Second-order statistics of a twisted gaussian Schell-model beam in turbulent atmosphere.
We present a detailed investigation of the second-order statistics of a twisted gaussian Schell-model (TGSM) beam propagating in turbulent atmosphere. Based on the extended Huygens-Fresnel integral, analytical expressions for the second-order moments of the Wigner distribution function of a TGSM beam in turbulent atmosphere are derived. Evolution properties of the second-order statistics, such as the propagation factor, the effective radius of curvature (ERC) and the Rayleigh range, of a TGSM beam in turbulent atmosphere are explored in detail. Our results show that a TGSM beam is less affected by the turbulence than a GSM beam without twist phase. In turbulent atmosphere the Rayleigh range doesn't equal to the distance where the ERC takes a minimum value, which is much different from the result in free space. The second-order statistics are closely determined by the parameters of the turbulent atmosphere and the initial beam parameters. Our results will be useful in long-distance free-space optical communications.


Existing bitter medicines for fighting 2019-nCoV-associated infectious diseases.
The sudden outbreak of COVID-19 has led to more than seven thousand deaths. Unfortunately, there are no specific drugs available to cure this disease. Type 2 taste receptors (TAS2Rs) may play an important role in host defense mechanisms. Based on the idea of host-directed therapy (HDT), we performed a negative co-expression analysis using big data of 60 000 Affymetrix expression arrays and 5000 TCGA data sets to determine the functions of TAS2R10, which can be activated by numerous bitter substances. Excitingly, we found that the main functions of TAS2R10 involved controlling infectious diseases caused by bacteria, viruses, and parasites, suggesting that TAS2R10 is a key trigger of host defense pathways. To quickly guide the clinical treatment of 2019-nCoV, we searched currently available drugs that are agonists of TAS2Rs. We identified many cheap, available, and safe medicines, such as diphenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, and dextromethorphan, which may target the most common symptoms caused by 2019-nCoV. We suggest that a cocktail-like recipe of existing bitter drugs may help doctors to fight this catastrophic disease and that the general public may drink or eat bitter substances, such as coffee, tea, or bitter vegetables, to reduce the risk of infection.


Neurodevelopmental alcohol exposure elicits long-term changes to gene expression that alter distinct molecular pathways dependent on timing of exposure.
Maternal alcohol consumption is known to adversely affect fetal neurodevelopment. While it is known that alcohol dose and timing play a role in the cognitive and behavioral changes associated with prenatal alcohol exposure, it is unclear what developmental processes are disrupted that may lead to these phenotypes. Mice (n=6 per treatment per developmental time) were exposed to two acute doses of alcohol (5 g/kg) at neurodevelopmental times representing the human first, second, or third trimester equivalent. Mice were reared to adulthood and changes to their adult brain transcriptome were assessed using expression arrays. These were then categorized based on Gene Ontology annotations, canonical pathway associations, and relationships to interacting molecules. The results suggest that ethanol disrupts biological processes that are actively occurring at the time of exposure. These include cell proliferation during trimester one, cell migration and differentiation during trimester two, and cellular communication and neurotransmission during trimester three. Further, although ethanol altered a distinct set of genes depending on developmental timing, many of these show interrelatedness and can be associated with one another via 'hub' molecules and pathways such as those related to huntingtin and brain-derived neurotrophic factor. These changes to brain gene expression represent a 'molecular footprint' of neurodevelopmental alcohol exposure that is long-lasting and correlates with active processes disrupted at the time of exposure. This study provides further support that there is no neurodevelopmental time when alcohol cannot adversely affect the developing brain.


Shiga toxin sub-type 2a increases the efficiency of Escherichia coli O157 transmission between animals and restricts epithelial regeneration in bovine enteroids.
Specific Escherichia coli isolates lysogenised with prophages that express Shiga toxin (Stx) can be a threat to human health, with cattle being an important natural reservoir. In many countries the most severe pathology is associated with enterohaemorrhagic E. coli (EHEC) serogroups that express Stx subtype 2a. In the United Kingdom, phage type (PT) 21/28 O157 strains have emerged as the predominant cause of life-threatening EHEC infections and this phage type commonly encodes both Stx2a and Stx2c toxin types. PT21/28 is also epidemiologically linked to super-shedding (>103 cfu/g of faeces) which is significant for inter-animal transmission and human infection as demonstrated using modelling studies. We demonstrate that Stx2a is the main toxin produced by stx2a+/stx2c+ PT21/28 strains induced with mitomycin C and this is associated with more rapid induction of gene expression from the Stx2a-encoding prophage compared to that from the Stx2c-encoding prophage. Bacterial supernatants containing either Stx2a and/or Stx2c were demonstrated to restrict growth of bovine gastrointestinal organoids with no restriction when toxin production was not induced or prevented by mutation. Isogenic strains that differed in their capacity to produce Stx2a were selected for experimental oral colonisation of calves to assess the significance of Stx2a for both super-shedding and transmission between animals. Restoration of Stx2a expression in a PT21/28 background significantly increased animal-to-animal transmission and the number of sentinel animals that became super-shedders. We propose that while both Stx2a and Stx2c can restrict regeneration of the epithelium, it is the relatively rapid and higher levels of Stx2a induction, compared to Stx2c, that have contributed to the successful emergence of Stx2a+ E. coli isolates in cattle in the last 40 years. We propose a model in which Stx2a enhances E. coli O157 colonisation of in-contact animals by restricting regeneration and turnover of the colonised gastrointestinal epithelium.


Cycling probe technology to quantify and discriminate between wild-type varicella-zoster virus and Oka vaccine strains.
Rapid differentiation between wild-type varicella zoster virus (VZV) and Oka-vaccine (vOka) strains is important for monitoring side reactions of varicella vaccination. To develop a high-throughput molecular diagnostic method for the differentiation of wild-type VZV and vOka strains based on cycling probe technology. The primers were designed to amplify common sequences spanning a single nucleotide polymorphism (SNP) in gene 62 of VZV. DNA-RNA chimeric probes (cycling probes) were designed to detect the SNP at nucleotide 105705. The cycling probe real-time PCR assays for VZV wild-type and vOka strains specifically amplified plasmids containing target sequences that ranged between 10 and 1×10(6) copies per reaction. The inter- and intra-assay coefficients of variation were less than 5%. After initial validation studies, the clinical reliability of this method was evaluated using 38 swab samples that were collected from patients suspected of being zoster. Compared to the loop mediated isothermal amplification method, which is defined as the gold standard, cycling probe real-time PCR was highly sensitive and specific. The cycling probe real-time PCR technology is a reliable tool for differentiating between wild-type VZV and vOka strains in clinical samples.


Effects of glucagon on postprandial carbohydrate metabolism in nondiabetic humans.
The present experiments sought to determine whether glucagon concentrations mimicking those observed in people with diabetes mellitus alter postprandial carbohydrate metabolism in nondiabetic humans. We measured the gastric emptying of solids and liquids, the systemic rate of appearance of ingested glucose, and endogenous glucose production either when postprandial suppression of glucagon was prevented by infusing glucagon at a rate of 0.65 ng/kg/min, when postprandial glucagon concentrations were elevated by infusing glucagon at a rate of 3.0 ng/kg/min, or when postprandial suppression of glucagon was permitted by infusion of saline. Despite marked differences in glucagon concentrations, postprandial glucose and insulin concentrations did not differ on any occasion. Although gastric emptying of liquids and solids was comparable on all three occasions, the high-dose, but not the low-dose, glucagon infusion caused a slight delay in the systemic appearance of ingested glucose and a significant decrease (P < .01) in postprandial D-xylose concentrations, suggesting a delay in carbohydrate absorption. However, this was offset by an increase (P < .05) in endogenous glucose production, resulting in no difference in postprandial glucose appearance. We conclude that in the absence of insulin deficiency, neither a lack of suppression of glucagon nor an elevation of glucagon to levels encountered in uncontrolled diabetes mellitus cause postprandial hyperglycemia in nondiabetic humans.


Hybrid Deep Learning on Single Wide-field Optical Coherence tomography Scans Accurately Classifies Glaucoma Suspects.
Existing summary statistics based upon optical coherence tomographic (OCT) scans and/or visual fields (VFs) are suboptimal for distinguishing between healthy and glaucomatous eyes in the clinic. This study evaluates the extent to which a hybrid deep learning method (HDLM), combined with a single wide-field OCT protocol, can distinguish eyes previously classified as either healthy suspects or mild glaucoma. In total, 102 eyes from 102 patients, with or suspected open-angle glaucoma, had previously been classified by 2 glaucoma experts as either glaucomatous (57 eyes) or healthy/suspects (45 eyes). The HDLM had access only to information from a single, wide-field (9×12 mm) swept-source OCT scan per patient. Convolutional neural networks were used to extract rich features from maps derived from these scans. Random forest classifier was used to train a model based on these features to predict the existence of glaucomatous damage. The algorithm was compared against traditional OCT and VF metrics. The accuracy of the HDLM ranged from 63.7% to 93.1% depending upon the input map. The retinal nerve fiber layer probability map had the best accuracy (93.1%), with 4 false positives, and 3 false negatives. In comparison, the accuracy of the OCT and 24-2 and 10-2 VF metrics ranged from 66.7% to 87.3%. The OCT quadrants analysis had the best accuracy (87.3%) of the metrics, with 4 false positives and 9 false negatives. The HDLM protocol outperforms standard OCT and VF clinical metrics in distinguishing healthy suspect eyes from eyes with early glaucoma. It should be possible to further improve this algorithm and with improvement it might be useful for screening.


