; p<0.001) and Article Influence Score (r=0.608; p<0.001). The SMi's temporal stability and correlation with journal impact factors suggests that it may be a stable indicator of impact for medical education websites. Further study is needed to determine whether impact correlates with quality and how learners and educators can best utilize this tool.


Randomized clinical trial comparing collagen plug and advancement flap for trans-sphincteric anal fistula.
The role of a collagen plug for treating anal fistula is not well established. A randomized prospective multicentre non-inferiority study of surgical treatment of trans-sphincteric cryptogenic fistulas was undertaken, comparing the anal fistula plug with the mucosal advancement flap with regard to fistula recurrence rate and functional outcome. Patients with an anal fistula were evaluated for eligibility in three centres, and randomized to either mucosal advancement flap surgery or collagen plug, with clinical follow-up at 3 and 12 months. The primary outcome was the fistula recurrence rate. Anal pain (visual analogue scale), anal incontinence (St Mark's score) and quality of life (Short Form 36 questionnaire) were also reported. Ninety-four patients were included; 48 were allocated to the plug procedure and 46 to advancement flap surgery. The median follow-up was 12 (range 9-24) months. The recurrence rate at 12 months was 66 per cent (27 of 41 patients) in the plug group and 38 per cent (15 of 40) in the flap group (P = 0·006). Anal pain was reduced after operation in both groups. Anal incontinence did not change in the follow-up period. Patients reported an increased quality of life after 3 months. There were no differences between the groups with regard to pain, incontinence or quality of life. There was a considerably higher recurrence rate after the anal fistula plug procedure than following advancement flap repair. Registration number: NCT01021774 (http://www.clinicaltrials.gov).


The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
HIV dementia is an important neurological complication of advanced HIV infection. The use of a cross-cultural screening test to detect HIV dementia within the international community is critical for diagnosing this condition. The objective of this study was to evaluate the sensitivity and specificity of a new screening test for HIV dementia, the International HIV Dementia Scale (IHDS) in cohorts from the US and Uganda. Two cross-sectional cohort studies designed to evaluate for the presence of HIV dementia. Sixty-six HIV-positive individuals in the US and 81 HIV-positive individuals in Uganda received the IHDS and full standardized neurological and neuropsychological assessments. The sensitivity and specificity of varying cut-off scores of the IHDS were evaluated in the two cohorts. In the US cohort, the mean IHDS score for HIV-positive individuals without dementia and with dementia were 10.6 and 9.3 respectively (P < 0.001). Using the cut-off of < or = 10, the sensitivity and specificity for HIV dementia with the IHDS were 80% and 57% respectively in the US cohort, and 80% and 55% respectively in the Uganda cohort. The IHDS may be a useful screening test to identify individuals at risk for HIV dementia in both the industrialized world and the developing world. Full neuropsychological testing should then be performed to confirm a diagnosis of HIV dementia.


The Latent Variable-Autoregressive Latent Trajectory Model: A General Framework for Longitudinal Data Analysis.
In recent years, longitudinal data have become increasingly relevant in many applications, heightening interest in selecting the best longitudinal model to analyze them. Too often traditional practice rather than substantive theory guide the specific model selected. This opens the possibility that alternative models might better correspond to the data. In this paper, we present a general longitudinal model that we call the Latent Variable Autoregressive Latent Trajectory (LV-ALT) model that includes most other longitudinal models with continuous outcomes as special cases. It is capable of specializing to most models dictated by theory or prior research while having the capacity to compare them to alternative ones. If there is little guidance on the best model, the LV-ALT provides a way to determine the appropriate empirical match to the data. We present the model, discuss its identification and estimation, and illustrate how the LV-ALT reveals new things about a widely used empirical example.


Cytogenetic effects of formaldehyde exposure in students of mortuary science.
The effect of low-level exposure to formaldehyde on oral, nasal, and lymphoycte biological markers was studied prospectively in a group of 29 mortician students who were about to take a course in embalming. During the 85-day study period, the subjects performed an average of 6.9 embalmings and had average cumulative formaldehyde exposures of 14.8 ppm-h, with an average air concentration of 1.4 ppm during embalming. Since the average time spent embalming was 125 min, formaldehyde exposures calculated as an 8-h time-weighted average were 0.33 ppm on days when embalmings were done, which was less than the Occupational Safety and Health Administration permissible exposure limit of 0.75 ppm. Epithelial cells from the buccal area of the mouth showed a 12-fold increase in micronucleus frequency during the study period, from 0.046 +/- 0.17/1000 cells preexposure to 0.60 +/- 1.27/1000 cells at the end of the course (P < 0.05). Nasal epithelial micronuclei increased 22%, from 0.41 +/- 0.52/1000 cells to 0.50 +/- 0.67/1000 cells (P = 0.26). In blood cells, the frequency of micronucleated lymphocytes increased 28%, from 4.95 +/- 1.72/1000 cells to 6.36 +/- 2.03/1000 cells (P < 0.05), while sister chromatid exchanges decreased 7.5% (P < 0.05). A dose-response relationship was observed between cumulative exposure to formaldehyde and increases in buccal micronuclei in the 22 male subjects but not in the 7 female subjects. We conclude that low-level exposure to formaldehyde is associated with cytogenetic changes in epithelial cells of the mouth and in blood lymphocytes. These cytogenetic effects may be useful as markers of biologically effective dose.