Promoting Racial/Ethnic Equity in Psychosocial Treatment Outcomes for Child and Adolescent Anxiety and Depression.
Anxiety and depression are the most prevalent and least treated pediatric mental health problems. Racial/ethnic minority youths face greater risks for developing anxiety and depression and experience higher burden as they are less likely to receive adequate mental health services for these conditions or to have their needs met. Further, standard evidence-based interventions for youth anxiety and depression may show diminished effects with racial/ethnic minority youths and with families of lower socioeconomic status. While community-level interventions to combat structural racism and reduce population-level risk are sorely needed, many youths will continue to require acute treatment services for anxiety and depression and interventionists must understand how to bring equity to the forefront of care. In this review, we adopt a health system framework to examine racial/ethnic disparities in system-, intervention-, provider-, and patient-level factors for psychosocial treatment of pediatric anxiety and depression. Current evidence on disparities in access and in efficacy of psychosocial intervention for anxious and depressed youths is summarized, and we use our work in primary care as a case example of adapting an intervention to mitigate disparities and increase equity. We conclude with recommendations for disparity action targets at each level of the health system framework and provide example strategies for intervening on these mechanisms to improve the outcomes of racial/ethnic minority youths.


Stacked abdominal flap for unilateral breast reconstruction.
The abdominal flap can be used in a stacked, double-pedicle configuration for unilateral breast reconstruction. Aided by preoperative mapping, this is a good option when a single-pedicle flap is deemed unsuitable. We present reliable outcomes using the stacked flap and a logical classification system for its use. From 2008 to 2013, 18 patients underwent a stacked abdominal flap for unilateral breast reconstruction. Flaps utilized deep inferior epigastric (D) and superficial inferior epigastric (S) pedicle combinations. Preoperative computed tomography angiogram was performed on all patients. Medical records were reviewed for complications and clinical data, and a thorough clinical evaluation was performed on all patients at follow-up. Flaps were all double-pedicled, with the secondary pedicle anastomosed onto the primary pedicle (type 1 to 3) or onto a second recipient vessel (type 4). Flaps were then classified into groups, based on pedicle dominance and intraflap anastomosis. Twelve reconstructions were immediate and six delayed. Mean operative time was 7 hours, the most frequently used configuration being a type 1 DD, that is, secondary pedicle (D) anastomosed end-to-end onto the superior continuation of the primary pedicle (D). Average hospital stay was 6 days. There were no flap losses and minimal complications, and mean follow-up was 20 months. Use of this flap poses a greater challenge to the microsurgical breast reconstruction. We demonstrate its reliable use in women deemed unsuitable for a single-pedicle flap. Our structured system clarifies vascular options, and preoperative perforator mapping tools are essential to the success of this technique.


Effect of training on voluntary activation of human fusimotor neurons.
The study was designed to determine if human subjects could develop a strategy that would allow them to activate muscle spindle afferents selectively, without contraction or stretch of the receptor-bearing muscle. Recordings were made from 19 identified muscle spindle afferents using insulated tungsten microelectrodes inserted into motor fascicles innervating ankle dorsiflexors, ankle plantar-flexors, and intrinsic muscles of the hand. The discharge of nine of the spindle endings accelerated in voluntary contractions at low levels of effort (less than 10% of maximum force). The remaining 10 endings had relatively high thresholds for activation in voluntary contractions. Despite periods of relative freedom to move and prolonged feedback of the spindle discharge and relevant electromyographic signals, subjects did not develop a strategy with which they could activate any of the afferents selectively. The findings suggest that fusimotor neurons in awake human subjects cannot be activated voluntarily without also activating low-threshold alpha-motoneurons. This is in contrast to reports of selective activity in muscle spindle afferents in freely moving cats. There are two possible explanations: 1) the motor tasks studied in man and cat are not equivalent, or 2) there is a species difference in the control and excitability of fusimotor neurons.


Dark Web Marketplaces and COVID-19: before the vaccine.
The COVID-19 pandemic has reshaped the demand for goods and services worldwide. The combination of a public health emergency, economic distress, and misinformation-driven panic have pushed customers and vendors towards the shadow economy. In particular, dark web marketplaces (DWMs), commercial websites accessible via free software, have gained significant popularity. Here, we analyse 851,199 listings extracted from 30 DWMs between January 1, 2020 and November 16, 2020. We identify 788 listings directly related to COVID-19 products and monitor the temporal evolution of product categories including Personal Protective Equipment (PPE), medicines (e.g., hydroxyclorochine), and medical frauds. Finally, we compare trends in their temporal evolution with variations in public attention, as measured by Twitter posts and Wikipedia page visits. We reveal how the online shadow economy has evolved during the COVID-19 pandemic and highlight the importance of a continuous monitoring of DWMs, especially now that real vaccines are available and in short supply. We anticipate our analysis will be of interest both to researchers and public agencies focused on the protection of public health.


Prevalence of depressive symptoms among Italian medical students: The multicentre cross-sectional "PRIMES" study.
Four percent of the world's population suffers from depression, which is a major public health issue. Medical students are at risk, as their depressive symptoms (DS) prevalence is reported to be approximately 27% worldwide. Since few data on Italian medical students exist, this study aimed to estimate their DS prevalence and assess risk and protective factors. The PRIMES was a multicentre cross-sectional study performed in 12 Italian medical schools. Questionnaires were self-reported and included 30 sociodemographic items and the Beck Depression Inventory-II (BDI-II). The primary outcome was the presence of DS (BDI-II score≥14). The main analyses were chi-squared tests and multivariable logistic regressions with a p-value<0.05 considered significant. The number of collected questionnaires was 2,513 (117 BDI-II incomplete). Females accounted for 61.3% of the respondents, and the median age was 22 years (IQR = 4). The prevalence of DS was 29.5%. Specifically, 14.0% had mild depression, 11.1% had moderate depression, and 4.5% had severe depression. The main risk factors for DS were age, being female, bisexual/asexual orientation, living with partner/housemates, poor economic status (worsened by living far from home), less than 90 min of weekly exercise, relatives with psychiatric disorders, personal chronic disease, judging medical school choice negatively, unsatisfying friendships with classmates, competitive and hostile climate among classmates, thinking that medical school hinders specific activities and being worried about not measuring up to the profession. Protective factors included family cohesion, hobbies, intellectual curiosity as a career motivation and no worries about the future. Italian medical students are at high risk of reporting DS, similar to the global population of medical students'. Medical schools must make efforts to implement preventive and treatment interventions by offering counselling and working on modifiable factors, such as lifestyle and learning climate.


A longitudinal study of the effects of graduate medical education on hospital operating costs.
To examine the effect of graduate medical education sponsorship on hospital operating costs over a seven-year period, to test for a longitudinal association between teaching intensity and cost, and to determine whether the indirect medical education (IME) payment adjustments made under Medicare's Prospective Payment System are appropriate. Medicare cost and payment data from the Hospital Cost Report Information System and other related HCFA files, from FFY 1989 through 1995. The study population consists of all short-stay hospitals (approximately 5,000) participating in Medicare and receiving case payments by diagnosis-related groups. The original cost functions used to develop indirect medical education payment adjustments under PPS are re-estimated with panel data. Specification changes are included based on findings from critiques of the original hospital cost model. Additional variations on the model are explored to test for differences by hospital status, to control for the effect of additional disproportionate share and outlier payments, and to isolate the effects of improved case-mix measurement on model results. Fixed effects regression produces no evidence of a significant within-hospital association between increased sponsorship of medical residents and increased cost per case. In models designed to capture a cross-sectional association, operating costs are positively related to teaching activity, but the association shows a decline in strength over time. In all years, the strength of the association is significantly greater among hospitals eligible for disproportionate share adjustments and among major teaching hospitals. Controlling for secular trends of increased teaching intensity results in a pattern of declining cross-sectional teaching coefficients that supports a theory that observed teaching effects are the result of unmeasured case severity. A significant but declining cost differential is observed between teaching and nonteaching hospitals. The association appears to be related to hospital and patient characteristics that cannot be controlled using currently available case-mix and wage indices. Longitudinal models do not provide evidence to support a payment adjustment formula that allows individual hospitals to recompute their IME adjustment rates as their teaching ratios rise or fall from year to year. Cross-sectional findings suggest that re-estimations of the teaching effect may be appropriate when significant improvements occur in Medicare case-mix measurement.


Enhanced Size Selection in Two-Photon Excitation for CsPbBr3 Perovskite Nanocrystals.
Cesium lead bromide (CsPbBr3) perovskite nanocrystals (NCs), with large two-photon absorption (TPA) cross-section and bright photoluminescence (PL), have been demonstrated as stable two-photon-pumped lasing medium. With two-photon excitation, red-shifted PL spectrum and increased PL lifetime is observed compared with one-photon excitation. We have investigated the origin of such difference using time-resolved laser spectroscopies. We ascribe the difference to the enhanced size selection of NCs by two-photon excitation. Because of inherent nonlinearity, the size dependence of absorption cross-section under TPA is stronger. Consequently, larger size NCs are preferably excited, leading to longer excited-state lifetime and red-shifted PL emission. In a broad view, the enhanced size selection in two-photon excitation of CsPbBr3 NCs is likely a general feature of the perovskite NCs and can be tuned via NC size distribution to influence their performance within NC-based nonlinear optical materials and devices.


Highly Active Cranberry's Polyphenolic Fraction: New Advances in Processing and Clinical Applications.
Cranberry is a fruit originally from New England and currently growing throughout the east and northeast parts of the USA and Canada. The supplementation of cranberry extracts as nutraceuticals showed to contribute to the prevention of urinary tract infections, and most likely it may help to prevent cardiovascular and gastroenteric diseases, as highlighted by several clinical trials. However, aiming to validate the efficacy and safety of clinical applications as long-term randomized clinical trials (RCTs), further investigations of the mechanisms of action are required. In addition, a real challenge for next years is the standardization of cranberry's polyphenolic fractions. In this context, the optimization of the extraction process and downstream processing represent a key point for a reliable active principle for the formulation of a food supplement. For this reason, new non-conventional extraction methods have been developed to improve the quality of the extracts and reduce the overall costs. The aim of this survey is to describe both technologies and processes for highly active cranberry extracts as well as the effects observed in clinical studies and the respective tolerability notes.