Medical calculators: Prevalence, and barriers to use.
Medical calculators synthesize measurable evidence and help introduce new medical guidelines and standards. Some medical calculators can fulfill the role of CDS for Meaningful Use purposes. However, there are barriers for clinicians to use medical calculators in practice. Objectives of this study were to determine whether lack of EHR integration would be a barrier to use of medical calculators, and understand factors that may limit use and perceived usefulness of calculators METHODS: A survey about medical calculators as they relate to clinical efficiency, perceived usefulness, and barriers to effective use was conducted at a medium-sized academic medical center. 819 physicians were invited to participate in an online survey with a 13% response rate. Results were statistically analyzed to highlight factors related to use or non-use of medical calculators. We found a negative correlation between use of medical calculators and years of experience (p < 0.001), with decreasing calculator use as experience goes up. Barriers to using medical calculators by non-users and users of medical calculators show that necessity and integration are significantly different with p < 0.001 and p = 0.037, respectively. 46.7% of non-users reported necessity as a barrier compared to 7.7% of users. Integration was reported as a barrier for 43.6% of users, but only 13.3% of non-users. 61% of users indicated that calculators made them more efficient, and 70% reported that unavailability of normally used calculators make them less efficient. 60% of users indicated that they are somewhat or very likely to use newly published medical calculators. The results highlight that medical calculators are important for care delivery by both users and non-users. For non-users, they are seen as having a potentially positive impact on patient care, but unnecessary as part of clinical practice. For medical calculator users, calculators are an important part of regular workflow for efficiency improvement. Clinicians with fewer years of experience show an eagerness to consume newly published calculators, making these kinds of CDS a potentially useful way to disseminate new medical evidence. The survey results suggest that when medical calculators can be automated and integrated into the EHR as part of everyday workflow then efficiency and adoption may increase.


Walking in a cube: novel metaphors for safely navigating large virtual environments in restricted real workspaces.
Immersive spaces such as 4-sided displays with stereo viewing and high-quality tracking provide a very engaging and realistic virtual experience. However, walking is inherently limited by the restricted physical space, both due to the screens (limited translation) and the missing back screen (limited rotation). In this paper, we propose three novel locomotion techniques that have three concurrent goals: keep the user safe from reaching the translational and rotational boundaries; increase the amount of real walking and finally, provide a more enjoyable and ecological interaction paradigm compared to traditional controller-based approaches. We notably introduce the "Virtual Companion", which uses a small bird to guide the user through VEs larger than the physical space. We evaluate the three new techniques through a user study with travel-to-target and path following tasks. The study provides insight into the relative strengths of each new technique for the three aforementioned goals. Specifically, if speed and accuracy are paramount, traditional controller interfaces augmented with our novel warning techniques may be more appropriate; if physical walking is more important, two of our paradigms (extended Magic Barrier Tape and Constrained Wand) should be preferred; last, fun and ecological criteria would favor the Virtual Companion.


Event-related beta oscillations are affected by emotional eliciting stimuli.
According to previous results, negative emotional facial expressions elicit oscillatory beta responses. The present study analyzes event-related beta oscillations upon presentation of International Affective Picture System (IAPS) and aims to show whether behavior of beta in response to negative IAPS pictures also have similar dynamics. IAPS pictures (unpleasant, pleasant, and neutral) were presented as a block and random passive viewing to 14 healthy subjects (8 male). Only with pictures with similar luminance level were selected as stimuli. Event-Related Potentials (ERPs) were recorded from 30 different scalp locations, and adaptive digital filtering was used for analysis in different frequency windows. The maximum peak-to-peak amplitudes were measured for each subject's averaged beta responses (15-30Hz) in the 0 and 300ms time window. Beta responses were significantly higher for unpleasant pictures than for pleasant and neutral pictures (average 50%). Beta responses were significantly higher for unpleasant than for pleasant pictures over frontal, central and parietal electrode sides (p<0.05). Furthermore, beta responses were significantly higher for unpleasant than for neutral pictures over parietal and occipital electrodes (p<0.04). In addition, the pleasant pictures elicited higher beta responses than neutral pictures over occipital electrode sites (p<0.04). The results of the present study indicate that negative emotions are related to increased beta responses in humans, independent of stimulus types (facial expression or IAPS pictures). Accordingly, beta responses to negative emotions are possibly a common phenomenon. The standardization of luminance in pictures may reduce divergences between results from different laboratories.


Characteristic image quality of a third generation dual-source MDCT scanner: Noise, resolution, and detectability.
The purpose of this work was to assess the inherent image quality characteristics of a new multidetector computed tomography system in terms of noise, resolution, and detectability index as a function of image acquisition and reconstruction for a range of clinically relevant settings. A multisized image quality phantom (37, 30, 23, 18.5, and 12 cm physical diameter) was imaged on a SOMATOM Force scanner (Siemens Medical Solutions) under variable dose, kVp, and tube current modulation settings. Images were reconstructed with filtered back projection (FBP) and with advanced modeled iterative reconstruction (ADMIRE) with iterative strengths of 3, 4, and 5. Image quality was assessed in terms of the noise power spectrum (NPS), task transfer function (TTF), and detectability index for a range of detection tasks (contrasts of approximately 45, 90, 300, -900, and 1000 HU, and 2-20 mm diameter) based on a non-prewhitening matched filter model observer with eye filter. Image noise magnitude decreased with decreasing phantom size, increasing dose, and increasing ADMIRE strength, offering up to 64% noise reduction relative to FBP. Noise texture in terms of the NPS was similar between FBP and ADMIRE (<5% shift in peak frequency). The resolution, based on the TTF, improved with increased ADMIRE strength by an average of 15% in the TTF 50% frequency for ADMIRE-5. The detectability index increased with increasing dose and ADMIRE strength by an average of 55%, 90%, and 163% for ADMIRE 3, 4, and 5, respectively. Assessing the impact of mA modulation for a fixed average dose over the length of the phantom, detectability was up to 49% lower in smaller phantom sections and up to 26% higher in larger phantom sections for the modulated scan compared to a fixed tube current scan. Overall, the detectability exhibited less variability with phantom size for modulated scans compared to fixed tube current scans. Image quality increased with increasing dose and decreasing phantom size. The CT system exhibited nonlinear noise and resolution properties, especially at very low-doses, large phantom sizes, and for low-contrast objects. Objective image quality metrics generally increased with increasing dose and ADMIRE strength, and with decreasing phantom size. The ADMIRE algorithm could offer comparable image quality at reduced doses or improved image quality at the same dose. The use of tube current modulation resulted in more consistent image quality with changing phantom size.


Initial Management of Noncastrate Advanced, Recurrent, or Metastatic Prostate Cancer: ASCO Guideline Update.
Update all preceding ASCO guidelines on initial hormonal management of noncastrate advanced, recurrent, or metastatic prostate cancer. The Expert Panel based recommendations on a systematic literature review. Recommendations were approved by the Expert Panel and the ASCO Clinical Practice Guidelines Committee. Four clinical practice guidelines, one clinical practice guidelines endorsement, 19 systematic reviews with or without meta-analyses, 47 phase III randomized controlled trials, nine cohort studies, and two review papers informed the guideline update. Docetaxel, abiraterone, enzalutamide, or apalutamide, each when administered with androgen deprivation therapy (ADT), represent four separate standards of care for noncastrate metastatic prostate cancer. Currently, the use of any of these agents in any particular combination or series cannot be recommended. ADT plus docetaxel, abiraterone, enzalutamide, or apalutamide should be offered to men with metastatic noncastrate prostate cancer, including those who received prior therapies, but have not yet progressed. The combination of ADT plus abiraterone and prednisolone should be considered for men with noncastrate locally advanced nonmetastatic prostate cancer who have undergone radiotherapy, rather than castration monotherapy. Immediate ADT may be offered to men who initially present with noncastrate locally advanced nonmetastatic disease who have not undergone previous local treatment and are unwilling or unable to undergo radiotherapy. Intermittent ADT may be offered to men with high-risk biochemically recurrent nonmetastatic prostate cancer. Active surveillance may be offered to men with low-risk biochemically recurrent nonmetastatic prostate cancer. The panel does not support use of either micronized abiraterone acetate or the 250 mg dose of abiraterone with a low-fat breakfast in the noncastrate setting at this time.Additional information is available at www.asco.org/genitourinary-cancer-guidelines.


Characterisation of data resources for in silico modelling: benchmark datasets for ADME properties.
The cost of in vivo and in vitro screening of ADME properties of compounds has motivated efforts to develop a range of in silico models. At the heart of the development of any computational model are the data; high quality data are essential for developing robust and accurate models. The characteristics of a dataset, such as its availability, size, format and type of chemical identifiers used, influence the modelability of the data. Areas covered: This review explores the usefulness of publicly available ADME datasets for researchers to use in the development of predictive models. More than 140 ADME datasets were collated from publicly available resources and the modelability of 31 selected datasets were assessed using specific criteria derived in this study. Expert opinion: Publicly available datasets differ significantly in information content and presentation. From a modelling perspective, datasets should be of adequate size, available in a user-friendly format with all chemical structures associated with one or more chemical identifiers suitable for automated processing (e.g. CAS number, SMILES string or InChIKey). Recommendations for assessing dataset suitability for modelling and publishing data in an appropriate format are discussed.