Epidemiology and clinical features of toxicity following recreational use of synthetic cannabinoid receptor agonists: a report from the United Kingdom National Poisons Information Service.
Toxicity from the use of synthetic cannabinoid receptor agonists (SCRAs) has been encountered increasingly frequent in many countries. To characterise presentation rates, demographic profiles and reported clinical features for users of SCRAs referred by health professionals in the United Kingdom to the National Poisons Information Service (NPIS), to compare reported toxicity between commonly used branded products, and to examine the impact of legal control measures on enquiry numbers. NPIS telephone enquiry records were searched for SCRA-related terms for the 8-year period 1st January 2007 to 31st December 2014, consolidating multiple enquiries about the same case into a single record. Demographic data, reported exposure details, clinical features and poisoning severity were analysed, excluding cases where SCRA exposure was unlikely. Enquiries to the NPIS were made concerning 510 individuals relating to probable SCRA use, with annual numbers increasing year on year. Most patients were male (80.8%) and <25 years old (65.1%). Common clinical features reported in the 433 (84.9%) patients reporting SCRA use without other substances included tachycardia (n = 73, 16.9%), reduced level of consciousness (n = 70, 16.2%), agitation or aggression (n = 45, 10.4%), vomiting (n = 30, 6.9%), dizziness (n = 26, 6.0%), confusion (n= 21, 4.8%), mydriasis (n = 20, 4.6%) and hallucinations (n = 20, 4.6%). The Maximum Poisoning Severity Score (PSS) indicated severe toxicity in 36 cases (8.3%). Legal control of "second generation" SCRAs did not affect the rate of growth in enquiry numbers or the proportion with severe toxicity. The three most commonly reported products were "Black Mamba" (n= 88, 20.3%), "Pandora's Box" (n= 65, 15.0%) and "Clockwork Orange" (n= 27, 6.2%). Neurological and general features were recorded more often with "Clockwork Orange" than for "Black Mamba" and "Pandora's Box", but moderate or severe toxicity was significantly less common after reported use of this product. Enquiries about SCRA-related toxicity have become increasingly frequent in the UK in spite of legal controls and commonly involve younger males. Differences in the patterns of toxicity associated with different branded preparations may occur, although further work with larger patient numbers is needed to confirm this.


Effect of Wear Conditions, Parameters and Sliding Motions on Tribological Characteristics of Basalt and Glass Fibre Reinforced Epoxy Composites.
Basalt fibre is a promising mineral fibre that has high potential to replace synthetic based glass fibre in today's stringent environmental concern. In this study, friction and wear characteristics of glass and basalt fibres reinforced epoxy composites were studied and comparatively evaluated at two test stages. The first stage was conducted at fixed load, speed and distance under three different conditions; adhesive, abrasive and erosive wear, wherein each composite specimens slide against steel, silicon carbide, and sand mixtures, respectively. The second stage was conducted involving different types of adhesive sliding motions against steel counterpart; unidirectional and reciprocating motion, with the former varied at pressure-velocity (PV) factor; 0.23 MPa·m/s and 0.93 MPa·m/s, while the latter varied at counterpart's configuration; ball-on-flat (B-O-F) and cylinder-on-flat (C-O-F). It was found that friction and wear properties of composites are highly dependent on test conditions. Under 10 km test run, Basalt fibre reinforced polymer (BFRP) composite has better wear resistance against erosive sand compared to Glass fibre reinforced polymer (GFRP) composite. In second stage, BFRP composite showed better wear performance than GFRP composite under high PV of unidirectional sliding test and under B-O-F configuration of reciprocating sliding test. BFRP composite also exhibited better friction properties than GFRP composite under C-O-F configuration, although its specific wear rate was lower. In scanning electron microscopy examination, different types of wear mechanisms were revealed in each of the test conducted.


Up-to-date report of botulinum toxin type A treatment in patients with gustatory sweating (Frey's syndrome).
Several therapeutic approaches exist to treat gustatory sweating (Frey's syndrome) following parotidectomy. Because of the lack of effective treatment, a new therapeutic modality using botulinum toxin injections was presented previously by our group. The duration of the demonstrated positive effect was essentially unknown so far. Based on our experiences using this technique since December 1993, the purpose of this clinical investigation was to make an up-to-date report and demonstrate the duration of effect of BOTOX injections in patients with severe gustatory sweating. Nineteen patients with severe gustatory sweating have been treated with BOTOX by intracutaneous injections into the affected skin areas. The maximal follow-up time was 33 months. The results were obtained by interviews and controls using Minor's starch iodine test. In all treated cases (n = 19 patients, 22 treated sides) gustatory sweating ceased completely within 2 days. Side effects were absent. In 12 patients gustatory sweating reappeared. The mean duration of effect was 17.3 months (subjective personal communication of 18 patients). Findings show that intracutaneous injection of BOTOX is a highly effective, safe, and minimally invasive treatment of Frey's syndrome with long-lasting therapeutic effect.


Barriers to referral to inpatient palliative care units in Japan: a qualitative survey with content analysis.
We investigated the barriers to referral to inpatient palliative care units (PCUs) through a qualitative study across various sources of information, including terminal cancer patients, their families, physicians, and nurses. There were 63 participants, including 13 advanced cancer patients, 10 family members, 20 physicians, and 20 nurses in palliative care and acute care cancer settings from five regional cancer institutes in Japan. Semi-structured interviews were conducted regarding barriers to referral to PCU, and data were analyzed by content analysis method. A total of 21 barriers were identified by content analysis. The leading barriers were (1) a negative image of PCUs by patients and families (n = 39), (2) delay of termination of anti-cancer treatment by physicians in the general wards (n = 24), (3) unwillingness to end anti-cancer treatment and denial of the fatal nature of the disease by patients and families (n = 22), (4) patient's wish to receive care from familiar physicians and nurses (n = 20), and (5) insufficient knowledge of PCUs by medical staff in general wards (n = 17). To correct these unfavorable images and misconceptions of PCUs, it is important to eliminate the negative image of PCUs from the general population, patients, families, and medical staffs. In addition, early introduction of palliative care options to patients and communication skills training regarding breaking bad news are relevant issues for a smooth transition from anti-cancer treatment to palliative care.


Menopausal symptoms and quality of life among Saudi women visiting primary care clinics in Riyadh, Saudi Arabia.
Menopause is associated with somatic, vasomotor, psychological, and sexual complaints that may affect quality of life. We determined the prevalence and severity of menopausal symptoms and their impact on the quality of life among Saudi women visiting primary care centers in Riyadh, Saudi Arabia. A cross-sectional study was conducted from October to November 2010. In total, 119 women aged 45-60 years were randomly interviewed using a questionnaire. Participants were divided into three categories: premenopausal (n=31), perimenopausal (n=49), and postmenopausal (n=39). The Menopause Rating Scale (MRS) assessed the prevalence and severity of eleven menopausal symptoms. Mean scores of menopausal categories were compared for different symptoms. The mean age at menopause was 48.3±3 years (median, 49 years). The symptoms reported to be most prevalent were joint and muscle pain (80.7%), physical and mental exhaustion (64.7%), and hot flushes and sweating (47.1%). Somatic and psychological symptoms were highly prevalent in perimenopausal women compared to other groups. The mean overall quality-of-life score was higher in perimenopausal women, while the total MRS score indicated that the symptoms were mild in severity (MRS <9). The prevalence of menopausal symptoms was comparable to previous studies in Asian women; however, the prevalence of classic symptoms of hot flushes and night sweats was lower than reported in Western studies. Saudi women reported an MRS score indicating milder severity of symptoms, reflecting better quality of life and ability to cope with climacteric symptoms.


Neurochemical regulation of the states of alertness.
Sleep and wakefulness are two active states of the central nervous system, and sleep is further subdivided into two components: orthodox sleep (OS) and paradoxical sleep (PS). The relationships between sleep and wakefulness are asymmetrical inasmuch as wakefulness can override sleep whereas the converse occurs much more rarely. This probably indicates that sleep and wakefulness are mediated by different sorts of neurotransmitter systems. The types of neurotransmission, and the concepts of cotransmitter and neuromodulation are briefly outlined. The role of particular wiring of some neurones is also relevant in the understanding vigilance regulation. Activation of catecholamine pathways is coincident with wakefulness and deactivation is one of the conditions necessary for sleep to take place. The induction of PS is also positively related to brain catecholaminergic activity; the level of activation of these systems appears, however, to be lower during PS than during wakefulness. Serotonin, once thought to be the main transmitter in sleep, now appears to regulate the synthesis of yet unidentified sleep factors, responsible for OS and PS realization. Cholinergic mechanisms are also involved in wakefulness and in PS triggering. Such mechanisms may be part of the switch between wakefulness and PS, possibly by controlling the level of catecholaminergic activity. Gamma-aminobutyric acid also participates in the vigilance states, and benzodiazepines exert hypnogenic effects by modulating gamma-aminobutyric acid transmission. Sleep factors and hypnogenic peptides probably exist, but none of the substances so far described can yet be identified as the critical component in the subtle and still largely elusive mechanisms of vigilance regulation.