Transcriptional regulation of the endogenous danger signal tenascin-C: a novel autocrine loop in inflammation.
Inappropriate expression of proinflammatory mediators underpins the pathogenesis of autoimmune disease and tumor metastasis. The extracellular matrix glycoprotein tenascin-C is an endogenous activator of innate immunity that promotes the synthesis of inflammatory cytokines via activation of TLR4. Little tenascin-C is observed in most healthy adult tissues, but expression is specifically upregulated at sites of inflammation. Moreover, high levels of tenascin-C are associated with chronic inflammation and found in the tumor stroma. In this study, we show that the expression of tenascin-C is induced in immune myeloid cells activated by a variety of inflammatory stimuli, including specific TLR ligands. Its synthesis is transcriptionally regulated and requires the specific activation of AKT/PI3K and NF-kappaB signaling pathways. Using a bioinformatic approach, we identified a large number of conserved noncoding regions throughout the tenascin-C genomic locus that may contribute to its transcriptional regulation during inflammation. We also demonstrate that tenascin-C expression is transient during acute inflammation. In contrast, persistently high levels of expression occur in the inflamed synovium of joints from rheumatoid arthritis patients. Thus, misregulated expression of this endogenous danger signal may promote an autocrine loop of inflammation and contribute to the persistence of inflammation in autoimmune diseases or to tumor egress and invasion during metastasis.


ERK1/2 and p38 MAPKs are complementarily involved in estradiol 17ß-D-glucuronide-induced cholestasis: crosstalk with cPKC and PI3K.
The endogenous, cholestatic metabolite estradiol 17ß-D-glucuronide (E(2)17G) induces endocytic internalization of the canalicular transporters relevant to bile formation, Bsep and Mrp2. We evaluated here whether MAPKs are involved in this effect. ERK1/2, JNK1/2, and p38 MAPK activation was assessed by the increase in their phosphorylation status. Hepatocanalicular function was evaluated in isolated rat hepatocyte couplets (IRHCs) by quantifying the apical secretion of fluorescent Bsep and Mrp2 substrates, and in isolated, perfused rat livers (IPRLs), using taurocholate and 2,4-dinitrophenyl-S-glutathione, respectively. Protein kinase participation in E(2)17G-induced secretory failure was assessed by co-administering selective inhibitors. Internalization of Bsep/Mrp2 was assessed by confocal microscopy and image analysis. E(2)17G activated all kinds of MAPKs. The PI3K inhibitor wortmannin prevented ERK1/2 activation, whereas the cPKC inhibitor Gö6976 prevented p38 activation, suggesting that ERK1/2 and p38 are downstream of PI3K and cPKC, respectively. The p38 inhibitor SB203580 and the ERK1/2 inhibitor PD98059, but not the JNK1/2 inhibitor SP600125, partially prevented E(2)17G-induced changes in transporter activity and localization in IRHCs. p38 and ERK1/2 co-inhibition resulted in additive protection, suggesting complementary involvement of these MAPKs. In IPRLs, E(2)17G induced endocytosis of canalicular transporters and a rapid and sustained decrease in bile flow and biliary excretion of Bsep/Mrp2 substrates. p38 inhibition prevented this initial decay, and the internalization of Bsep/Mrp2. Contrarily, ERK1/2 inhibition accelerated the recovery of biliary secretion and the canalicular reinsertion of Bsep/Mrp2. cPKC/p38 MAPK and PI3K/ERK1/2 signalling pathways participate complementarily in E(2)17G-induced cholestasis, through internalization and sustained intracellular retention of canalicular transporters, respectively.


A guide to viral inclusions, membrane rearrangements, factories, and viroplasm produced during virus replication.
Virus replication can cause extensive rearrangement of host cell cytoskeletal and membrane compartments leading to the "cytopathic effect" that has been the hallmark of virus infection in tissue culture for many years. Recent studies are beginning to redefine these signs of viral infection in terms of specific effects of viruses on cellular processes. In this chapter, these concepts have been illustrated by describing the replication sites produced by many different viruses. In many cases, the cellular rearrangements caused during virus infection lead to the construction of sophisticated platforms in the cell that concentrate replicase proteins, virus genomes, and host proteins required for replication, and thereby increase the efficiency of replication. Interestingly, these same structures, called virus factories, virus inclusions, or virosomes, can recruit host components that are associated with cellular defences against infection and cell stress. It is possible that cellular defence pathways can be subverted by viruses to generate sites of replication. The recruitment of cellular membranes and cytoskeleton to generate virus replication sites can also benefit viruses in other ways. Disruption of cellular membranes can, for example, slow the transport of immunomodulatory proteins to the surface of infected cells and protect against innate and acquired immune responses, and rearrangements to cytoskeleton can facilitate virus release.


[Prokaryotic expression and identification of S-dsRNA gene from Cryptosporidium parvum virus].
To clone and express S-dsRNA gene of Cryptosporidium parvum virus, and investigate the reactogenicity of the recombinant. Total RNA was extracted from Cryptosporidium parvum and S-dsRNA gene was amplified by RT-PCR. The PCR product was cloned into pET-28a(+) expression vector. The recombinant plasmid pET-28a(+)-S was transformed into E. coli BL21 (DE3) and induced with IPTG. The expression situation of recombinant protein was analyzed by SDS-PAGE. Its reactogenicity was examined by Western blotting analysis. pET-28a (+)-S was identified by PCR and double endonuclease digestion. SDS-PAGE result showed that the recombinant protein (M, 37,000) was expressed in the form of inclusion body. High level expression of recombinant protein was found at 1 mmol/L IPTG condition after incubation at 37 degrees C for 4 h and reached up to 72.6% of the total protein. The protein was recognized by the antisera from mice immunized with antigens from Cryptosporidium parvum oocysts. The S-dsRNA gene of Cryptosporidium parvum virus has been expressed with adequate reactogenicity.


The effects of weight loss on imaging outcomes in osteoarthritis of the hip or knee in people who are overweight or obese: a systematic review.
To evaluate the structural effects of weight loss on hip or knee osteoarthritis (OA) and to summarize which structural joint pathologies have been examined and the evidence for the outcome measurement instruments applied. Based on a pre-specified protocol (available: PROSPERO CRD42017065263), we conducted a systematic search of the bibliographic databases, Medline, Embase and Web of Science identifying longitudinal articles reporting the effects of weight loss on structural imaging outcomes in OA of the hip or knee in people who are overweight or obese. From 1625 potentially eligible records, 14 articles (from 6 cohorts) were included. 2 cohorts were derived from RCTs. Evaluated pathologies were: articular cartilage (n = 7), joint space width (n = 3), bone marrow lesions (n = 5), synovitis (n = 2), effusion (n = 1), meniscus (n = 3), bone marrow density (n = 1) and infrapatellar fat pad (IPFP; n = 2). Cartilage showed conflicting results when evaluating cartilage thickness by direct thickness measurements. Compositional dGEMRIC and T2 mapping measures in early knee OA showed trends towards reduced cartilage degeneration. Joint space width on conventional radiographs showed no change. Weight loss reduced the size of the IPFP. Synovitis and effusion were not affected. Following weight loss DXA showed bone loss at the hip. We did not find consistent evidence of the effects of weight loss on OA structural pathology in people who are overweight or obese. There is a need to achieve consensus on which structural pathologies and measurements to apply in weight loss and OA research.


Losartan may attenuate altitude-related sleep disturbance.
Sleep disturbance is common at high altitude and likely driven by an exaggerated peripheral chemoreceptor response which leads to apnoeic episodes and arousal. We hypothesised that this heightened response is in part mediated through angiotensin II receptors in the carotid body. To examine this link, we studied the effect of angiotensin II receptor blocker on sleep disturbance. Twenty participants paired by age, gender and ACE phenotype ascended to the Whymper Hut (5000 m) on Chimborazo in the Ecuadorean Andes as part of a double-blinded randomised placebo-controlled study of physiological mechanisms. Subjects were randomised to either losartan 100 mg daily or placebo. The primary outcome of sleep efficiency was measured using wrist-mounted actigraphs. One pair was excluded from analysis after descending before the end of the study due to acute mountain sickness. There was a significantly different response to altitude between the two groups (F=3.274, p=0.029), as a decline in sleep efficiency in the placebo group (F=10.259, p<0.001) was not replicated in the angiotensin II receptor blocker group (F=0.459, p=0.713). The absence of any significant sleep disturbance in the intervention group suggests that peripheral chemoreceptor hypersensitivity is largely mediated by angiotensin II receptor activation. However, further research is needed to confirm our findings and to study the potential mechanisms of action.