Oxacillin-induced inhibition of protein and RNA synthesis in a tolerant Staphylococcus aureus isolate.
A clinical isolate of Staphylococcus aureus was found to be tolerant (MBC much greater than MIC) to a number of beta-lactam antibiotics, including oxacillin. Biophotometric analysis showed that a number of concentrations of oxacillin were capable of stimulating rapid cellular lysis in this organism, but the extent of lysis was antibiotic concentration dependent and limited. Cell cultures treated with an antibiotic concentration yielding the maximum rate and extent of lysis were analyzed for protein and RNA synthesis by pulse-labeling techniques. RNA synthesis was initially stimulated and then severely inhibited. Protein synthesis was not inhibited initially; however, the increase in the rate of synthesis expected as the result of logarithmic growth was not observed. Instead, the antibiotic-treated culture maintained for approximately 50 min the rate of protein synthesis ongoing at the time of antibiotic addition. The rate of protein synthesis declined thereafter. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis of protein samples taken 1 and 3 h after antibiotic addition showed that the shutdown of protein synthesis was not coordinate but rather was suggestive of the operation of a stress regulon perhaps similar to those responsible for heat shock, SOS, and oxidation stress.


Cutting edge: regulation of uterine NKT cells by a fetal class I molecule other than CD1.
The peri-implantation uterus contains an expanded population of NK1.1(+) V alpha 14(+) TCR(int) (NKT) lymphocytes. Although these cells bear the above features in common with other NKT cells populations in thymus, bone marrow, liver, and spleen, they differ from these other populations in terms of an altered V beta repertoire and absence of a CD4(+) component. In this study, we demonstrate that the uterine population also differs from other NKT cell populations because they recognize a class I/class I-like molecule other than CD1, whereas most previously described V alpha 14(+) NKT cells are CD1-restricted. Moreover, the class I/class I-like molecule leading to the uterine NKT cell expansion may be supplied by the fetus. These data demonstrate a novel mechanism whereby the fetus is capable of modulating the maternal immune system.


Delivery Room Management of Meconium-Stained Newborns and Respiratory Support.
: media-1vid110.1542/5839992674001PEDS-VA_2018-1485Video Abstract BACKGROUND AND OBJECTIVES: Recently, the Neonatal Resuscitation Program (NRP) recommended against routine endotracheal suctioning of meconium-stained nonvigorous newborns but suggested resuscitation with positive pressure ventilation. Our purpose is to study the effects of this change in management. In this multicenter cohort study, we compare 130 nonvigorous newborns born during the retrospective 1-year period before the implementation of new NRP guidelines (October 1, 2015, to September 30, 2016) to 101 infants born during the 1-year prospective period after implementation (October 1, 2016, to September 30, 2017). Endotracheal suctioning was performed predominantly in the retrospective group compared with the prospective group (70% vs 2%), indicating the change in practice. A significantly higher proportion of newborns were admitted to the NICU for respiratory issues in the prospective group compared with the retrospective group (40% vs 22%) with an odds ratio (OR) of 2.2 (95% confidence interval [CI]: 1.2-3.9). Similarly, a significantly higher proportion of infants needed oxygen therapy (37% vs 19%) with an OR of 2.5 (95% CI: 1.2-4.5), mechanical ventilation (19% vs 9%) with an OR of 2.6 (95% CI: 1.1-5.8), and surfactant therapy (10% vs 2%) with an OR of 5.8 (95% CI: 1.5-21.8). There were no differences in the incidence of other outcomes, including meconium aspiration syndrome. The recent NRP guideline change was not associated with an increased incidence of meconium aspiration syndrome but was associated with an increased incidence of NICU admissions for respiratory issues. Also, the need for mechanical ventilation, oxygen, and surfactant therapy increased.


Men who have sex with men account for nonuse of condoms.
Despite several decades of health promotion activity targeted at men who have sex with men (MSM), rates for nonuse of condoms for anal sex among MSM worldwide and in New Zealand have been increasing in recent times. In this article we report on the first local qualitative investigation undertaken in Auckland, New Zealand, of how members of a particular group of MSM account for nonuse of condoms for anal sex with other men. We collected qualitative data from 22 MSM (17 face-to-face interviews, and three online interviews involving 5 men). Thematic analysis led to the identification of five patterns that account for the nonuse of condoms: (a) substance use, (b) psychological aspects, (c) difficulties using condoms, (d) condoms in relationships, and (e) managing risk. We conclude that although this information generally confirms the findings in the wider research literature, it is also important in the local context as the first research that can be used with confidence in developing and refining health promotion initiatives to address this issue.


Evidence Use in Mental Health Policy Making for Children in Foster Care.
Considerable attention is being given to the use of research evidence to inform public policy making. Building upon Weiss's model of research utilization, we examined the types and uses of evidence that child welfare administrators used in response to federal policy reforms requiring psychotropic medications oversight for children in foster care. Participants relied on a range of "global" and "local" evidence types throughout the policy development phase. Global research evidence was used to raise awareness about problems associated with psychotropic medication use. Local evidence helped to contextualize concerns and had problem-solving and political uses. In most states, policy actions were informed by a combination of evidence types.


Hodgkin's disease presenting below the diaphragm. The experience of the Gruppo Italiano Studio Linfomi (GISL).
Infradiaphragmatic Hodgkin's disease is rare, making up 5-12% of cases in clinical stages I and II; consequently, several questions concerning prognosis and treatment strategy remain to be answered. The aim of this study was to analyze the clinical and prognostic characteristics and outcome of this condition. A series of 282 patients with CS I-II Hodgkin's disease (HD) was investigated. In 31 patients the disease was confined below the diaphragm (BDHD), and in the remaining above the diaphragm (ADHD). The presenting features and outcomes were compared in the two groups. The BDHD group was older (p < 0.0002), had a higher frequency of males (p < 0.08) and a different histological subtype group distribution (p < 0.0001). Stage II BDHD patients had a worse overall survival rate (OS) than stage II ADHD patients (68.8% vs 86.6% at 8 years, p < 0.01) if age is not considered; patients with more than 40 years of age, in fact, had the same survival rates as those with ADHD. BDHD patients with intra-abdominal disease alone had worse prognostic factors and OS (p = 0.12) than patients with inguinal-femoral nodes. Although BDHD patients present distinct features, they have the same OS and relapse-free survival rate as age-adjusted ADHD patients. According to our experience patients with stage I peripheral BDHD respond well to radiotherapy-based regimens. Those with stage II and or intra-abdominal disease are more challenging; chemotherapy or a combined therapy seem to be more suitable approaches for these patients.


Smoking marijuana in public: the spatial and policy shift in New York City arrests, 1992-2003.
During the 1990s, the New York Police Department (NYPD) greatly expanded arrests for smoking marijuana in public view (MPV). By 2000, MPV accounted for 15% of all arrests. The NYPD's supporters report this arrest activity is just part of quality-of-life (QOL) policing, which seeks to promote order in public locations by aggressively patrolling for behaviors that offend the general population. The NYPD's critics contend the NYPD has disproportionately targeted poor, black and Hispanic communities. This paper analyzes the geographic distribution of MPV arrests from 1992 to 2003 to evaluate these alternative perspectives. A sequence of maps identify that the focus of MPV arrests shifted over time. In the early 1990s, most MPV arrests were recorded in the lower half of Manhattan (NYC's business and cultural center) and by the transit police. However, in the later 1990s and into the 2000s, most MPV arrests were recorded in high poverty, minority communities outside the lower Manhattan area and by the NYPD's policing of low-income housing projects. These findings suggest that current levels of MPV arrests in NYC may not be justifiable, at least based solely on the purpose of QOL policing. Accordingly, we suggest the NYPD seriously consider less stringent measures for public marijuana smokers, especially for use outside of highly public locations in recessed locations hidden from open view (like the stairwell of a housing project). Alternatives could include Desk Appearance Tickets, fines, or simply requiring smokers to desist, discard their product, and move along.


Adenovirus-mediated transfer of dominant-negative rho-kinase induces a regression of coronary arteriosclerosis in pigs in vivo.
Small GTPase Rho and its target Rho-kinase/ROK/ROCK play an important role in various cellular functions, including smooth muscle contraction, actin cytoskeleton organization, and cell adhesion and migration, all of which may be involved in the pathogenesis of arteriosclerosis. Here, we show that adenovirus-mediated transfer of dominant-negative Rho-kinase (DNRhoK) induces a marked regression of coronary constrictive remodeling and abolishes coronary vasospastic activity in vivo. Porcine coronary segments were chronically treated with interleukin-1beta, which resulted in the development of constrictive remodeling and vasospastic responses to serotonin, as previously reported. Adenovirus-mediated transfer of DNRhoK, but not that of beta-galactosidase, into the interleukin-1beta-treated coronary segment caused a marked regression of the constrictive remodeling and abolished the vasospastic activity in 3 weeks. Western blot analysis showed that the phosphorylation of adducin and the ezrin/radixin/moesin family, the target proteins of Rho-kinase, were upregulated at the coronary lesions and were significantly suppressed by the transfer of DNRHOK: These results indicate that Rho-kinase is substantially involved in coronary constrictive remodeling and vasospastic responses, both of which can be reversed by the selective inhibition of the molecule in our porcine model in vivo.


Accommodation of structural rearrangements in the huntingtin-interacting protein 1 coiled-coil domain.
Huntingtin-interacting protein 1 (HIP1) is an important link between the actin cytoskeleton and clathrin-mediated endocytosis machinery. HIP1 has also been implicated in the pathogenesis of Huntington's disease. The binding of HIP1 to actin is regulated through an interaction with clathrin light chain. Clathrin light chain binds to a flexible coiled-coil domain in HIP1 and induces a compact state that is refractory to actin binding. To understand the mechanism of this conformational regulation, a high-resolution crystal structure of a stable fragment from the HIP1 coiled-coil domain was determined. The flexibility of the HIP1 coiled-coil region was evident from its variation from a previously determined structure of a similar region. A hydrogen-bond network and changes in coiled-coil monomer interaction suggest that the HIP1 coiled-coil domain is uniquely suited to allow conformational flexibility.