Enhanced semipermanent dialysis samplers for long-term environmental monitoring in saturated sediments.
The ability to sample in situ natural environmental processes has proven to be challenging when working with redox-sensitive contaminates in saturated sediments in wetland systems, especially within the rhizosphere, where sharp redox gradients are common. Many traditional approaches are invasive and disturb natural sediment chemistry. Through laboratory and field studies, the work presented in this study demonstrates a novel semipermanent dialysis sampler that allows for long-term, anaerobic monitoring of shallow sediments. Dialysis samplers were deployed and tested for over 1 year while being exposed to extremes in climate. These newly designed devices produce statistically reproducible data and capture sensitive redox trends. Results from the newly designed samplers were compared to conventional samplers. Initially, both the new and old designs yielded statistically similar data, but these data diverged over a period of months. The new devices are less invasive, so data gathered from these devices are more likely to be a closer representation of true conditions in the subsurface. By giving reliable data from a consistent location in space, these new samplers represent a significant step forward in capturing spatial and temporal variability in wetland redox chemistry during long-term monitoring.


Does "butyrylization" of acetylcholinesterase through substitution of the six divergent aromatic amino acids in the active center gorge generate an enzyme mimic of butyrylcholinesterase?
The active center gorge of human acetylcholinesterase (HuAChE) is lined by 14 aromatic residues, whereas in the closely related human butyrylcholinesterase (HuBChE) 3 of the aromatic active center residues (Phe295, Phe297, Tyr337) as well as 3 of the residues at the gorge entrance (Tyr72, Tyr124, Trp286) are replaced by aliphatic amino acids. To investigate whether this structural variability can account for the reactivity differences between the two enzymes, gradual replacement of up to all of the 6 aromatic residues in HuAChE by the corresponding residues in HuBChE was carried out. The affinities of the hexamutant (Y72N/Y124Q/W286A/F295L/F297V/Y337A) toward tacrine, decamethonium, edrophonium, huperzine A, or BW284C51 differed by about 5-, 80-, 170-, 25000-, and 17000-fold, respectively, from those of the wild-type HuAChE. For most of these prototypical noncovalent active center and peripheral site ligands, the hexamutant HuAChE displayed a reactivity phenotype closely resembling that of HuBChE. These results support the accepted view that the active center architectures of AChE and BChE differ mainly by the presence of a larger void space in BChE. Nevertheless, reactivity of the hexamutant HuAChE toward the substrates acetylthiocholine and butyrylthiocholine, or covalent ligands such as phosphonates and the transition state analogue m-(N,N,N-trimethylammonio)trifluoroacetophenone (TMTFA), is about 45-170-fold lower than that of HuBChE. Most of this reduction in reactivity can be related to the combined replacements of the three aromatic residues at the active center, Phe295, Phe297, and Tyr337. We propose that the hexamutant HuAChE, unlike BChE, is impaired in its capacity to accommodate certain tetrahedral species in the active center. This impairment may be related to the enhanced mobility of the catalytic histidine His447, which is observed in molecular dynamics simulations of the hexamutant and the F295L/F297V/Y337A HuAChE enzymes but not in the wild-type HuAChE.


Well-plate freeze-drying: a high throughput platform for screening of physical properties of freeze-dried formulations.
Freeze-drying in presence of excipients is a common practice to stabilize biomacromolecular formulations. The composition of this formulation is known to affect the quality of the final product. The aim of this study was to evaluate freeze-drying in well-plates as a high throughput platform for formulation screening of freeze-dried products. Model formulations consisting of mannitol, sucrose and bovine serum albumin were freeze-dried in brass well plates, plastic well plates and vials. Physical properties investigated were solid form, residual moisture, cake collapse and reconstitution time. Samples freeze-dried in well-plates had an acceptable visual cake appearance. Solid form analysis by high throughput X-ray powder diffraction indicated comparable polymorphic outcome independent of the container. The expected increase in moisture level due to increasing amount of amorphous matter in the samples was observed in both vials and well plates. Cake collapse was found to be representative in well plates and could be effectively quantified using image analysis. Reconstitution time was also found to be equal in all three platforms. Finally no significant edge effect was found for any of the quality attributes analyzed. Freeze-drying in well-plates was found to be a suitable and representative high throughput platform for formulation screening.