Multitrophic interactions in the rhizosphere microbiome of wheat: from bacteria and fungi to protists.
Plants modulate the soil microbiota by root exudation assembling a complex rhizosphere microbiome with organisms spanning different trophic levels. Here, we assessed the diversity of bacterial, fungal and cercozoan communities in landraces and modern varieties of wheat. The dominant taxa within each group were the bacterial phyla Proteobacteria, Actinobacteria and Acidobacteria; the fungi phyla Ascomycota, Chytridiomycota and Basidiomycota; and the Cercozoa classes Sarcomonadea, Thecofilosea and Imbricatea. We showed that microbial networks of the wheat landraces formed a more intricate network topology than that of modern wheat cultivars, suggesting that breeding selection resulted in a reduced ability to recruit specific microbes in the rhizosphere. The high connectedness of certain cercozoan taxa to bacteria and fungi indicated trophic network hierarchies where certain predators gain predominance over others. Positive correlations between protists and bacteria in landraces were preserved as a subset in cultivars as was the case for the Sarcomonadea class with Actinobacteria. The correlations between the microbiome structure and plant genotype observed in our results suggest the importance of top-down control by organisms of higher trophic levels as a key factor for understanding the drivers of microbiome community assembly in the rhizosphere.


Right and Left Ventricular Function and Mass in Male Elite Master Athletes: A Controlled Contrast-Enhanced Cardiovascular Magnetic Resonance Study.
It is under debate whether the cumulative effects of intensive endurance exercise induce chronic cardiac damage, mainly involving the right heart. The aim of this study was to examine the cardiac structure and function in long-term elite master endurance athletes with special focus on the right ventricle by contrast-enhanced cardiovascular magnetic resonance. Thirty-three healthy white competitive elite male master endurance athletes (age range, 30-60 years) with a training history of 29±8 years, and 33 white control subjects pair-matched for age, height, and weight underwent cardiopulmonary exercise testing, echocardiography including tissue-Doppler imaging and speckle tracking, and cardiovascular magnetic resonance. Indexed left ventricular mass and right ventricular mass (left ventricular mass/body surface area, 96±13 and 62±10 g/m(2); P<0.001; right ventricular mass/body surface area, 36±7 and 24±5 g/m(2); P<0.001) and indexed left ventricular end-diastolic volume and right ventricular end-diastolic volume (left ventricular end-diastolic volume/body surface area, 104±13 and 69±18 mL/m(2); P<0.001; right ventricular end-diastolic volume/body surface area, 110±22 and 66±16 mL/m(2); P<0.001) were significantly increased in athletes in comparison with control subjects. Right ventricular ejection fraction did not differ between athletes and control subjects (52±8 and 54±6%; P=0.26). Pathological late enhancement was detected in 1 athlete. No correlations were found for left ventricular and right ventricular volumes and ejection fraction with N-terminal pro-brain natriuretic peptide, and high-sensitive troponin was negative in all subjects. Based on our results, chronic right ventricular damage in elite endurance master athletes with lifelong high training volumes seems to be unlikely. Thus, the hypothesis of an exercise-induced arrhythmogenic right ventricular cardiomyopathy has to be questioned.


Role of cyclin-dependent kinase 5 in early brain injury following experimental subarachnoid hemorrhage.
Increasing evidence indicates that early brain injury (EBI) can contribute to poor outcomes following subarachnoid hemorrhage (SAH), and is associated with apoptosis. Cyclin-dependent kinase 5 (Cdk5) is a key mediator of neuronal viability. The role of Cdk5 in several neurological disorders has been elucidated; however, its role in EBI after SAH remains unclear. The present study aimed to explore the involvement of Cdk5 in EBI after SAH. The expression levels of Cdk5, Cdk5 phosphorylated at Tyr15 (Cdk5-pTyr15) and p25 (a Cdk5 activator) were assessed by western blotting, and the cell distribution of Cdk5 was demonstrated by double immunofluorescence. The expression levels of caspase-3 and cytochrome c were evaluated by western blotting to assess the severity of neuronal apoptosis. Nissl and TUNEL staining experiments were performed to observe the effects of roscovitine, a Cdk5 inhibitor, on EBI following SAH. The results indicated that the expression levels of Cdk5, p25 and Cdk5-pTyr15 significantly increased in the rat temporal cortex following SAH. Immunofluorescence staining indicated that Cdk5 was expressed in the neurons and astrocytes of the rat cortex after SAH and that Cdk5 underwent nuclear translocation in neurons. Roscovitine administration effectively inhibited Cdk5 activation. In conclusion, roscovitine treatment significantly mitigated EBI and alleviated cerebral edema following SAH. These findings suggest that Cdk5 is an important target in SAH therapy.


An opioid pathway in the hypothalamus of the turkey that stimulates prolactin secretion.
Circulating prolactin (PRL) levels increase when dynorphin is infused into the turkey brain. This study tested the hypothesis that centrally infused dynorphin requires an intact vasoactive intestinal peptide (VIP) system in order to stimulate turkey PRL secretion. It also investigated the roles of the dopaminergic and serotonergic systems in dynorphin-induced PRL release. Drugs were infused into the third ventricle of anesthetized laying turkeys via stereotaxically guided cannulae and circulating blood was assayed for changes in PRL levels. When a highly selective kappa opioid receptor antagonist was given prior to dynorphin injection, the PRL response to dynorphin was almost totally blocked. The coinfusion of either a serotonin (5-HT) or a D(1) dopamine (DA) receptor antagonist with dynorphin prevented the increase in PRL observed in birds when dynorphin was infused alone. On the other hand, the kappa opioid receptor antagonist failed to prevent the 5-HT-induced release of PRL. In hens actively immunized against VIP, infused dynorphin was unable to increase plasma PRL levels and infused VIP gave a muted PRL rise, while large increases in PRL were seen in nonimmunized birds receiving the same infusions. These data show that: (1) dynorphin stimulates PRL secretion by activating kappa opioid receptors in the avian hypothalamus, and (2) dynorphin, 5-HT, DA, and VIP stimulate avian PRL secretion via a common pathway expressing kappa opioid, serotonergic, dopaminergic, and VIPergic receptors at synapses arranged serially in that functional order, with the VIPergic system as the final mediator (releasing factor).


rs62139665 Polymorphism in the Promoter Region of EpCAM Is Associated With Hepatitis C Virus-Related Hepatocellular Carcinoma Risk in Egyptians.
Hepatocellular carcinoma (HCC) is a universal health problem that is particularly alarming in Egypt. The major risk factor for HCC is hepatitis C virus (HCV) infection which is a main burden in Egypt. The epithelial cell adhesion molecule (EpCAM) is a stem cell marker involved in the tumorigenesis and progression of many malignancies, including HCC. We investigated the association of -935 C/G single nucleotide polymorphism in EpCAM promoter region (rs62139665) with HCC risk, EpCAM expression and overall survival in Egyptians. A total of 266 patients (128 HCV and 138 HCC cases) and 117 age- and sex-matched controls participated in this study. Genotyping, performed using allelic discrimination and confirmed by sequencing, revealed a significant association between EpCAM rs62139665 and HCC susceptibility, with higher GG genotype and G allele distribution in HCC patients than in non-HCC subjects. Such association was not detected in HCV patients compared to controls. EpCAM gene expression levels, determined in blood by RT-qPCR, and its serum protein expression levels, determined by ELISA, were significantly higher in GG relative to GC+CC genotype carriers in HCV and HCC patients in a recessive model. ROC analysis of EpCAM protein levels revealed significant discriminatory power between HCC patients and non-HCC subjects, with improved diagnostic accuracy when combining α-fetoprotein and EpCAM compared to that of α-fetoprotein alone. Altogether, EpCAM rs62139665 polymorphism is significantly associated with HCC and with EpCAM gene and protein expression levels in the Egyptian population. Moreover, serum EpCAM levels may hold promise for HCC diagnosis and for improving the diagnostic accuracy of α-fetoprotein.


[Bacterial factors and decompensation of cor pulmonale in patients with pulmonary tuberculosis].
Sputum from 88 patients with different forms of pulmonary tuberculosis complicated by chronic cor pulmonale (CCP) was tested for Mycobacterium tuberculosis (MBT) and nonspecific flora. The high occurrence of multidrug resistance of MBT and nonspecific causative agents are found in patients with signs of heart failure in the presence of decompensatory CCP in 20% of cases, the frequency of concomitant chronic bronchitis was 86%.


Insulin effects in clarias batrachus L.: a combined biochemical and anatomical study.
The effect of mammalian insulin was studied in a freshwater fish, Clarias batrachus, at both high and low ambient temperatures. The hormone produced a significant but delayed, yet recoverable, lowering of blood glucose, a concurrent decrease in liver glycogen, and an increase in the glycogen content of muscles. The decrease in brain glycogen occurred during advanced hypoglycemia. Hypoglycemic seizures developed intermittently in most of the fishes whose plasma glucose and brain glycogen levels had been considerably depleted. Necrobiotic changes in the pancreatic islets, including degranulation and atrophy, and necrosis of B cells, were seen in the treated fish. In some cases damage to A cells and the acinar tissue was also observed. With the restitution of normal glucose and glycogen values, the islet cells also seemed to have recuperated. Changes in glycemia, glycogen, and the islets were more pronounced in the fishes held at 24 degrees C than in those at 10 degrees C, indicating that the ambient temperature plays an important role in blood glucose homeostasis as well as insulin.


Combining oxytocin and cognitive bias modification training in a randomized controlled trial: Effects on trust in maternal support.
Research on the social effects of intranasal oxytocin in children is scarce. Oxytocin has been proposed to have clearer beneficial effects when added to social learning paradigms. The current study tested this proposition in middle childhood by assessing effects of cognitive bias modification (CBM) training and oxytocin on trust in maternal support. Children (N = 100, 8-12 years) were randomly assigned to one of two training conditions: CBM training aimed at increasing trust or neutral placebo training. Within each training condition, half the participants received oxytocin and half a placebo. Main and interaction effects were assessed on measures of trust-related interpretation bias and trust. We explored whether child characteristics moderated intervention effects. Children in the CBM training were faster to interpret maternal behaviour securely versus insecurely. Effects did not generalize to interpretation bias measures or trust. There were no main or interaction effects of oxytocin. Exploratory moderation analyses indicated that combining CBM training with oxytocin had less positive effects on trust for children with more internalizing problems. As this was the first study combining CBM and oxytocin, replication of the results is needed. This study combined a social learning paradigm with oxytocin in children. CBM training was effective at an automatic level of processing. Oxytocin did not enhance CBM effects or independently exert effects. Research in larger samples specifying when oxytocin might have beneficial effects is necessary before oxytocin can be used as intervention option in children.


Morph-specific proteins in pollen and styles of distylous turnera (Turneraceae).
We used nondenaturing isoelectric focusing (IEF) in a survey of plants from 11 populations to identify style and pollen proteins unique to the short-styled morph of Turnera scabra, T. sulnitata and T. krapovickasii. Three protein bands [approximately isoelectric points (pls) 6.1, 6.3 and 6.5] were found only in styles and stigmas of short-styled plants while two bands (approximately pls 6.7 and 6.8, M(r) 56 and 59 kD) occur only in pollen of short-styled plants. Some of these bands appear very late in development, within 24 hr before flowering. Two isozyme loci were mapped to an 8.7 cM region spanning the distyly locus. Using these isozyme markers we identified progeny exhibiting recombination adjacent to the distyly locus. No recombinants between the distyly locus and the locus or loci controlling the presence of the short-styled morph-specific proteins were obtained. This suggest that the loci encoding these proteins are either extremely tightly linked to the distyly locus and in complete disequilibrium with the S allele or exhibit morph-limited expression. Crosses to a plant showing an unusual style protein phenotype demonstrated that an additional unlinked locus is required for full expression of the style proteins. The function of the morph-specific proteins is unknown.


Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human colorectal carcinoma tissue.
Activation of transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to play a role in cell proliferation, apoptosis, cytokine production, and oncogenesis. The purpose of this study was to determine whether NF-kappaB was constitutively activated in human colorectal tumor tissues and, if so, to determine the role of NF-kappaB in colorectal tumorigenesis, and furthermore, to determine the association of RelA expression with tumor cell apoptosis and the expression of Bcl-2 and Bcl-x(L). Paraffin sections of normal epithelial, adenomatous and adenocarcinoma tissues were analysed immunohistochemically for expression of RelA, Bcl-2 and Bcl-x(L) proteins. Electrophoretic mobility shift assay (EMSA) was used to confirm the increased nuclear translocation of RelA in colorectal tumor tissues. The mRNA expressions of Bcl-2 and Bcl-x(L) were determined by reverse transcription polymerase chain reaction (RT-PCR) analysis. Apoptotic cells were detected by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate fluorescence nick end labeling (TUNEL) method. The activity of NF-kappaB was significantly higher in adenocarcinoma tissue in comparison with that in adenomatous and normal epithelial tissues. The apoptotic index (AI) significantly decreased in the transition from adenoma to adenocarcinoma. Meanwhile, the expressions of Bcl-2 and Bcl-x(L) protein and their mRNAs were significantly higher in adenocarcinoma tissues than that in adenomatous and normal epithelial tissues. NF-kappaB may inhibit apoptosis via enhancing the expression of the apoptosis genes Bcl-2 and Bcl-x(L). And the increased expression of RelA/nuclear factor-kappaB plays an important role in the pathogenesis of colorectal carcinoma.


Addition of (Tri-)Block Copolymers to Phospholipid Vesicles: A Study of the Molecular Morphology and Structure by Using Hydrophobic Dye Molecules as Bilayer Probes
A dispersion of soybean lecithin in water leads to the formation of multilamellar vesicles (MLVs), which on sonication break down into small unilamellar vesicles of approximately 50 nm in diameter. The addition of polymeric molecules in the liposomal system is thought to provide the liposomes with a steric barrier. The molecules used were (tri-) block copolymers (Synperonics) containing a central hydrophobic part (polypropylene oxide) and two hydrophilic chains (polyethylene oxide). The aim of this work was to study whether it was possible to anchor deep inside the lipid bilayer the copolymer hydrophobic block. The exact localization of the copolymer molecules was investigated using a multiprobe technique. The full spectra of two hydrophobic dyes, namely Nile red (NIL) and Pinacyanol chloride (PCYN), were compared while solubilized inside the liposome bilayer. The sensitivity of their spectral characteristics to polarity and self-aggregation produced a monitor of the bilayer microenvironment. The more hydrophobic NIL proved an accurate polarity sensor of the bilayer microenvironment and the formation of PCYN dimers and nonabsorbing aggregates can be directly related to the local (bilayer) concentration of the dye and the volume available to the solubilized dye molecules. Shifts of the maximum absorbance (lambdamax) for both dyes showed that the bilayer environment was becoming more apolar with increasing copolymer concentration. The absorbance peak of PCYN due to dimer/aggregate formation increased at moderate copolymer concentrations, indicating that the polymer is incorporated inside the lipid bilayer.


Structure of Acinetobacter strain ADP1 protocatechuate 3, 4-dioxygenase at 2.2 A resolution: implications for the mechanism of an intradiol dioxygenase.
The crystal structures of protocatechuate 3,4-dioxygenase from the soil bacteria Acinetobacterstrain ADP1 (Ac 3,4-PCD) have been determined in space group I23 at pH 8.5 and 5.75. In addition, the structures of Ac 3,4-PCD complexed with its substrate 3, 4-dihydroxybenzoic acid (PCA), the inhibitor 4-nitrocatechol (4-NC), or cyanide (CN(-)) have been solved using native phases. The overall tertiary and quaternary structures of Ac 3,4-PCD are similar to those of the same enzyme from Pseudomonas putida[Ohlendorf et al. (1994) J. Mol. Biol. 244, 586-608]. At pH 8.5, the catalytic non-heme Fe(3+) is coordinated by two axial ligands, Tyr447(OH) (147beta) and His460(N)(epsilon)(2) (160beta), and three equatorial ligands, Tyr408(OH) (108beta), His462(N)(epsilon)(2) (162beta), and a hydroxide ion (d(Fe-OH) = 1.91 A) in a distorted bipyramidal geometry. At pH 5.75, difference maps suggest a sulfate binds to the Fe(3+) in an equatorial position and the hydroxide is shifted [d(Fe-OH) = 2.3 A] yielding octahedral geometry for the active site Fe(3+). This change in ligation geometry is concomitant with a shift in the optical absorbance spectrum of the enzyme from lambda(max) = 450 nm to lambda(max) = 520 nm. Binding of substrate or 4-NC to the Fe(3+) is bidentate with the axial ligand Tyr447(OH) (147beta) dissociating. The structure of the 4-NC complex supports the view that resonance delocalization of the positive character of the nitrogen prevents substrate activation. The cyanide complex confirms previous work that protocatechuate 3,4-dioxygenases have three coordination sites available for binding by exogenous substrates. A significant conformational change extending away from the active site is seen in all structures when compared to the native enzyme at pH 8.5. This conformational change is discussed in its relevance to enhancing catalysis in protocatechuate 3,4-dioxygenases.


First trimester insulin resistance and subsequent preeclampsia: a prospective study.
Insulin resistance is implicated in the pathogenesis of preeclampsia, but prospective data are limited. SHBG, a marker of insulin resistance among nonpregnant individuals, has not been studied in detail during pregnancy. We conducted a prospective, nested, case-control study to test the hypothesis that increased insulin resistance, marked by reduced first trimester SHBG levels, is associated with increased risk of subsequent preeclampsia. First trimester SHBG levels were measured in 45 nulliparous women who subsequently developed preeclampsia (blood pressure, > or =140/90 mm Hg; proteinuria, either > or =2+ by dipstick or > or =300 mg/24 h, after 20 wk gestation) and in 90 randomly selected normotensive nulliparous controls. Compared with controls, women who developed preeclampsia had significantly reduced first trimester SHBG levels (302 +/- 130 vs. 396 +/- 186 nmol/liter; P < 0.01). Every 100 nmol/liter increase in SHBG was associated with a 31% reduced risk of preeclampsia [odds ratio (OR), 0.69; 95% confidence interval (CI), 0.55, 0.88; P < 0.01]. After adjusting for covariates in a multiple logistic regression model, the association between first trimester SHBG and preeclampsia remained significant (per 100 nmol/liter increase; OR, 0.66; 95% CI, 0.47, 0.92; P = 0.01). When subjects were stratified by body mass index (lean: body mass index, < 25 kg/m(2); overweight: body mass index, > or =25 kg/m(2)), overweight women had lower SHBG levels than lean women (286 +/- 156 vs. 410 +/- 166 nmol/liter; P < 0.01), and within each stratum, women with preeclampsia had lower SHBG levels than their respective controls. In a multivariable analysis, the association between SHBG and preeclampsia strengthened among lean women, such that every 100 nmol/liter increase in serum SHBG was associated with a 55% reduction in the risk of preeclampsia (OR, 0.45; 95% CI, 0.27, 0.77; P < 0.01), whereas in overweight women, the association was mitigated (OR, 1.02; 95% CI, 0.62, 1.69; P = 0.9). We conclude that increased early pregnancy insulin resistance is independently associated with subsequent preeclampsia. First trimester SHBG levels may be a useful biomarker for preeclampsia, especially among lean women who otherwise would be perceived to be at low risk.