Increased soluble vascular cell adhesion molecule 1 concentrations in patients with primary or systemic lupus erythematosus-related antiphospholipid syndrome: correlations with the severity of thrombosis.
Recent studies have shown that in vitro endothelial cells are activated by antiphospholipid antibodies and may support leukocyte adhesion. We studied levels of soluble intercellular adhesion molecule 1 (sICAM-1, sCD54), soluble vascular cell adhesion molecule 1 (sVCAM-1, sCD106), and soluble E-selectin (soluble endothelial leukocyte adhesion molecule 1 [sELAM-1, sCD62E]) in sera from patients with primary antiphospholipid syndrome (primary APS), and compared them with those from patients with systemic lupus erythematosus-associated APS (SLE-APS) or pure SLE, as well as with those from 2 control groups composed of healthy volunteers and patients with thrombosis unrelated to autoimmune diseases. Serum samples from 24 patients with primary APS, 15 patients with SLE-APS, 22 patients with pure SLE, 48 control patients with thrombosis, and 18 healthy volunteers were examined using enzyme-linked immunosorbent assays specific for sICAM-1, sVCAM-1, and sELAM-1. Serum levels of sVCAM-1, but not sICAM-1 or sELAM-1, were significantly increased in all patient study groups compared with thrombosis control patients and healthy volunteers, but did not differ between the groups of patients with primary APS, SLE-APS, or pure SLE. Concentrations of sVCAM-1 were significantly higher in primary APS or SLE-APS patients with severe, recurrent thrombosis and were negatively correlated with platelet counts in primary APS patients. In patients with primary APS, sVCAM-1 levels were higher if there was thrombotic kidney involvement and correlated with creatinemia. Serum sVCAM-1 concentrations are increased in patients with primary APS, especially those with repeated thrombotic events or kidney involvement. These findings suggest that endothelial/ monocyte interaction may be important in the pathogenesis of primary APS.


Trends in non-communicable disease mortality among adult residents in Nairobi's slums, 2003-2011: applying InterVA-4 to verbal autopsy data.
About 80% of deaths from non-communicable diseases (NCDs) occur in developing countries such as Kenya. However, not much is known about the burden of NCDs in slums, which account for about 60% of the residences of the urban population in Kenya. This study examines trends in NCD mortality from two slum settings in Nairobi. We use verbal autopsy data on 1954 deaths among adults aged 35 years and older who were registered in the Nairobi Urban Health and Demographic Surveillance System between 2003 and 2011. InterVA-4, a computer-based program, was used to assign causes of death for each case. RESULTS are presented as annualized cause-specific mortality rates (CSMRs) and cause-specific mortality fractions (CSMFs) by sex. The CSMRs for NCDs did not appear to change significantly over time for both males and females. Among males, cardiovascular diseases (CVDs) and neoplasms were the leading NCDs--contributing CSMFs of 8 and 5%, respectively, on average over time. Among females, CVDs contributed a CSMF of 14% on average over time, while neoplasms contributed 8%. Communicable diseases and related conditions remained the leading causes of death, contributing a CSMF of over 50% on average in males and females over time. Our findings are consistent with the Global Burden of Disease 2010 study which shows that communicable diseases remain the dominant cause of death in Africa, although NCDs were still significant contributors to mortality. We recommend an integrated approach towards disease prevention that focuses on health systems strengthening in resource-limited settings such as slums.


WAVE2 is required for directed cell migration and cardiovascular development.
WAVE2, a protein related to Wiskott-Aldrich syndrome protein, is crucial for Rac-induced membrane ruffling, which is important in cell motility. Cell movement is essential for morphogenesis, but it is unclear how cell movement is regulated or related to morphogenesis. Here we show the physiological functions of WAVE2 by disruption of the WAVE2 gene in mice. WAVE2 was expressed predominantly in vascular endothelial cells during embryogenesis. WAVE2-/- embryos showed haemorrhages and died at about embryonic day 10. Deficiency in WAVE2 had no significant effect on vasculogenesis, but it decreased sprouting and branching of endothelial cells from existing vessels during angiogenesis. In WAVE2-/- endothelial cells, cell polarity formed in response to vascular endothelial growth factor, but the formation of lamellipodia at leading edges and capillaries was severely impaired. These findings indicate that WAVE2-regulated actin reorganization might be required for proper cell movement and that a lack of functional WAVE2 impairs angiogenesis in vivo.


Measuring patient satisfaction with nursing care: experience of using the Newcastle Satisfaction with Nursing Scale.
Patient satisfaction with care has frequently been used as a measurement of quality, especially in attempts to demonstrate the benefits of changes in nursing practice. Unfortunately such attempts have frequently failed as patient satisfaction ratings have lacked sensitivity, consistently achieving very high scores. They have also failed to isolate the nursing component from the whole health care experience. The Newcastle Satisfaction with Nursing Scale (NSNS) has been developed after extensive research work as an attempt to establish reliable and valid measures of patients' experiences of and satisfaction with nursing care. This study evaluated the use of the NSNS in practice and found that it was readily understood by patients and easily administered by clinical staff. However, several lessons were learnt which could help its administration. The results demonstrated a very high degree of satisfaction with nursing care which left the discriminatory ability of the scale open to question, although its potential benefits in standard setting were demonstrated. Further evaluative studies are needed if the potential benefits of the NSNS are to be fully realised.