What should be the elements of any settlement with the tobacco industry?
Litigation and regulatory assaults on the tobacco companies may create a willingness among tobacco manufacturers to bargain resources and acceptance of public policy changes for limitations of liability, as has been seen by the recent settlement with the Liggett Group. Two elements absolutely critical to any plan are the elimination of tobacco advertising and promotion and the removal of addiction as a reason for tobacco use. Minimal components of any settlement should include: (a) acceptance by the tobacco manufacturers of the causal relationship between tobacco use and disease, and the addictive nature of nicotine; (b) a total ban on tobacco advertising and promotion; (c) FDA jurisdiction over tobacco products and their nicotine content, with the intent of removing nicotine as soon as acceptable nicotine substitution products are available; (d) reimbursement to the states for Medicaid and other state expenditures attributable to smoking, to the maximum extent feasible; (e) funding for local, state, and federal programmes and research in tobacco control; (f) acceptance of legislation and regulations protecting the right of non-smokers to breathe air free of tobacco smoke; (g) funding for a large, national, media-led, anti-tobacco campaign; and (h) cessation assistance for addicted smokers. If negotiations toward a settlement proceed, it is essential that the public health community participate in defining the elements of any agreement to ensure that whatever agreement develops is focused on reducing tobacco-related disease rather than continuing the profitability of American tobacco companies. That participation requires articulation of the core elements essential to an acceptable agreement. If resolution of the public health issues surrounding continued sale of tobacco products can be reached in the United States, it may provide a model for similar resolution in other countries.


Beyond KRAS mutation status: influence of KRAS copy number status and microRNAs on clinical outcome to cetuximab in metastatic colorectal cancer patients.
KRAS mutation is a negative predictive factor for treatment with anti-epidermal growth factor receptor (EGFR) antibodies in metastatic colorectal cancer (mCRC). Novel predictive markers are required to further improve the selection of patients for this treatment. We assessed the influence of modification of KRAS by gene copy number aberration (CNA) and microRNAs (miRNAs) in correlation to clinical outcome in mCRC patients treated with cetuximab in combination with chemotherapy and bevacizumab. Formalin-fixed paraffin-embedded primary tumour tissue was used from 34 mCRC patients in a phase III trial, who were selected based upon their good (n = 17) or poor (n = 17) progression-free survival (PFS) upon treatment with cetuximab in combination with capecitabine, oxaliplatin, and bevacizumab. Gene copy number at the KRAS locus was assessed using high resolution genome-wide array CGH and the expression levels of 17 miRNAs targeting KRAS were determined by real-time PCR. Copy number loss of the KRAS locus was observed in the tumour of 5 patients who were all good responders including patients with a KRAS mutation. Copy number gains in two wild-type KRAS tumours were associated with a poor PFS. In KRAS mutated tumours increased miR-200b and decreased miR-143 expression were associated with a good PFS. In wild-type KRAS patients, miRNA expression did not correlate with PFS in a multivariate model. Our results indicate that the assessment of KRAS CNA and miRNAs targeting KRAS might further optimize the selection of mCRC eligible for anti-EGFR therapy.


[The determination of susceptibility to measles, rubella, mumps and chickenpox in students of health-related areas].
We present an epidemiological and serological study in 286 health care students. We found susceptibility for measles in 11.7% individuals (95% confidence interval (95% CI): 8.0-15%), for rubella: 6.7% (95% CI: 3.8-9.6%) for mumps: 12.7% (95% CI: 8.0-16.6%) and for varicella 8.5% (95% CI: 5.3-11.7%). Compared to a similar study, performed in 1992 in a population of health care workers, we found an increasing susceptibility to these diseases except for mumps, that had decreased. Among those who received one dose of measles vaccine we found 12.1% non immune. We found an high level of immunity (97.1%) for those who received rubella vaccination. We could not draw any conclusions for mumps because only seven had been vaccinated.


[Hand transplantation in Sweden – preparations under way].
English summary: Hand transplantation in Sweden - preparations under way Some patients with a uni- or bilateral hand- or forearm amputation cannot use a hand prosthesis, although high-tech prostheses have been developed. A hand transplantation, particularly for those with bilateral amputations, may be an alternative solution. In a hand-transplanted patient, grip function, strength, sensibility and subsequent improved quality of life can be restored. Risks related to immunosuppression must be balanced by expected benefits, and thorough selection of patients has to be performed from both medical and psychological point of view. Therefore, a national network has been established in Sweden to achieve coordination with the needed competence.


Chemical characterization of DNA-immobilized InAs surfaces using X-ray photoelectron spectroscopy and near-edge X-ray absorption fine structure.
Single-stranded DNA immobilized on an III-V semiconductor is a potential high-sensitivity biosensor. The chemical and electronic changes occurring upon the binding of DNA to the InAs surface are essential to understanding the DNA-immobilization mechanism. In this work, the chemical properties of DNA-immobilized InAs surfaces were determined through high-resolution X-ray photoelectron spectroscopy (XPS) and near-edge X-ray absorption fine structure (NEXAFS). Prior to DNA functionalization, HF- and NH(4)OH- based aqueous etches were used to remove the native oxide from the InAs surface. The initial chemical state of the surface resulting from these etches were characterized prior to functionalization. F-tagged thiolated single-stranded DNA (ssDNA) was used as the probe species under two different functionalization methods. The presence of DNA immobilized on the surface was confirmed from the F 1s, N 1s, and P 2p peaks in the XPS spectra. The presence of salt had a profound effect on the density of immobilized DNA on the InAs surface. To study the interfacial chemistry, the surface was treated with thiolated ssDNA with and without the mercaptohexanol molecule. An analysis of the As 3d and In 3d spectra indicates that both In-S and As-S are present on the surface after DNA functionalization. The amount of In-S and As-S was determined by the functionalization method as well as the presence of mercaptohexanol during functionalization. The orientation of the adsorbed ssDNA is determined by polarization-dependent NEXAFS utilizing the N K-edge. The immobilized ssDNA molecule has a preferred tilt angle with respect to the substrate normal, but with a random azimuthal distribution.


Augmented reality visualization with use of image overlay technology for MR imaging-guided interventions: assessment of performance in cadaveric shoulder and hip arthrography at 1.5 T.
To prospectively assess overlay technology in providing accurate and efficient targeting for magnetic resonance (MR) imaging-guided shoulder and hip joint arthrography. A prototype augmented reality image overlay system was used in conjunction with a clinical 1.5-T MR imager. A total of 24 shoulder joint and 24 hip joint injections were planned in 12 human cadavers. Two operators (A and B) participated, each performing procedures on different cadavers using image overlay guidance. MR imaging was used to confirm needle positions, monitor injections, and perform MR arthrography. Accuracy was assessed according to the rate of needle adjustment, target error, and whether the injection was intraarticular. Efficiency was assessed according to arthrography procedural time. Operator differences were assessed with comparison of accuracy and procedure times between the operators. Mann-Whitney U test and Fisher exact test were used to assess group differences. Forty-five arthrography procedures (23 shoulders, 22 hips) were performed. Three joints had prostheses and were excluded. Operator A performed 12 shoulder and 12 hip injections. Operator B performed 11 shoulder and 10 hip injections. Needle adjustment rate was 13% (six of 45; one for operator A and five for operator B). Target error was 3.1 mm±1.2 (standard deviation) (operator A, 2.9 mm±1.4; operator B, 3.5 mm±0.9). Intraarticular injection rate was 100% (45 of 45). The average arthrography time was 14 minutes (range, 6-27 minutes; 12 minutes [range, 6-25 minutes] for operator A and 16 minutes [range, 6-27 min] for operator B). Operator differences were not significant with regard to needle adjustment rate (P=.08), target error (P=.07), intraarticular injection rate (P>.99), and arthrography time (P=.22). Image overlay technology provides accurate and efficient MR guidance for successful shoulder and hip arthrography in human cadavers.


[Muscular tumors of the digestive tract].
We report the experience of the General Surgery Service of Segovia General Hospital. In a 15-years-period (1976-1991), we have cared for 32 patients with muscular tumors of the gastrointestinal tract, including 22 leiomyomas and 11 leiomyosarcomas. These tumors were localized in stomach (46.8%), small intestine (40.6%), esophagus (9.3%) and colon-rectum (3.1%). A histologic study was developed on the basis of the mitosis number in 10 high power fields. Clinical manifestations, histological dates, treatment, and prognosis factors, outstanding the histological grade, size lesser than 10 cm, and tumor origin localization, are reviewed.


Density of alcohol outlets and teenage drinking: living in an alcogenic environment is associated with higher consumption in a metropolitan setting.
This study examines the relationship between physical, socio-economic and social environments and alcohol consumption and drunkenness among a general population sample of drinkers aged 12-17 years. DESIGN, SETTING, PARTICIPANTS AND MEASURES: The study was conducted in Auckland, New Zealand. The design comprised two components: (i) environmental measures including alcohol outlet density, locality-based measure of willingness to sell alcohol (derived from purchase surveys of outlets) and a locality-based neighbourhood deprivation measure calculated routinely in New Zealand (known as NZDEP); and (ii) the second component was a random telephone survey to collect individual-level information from respondents aged 12-17 years including ethnicity, frequency of alcohol supplied socially (by parents, friends and others), young person's income; frequency of exposure to alcohol advertising; recall of brands of alcohol and self-reported purchase from alcohol outlets. A multi-level model was fitted to predict typical-occasion quantity, frequency of drinking and drunkenness in drinkers aged 12-17 years. Typical-occasion quantity was predicted by: frequency of social supply (by parents, friends and others); ethnicity and outlet density; and self-reported purchasing approached significance. NZDEP was correlated highly with outlet density so could not be analysed in the same model. In a separate model, NZDEP was associated with quantity consumed on a typical drinking occasion. Annual frequency was predicted by: frequency of social supply of alcohol, self-reported purchasing from alcohol outlets and ethnicity. Feeling drunk was predicted by frequency of social supply of alcohol, self-reported purchasing from alcohol outlets and ethnicity; outlet density approached significance. Age and gender also had effects in the models, but retailers' willingness to sell to underage patrons had no effects on consumption, nor did the advertising measures. The young person's income was influential on typical-occasion quantity once deprivation was taken into account. Alcohol outlet density was associated with quantities consumed among teenage drinkers in this study, as was neighbourhood deprivation. Supply by family, friends and others also predicted quantities consumed among underage drinkers and both social supply and self-reported purchase were associated with frequency of drinking and drunkenness. The ethnic status of young people also had an effect on consumption.