Rare loss-of-function mutation in complement component C3 provides insight into molecular and pathophysiological determinants of complement activity.
The plasma protein C3 is a central element in the activation and effector functions of the complement system. A hereditary dysfunction of C3 that prevents complement activation via the alternative pathway (AP) was described previously in a Swedish family, but its genetic cause and molecular consequences have remained elusive. In this study, we provide these missing links by pinpointing the dysfunction to a point mutation in the β-chain of C3 (c.1180T > C; p.Met(373)Thr). In the patient's plasma, AP activity was completely abolished and could only be reconstituted with the addition of normal C3. The M373T mutation was localized to the macroglobulin domain 4 of C3, which contains a binding site for the complement inhibitor compstatin and is considered critical for the interaction of C3 with the AP C3 convertase. Structural analyses suggested that the mutation disturbs the integrity of macroglobulin domain 4 and induces conformational changes that propagate into adjacent regions. Indeed, C3 M373T showed an altered binding pattern for compstatin and surface-bound C3b, and the presence of Thr(373) in either the C3 substrate or convertase-affiliated C3b impaired C3 activation and opsonization. In contrast to known gain-of-function mutations in C3, patients affected by this loss-of-function mutation did not develop familial disease, but rather showed diverse and mostly episodic symptoms. Our study therefore reveals the molecular mechanism of a relevant loss-of-function mutation in C3 and provides insight into the function of the C3 convertase, the differential involvement of C3 activity in clinical conditions, and some potential implications of therapeutic complement inhibition.


Noise models for low counting rate coherent diffraction imaging.
Coherent diffraction imaging (CDI) is a lens-less microscopy method that extracts the complex-valued exit field from intensity measurements alone. It is of particular importance for microscopy imaging with diffraction set-ups where high quality lenses are not available. The inversion scheme allowing the phase retrieval is based on the use of an iterative algorithm. In this work, we address the question of the choice of the iterative process in the case of data corrupted by photon or electron shot noise. Several noise models are presented and further used within two inversion strategies, the ordered subset and the scaled gradient. Based on analytical and numerical analysis together with Monte-Carlo studies, we show that any physical interpretations drawn from a CDI iterative technique require a detailed understanding of the relationship between the noise model and the used inversion method. We observe that iterative algorithms often assume implicitly a noise model. For low counting rates, each noise model behaves differently. Moreover, the used optimization strategy introduces its own artefacts. Based on this analysis, we develop a hybrid strategy which works efficiently in the absence of an informed initial guess. Our work emphasises issues which should be considered carefully when inverting experimental data.


Fiber-optic pH-sensors in long-period fiber gratings using electrostatic self-assembly.
A novel pH sensor based on the deposition of electrostatic self-assembled polyallylamine hydrochloride and polyacrylic acid on the cladding of a long-period fiber grating has been designed. The overlay thickness is of the order of magnitude of the light wavelength used to interrogate the sensor. A theoretical model of multilayer cylindrical waveguides based on coupled-mode theory has been used to predict the position of the attenuation bands as a function of the overlay thickness. A study of the role that pH plays in the thickness of the sensitive overlay was carried out. Experimentally, a wavelength shift of the attenuation bands of up to 85 nm was obtained in the 4-7 range of pH units. The results are reproducible, which indicates the possibilities of a multiple-use sensor.


The Superior Colliculus and Amygdala Support Evaluation of Face Trait in Blindsight.
Humans can respond rapidly to viewed expressions of fear, even in the absence of conscious awareness. This is demonstrated using visual masking paradigms in healthy individuals and in patients with cortical blindness due to damage to the primary visual cortex (V1) - so called affective blindsight. Humans have also been shown to implicitly process facial expressions representing important social dimensions. Two major axes, dominance and trustworthiness, are proposed to characterize the social dimensions of face evaluation. The processing of both types of implicit stimuli is believed to occur via similar subcortical pathways involving the amygdala. However, we do not know whether unconscious processing of more subtle expressions of facial traits can occur in blindsight, and if so, how. To test this, we studied 13 patients with unilateral V1 damage and visual field loss. We assessed their ability to detect and discriminate faces that had been manipulated along two orthogonal axes of trustworthiness and dominance to generate five trait levels inside the blind visual field: dominant, submissive, trustworthy, untrustworthy, and neutral. We compared neural activity and functional connectivity in patients classified as blindsight positive or negative for these stimuli. We found that dominant faces were most likely to be detected above chance, with individuals demonstrating unique interactions between performance and face trait. Only patients with blindsight (n = 8) showed significant preference in the superior colliculus and amygdala for face traits in the blind visual field, and a critical functional connection between the amygdala and superior colliculus in the damaged hemisphere. We also found a significant correlation between behavioral performance and fMRI activity in the amygdala and lateral geniculate nucleus across all participants. Our findings confirm that affective blindsight involving the superior colliculus and amygdala extends to the processing of socially salient but emotionally neutral facial expressions when V1 is damaged. This pathway is distinct from that which supports motion blindsight, as both types of blindsight can exist in the absence of the other with corresponding patterns of residual connectivity.