Environmental disasters and birth outcomes: Impact of a tailings dam breakage in Brazil.
There is evidence of a relationship between in utero exposure to catastrophic events and adverse birth outcomes, usually attributed to heightened maternal stress. The objective of our work was to evaluate if the breakage of a dam containing wastefrom a mining cite in Brazil, in 2015, an environmental disaster popularly known as the Mariana Tragedy, affected the health of newborns exposed in utero. We used administrative data on birth records and reports on the Mariana Tragedy to identify all births from newborns exposed in utero and the intensity of that exposure, according to the mother's municipality of residence. Using a difference-in-differences framework, we estimated the impact of different intensities of exposure on birth outcomes. We found that being directly exposed in utero to the Tragedy resulted in 1.86 days shorter gestational age and 2.6 percentage points higher incidence of preterm birth (<37 weeks). We found no impact on birthweight related outcomes. The effect is larger than previously identified for other catastrophic events. We hypothesize that this is probably due to the Tragedy impacting birth outcomes not exclusively through heightened maternal stress, but also through depressed economic activity in directly affected municipalities.


Protein phosphatase 2A controls ethylene biosynthesis by differentially regulating the turnover of ACC synthase isoforms.
The gaseous hormone ethylene is one of the master regulators of development and physiology throughout the plant life cycle. Ethylene biosynthesis is stringently regulated to permit maintenance of low levels during most phases of vegetative growth but to allow for rapid peaks of high production at developmental transitions and under stress conditions. In most tissues ethylene is a negative regulator of cell expansion, thus low basal levels of ethylene biosynthesis in dark-grown seedlings are critical for optimal cell expansion during early seedling development. The committed steps in ethylene biosynthesis are performed by the enzymes 1-aminocyclopropane 1-carboxylate synthase (ACS) and 1-aminocyclopropane 1-carboxylate oxidase (ACO). The abundance of different ACS enzymes is tightly regulated both by transcriptional control and by post-translational modifications and proteasome-mediated degradation. Here we show that specific ACS isozymes are targets for regulation by protein phosphatase 2A (PP2A) during Arabidopsis thaliana seedling growth and that reduced PP2A function causes increased ACS activity in the roots curl in 1-N-naphthylphthalamic acid 1 (rcn1) mutant. Genetic analysis reveals that ethylene overproduction in PP2A-deficient plants requires ACS2 and ACS6, genes that encode ACS proteins known to be stabilized by phosphorylation, and proteolytic turnover of the ACS6 protein is retarded when PP2A activity is reduced. We find that PP2A and ACS6 proteins associate in seedlings and that RCN1-containing PP2A complexes specifically dephosphorylate a C-terminal ACS6 phosphopeptide. These results suggest that PP2A-dependent destabilization requires RCN1-dependent dephosphorylation of the ACS6 C-terminus. Surprisingly, rcn1 plants exhibit decreased accumulation of the ACS5 protein, suggesting that a regulatory phosphorylation event leads to ACS5 destabilization. Our data provide new insight into the circuitry that ensures dynamic control of ethylene synthesis during plant development, showing that PP2A mediates a finely tuned regulation of overall ethylene production by differentially affecting the stability of specific classes of ACS enzymes.


Synthesis and preliminary in vivo evaluation of well-dispersed biomimetic nanocrystalline apatites labeled with positron emission tomographic imaging agents.
In recent years, biomimetic synthetic apatite nanoparticles (AP-NPs), having chemical similarity with the mineral phase of bone, have attracted a great interest in nanomedicine as potential drug carriers. To evaluate the therapeutic perspectives of AP-NPs through the mechanisms of action and organs they interact with, the noninvasive monitoring of their in vivo behavior is of paramount importance. To this aim, here the feasibility to radiolabel AP-NPs ("naked" and surface-modified with citrate to reduce their aggregation) with two positron emission tomographic (PET) imaging agents ([(18)F]NaF and (68)Ga-NO2AP(BP)) was investigated. [(18)F]NaF was used for the direct incorporation of the radioisotope into the crystal lattice, while the labeling by surface functionalization was accomplished by using (68)Ga-NO2AP(BP) (a new radio-metal chelating agent). The labeling results with both tracers were fast, straightforward, and reproducible. AP-NPs demonstrated excellent ability to bind relevant quantities of both radiotracers and good in vitro stability in clinically relevant media after the labeling. In vivo PET studies in healthy Wistar rats established that the radiolabeled AP-NPs gave significant PET signals and they were stable over the investigated time (90 min) since any tracer desorption was detected. These preliminary in vivo studies furthermore showed a clear ability of citrated versus naked AP-NPs to accumulate in different organs. Interestingly, contrary to naked AP-NPs, citrated ones, which unveiled higher colloidal stability in aqueous suspensions, were able to escape the first physiological filter, i.e., the lungs, being then accumulated in the liver and, to a lesser extent, in the spleen. The results of this work, along with the fact that AP-NPs can be also functionalized with targeting ligands, with therapeutic agents, and also with metals for a combination of different imaging modalities, make AP-NPs very encouraging materials for further investigations as theranostic agents in nanomedicine.


Effects of metyrapone and a combined alpha- and beta-adrenergic blockade on plasma glucose recovery from insulin-induced hypoglycaemia in pigs.
The recovery of plasma glucose from insulin-induced hypoglycaemia was investigated in growing pigs during an inhibition of corticosteroid secretion (metyrapone infusion), an alpha- and beta-adrenergic blockade (phentolamine and propranolol infusion) or a combination of both treatments. In pigs which received an infusion of metyrapone for 4 h before and 3 h after a bolus injection of insulin (0.1 IU/kg body-weight), the plasma glucose response did not differ significantly from control animals. The infusion of phentolamine and propranolol (in each case 120 micrograms/kg/h for 3 h after a priming dose of 100 micrograms/kg) starting at the time of insulin injection significantly attenuated the restoration of normoglycaemia. An additional infusion of metyrapone increased this effect significantly only at the end of the experiment. The results indicate that adrenergic mechanisms are involved in the glucose counterregulation after an insulin-induced hypoglycaemia in pigs and the glucocorticoid secretion may become critical when the catecholamine response is impaired.


Experiment design through dynamical characterisation of non-linear systems biology models utilising sparse grids.
The sparse grid-based experiment design algorithm sequentially selects an experimental design point to discriminate between hypotheses for given experimental conditions. Sparse grids efficiently screen the global uncertain parameter space to identify acceptable parameter subspaces. Clustering the located acceptable parameter vectors by the similarity of the simulated model trajectories characterises the data-compatible model dynamics. The experiment design algorithm capitalizes on the diversity of the experimentally distinguishable system output dynamics to select the design point that best discerns between competing model-structure and parameter-encoded hypotheses. As opposed to designing the experiments to explicitly reduce uncertainty in the model parameters, this approach selects design points to differentiate between dynamical behaviours. This approach further differs from other experimental design methods in that it simultaneously addresses both parameter- and structural-based uncertainty that is applicable to some ill-posed problems where the number of uncertain parameters exceeds the amount of data, places very few requirements on the model type, available data and a priori parameter estimates, and is performed over the global uncertain parameter space. The experiment design algorithm is demonstrated on a mitogen-activated protein kinase cascade model. The results show that system dynamics are highly uncertain with limited experimental data. Nevertheless, the algorithm requires only three additional experimental data points to simultaneously discriminate between possible model structures and acceptable parameter values. This sparse grid-based experiment design process provides a systematic and computationally efficient exploration over the entire uncertain parameter space of potential model structures to resolve the uncertainty in the non-linear systems biology model dynamics.


Do Technical Aids for Patient Handling Prevent Musculoskeletal Complaints in Health Care Workers?-A Systematic Review of Intervention Studies.
The physical load ensuing from the repositioning and moving of patients puts health care workers at risk of musculoskeletal complaints. Technical equipment developed to aid with patient handling should reduce physical strain and workload; however, the efficacy of these aids in preventing musculoskeletal disorders and complaints is still unclear. A systematic review of controlled intervention studies was conducted to examine if the risk of musculoskeletal complaints and disorders is reduced by technical patient handling equipment. MEDLINE®/PubMed®, EMBASE®, Allied and Complementary Medicine Database (AMED), and Cumulative Index of Nursing and Allied Health Literature (CINAHL®) were searched using terms for nursing, caregiving, technical aids, musculoskeletal injuries, and complaints. Randomized controlled trials and controlled before-after studies of interventions including technical patient handling equipment were included. The titles and abstracts of 9554 publications and 97 full-texts were screened by two reviewers. The qualitative synthesis included one randomized controlled trial (RCT) and ten controlled before-after studies. A meta-analysis of four studies resulted in a pooled risk ratio for musculoskeletal injury claims (post-intervention) of 0.78 (95% confidence interval 0.68-0.90). Overall, the methodological quality of the studies was poor and the results often based on administrative injury claim data, introducing potential selection bias. Interventions with technical patient handling aids appear to prevent musculoskeletal complaints, but the certainty of the evidence according to GRADE approach ranged from low to very low.


Treatment of pediatric supracondylar humerus fractures accompanied with pink pulseless hands.
The optimal treatment for pediatric supracondylar humeral fractures accompanied with a pink pulseless hand is controversial. Some clinicians recommend close observation after closed reduction and percutaneous pinning of the fractures, while some recommend surgical exploration if the radial pulse is unpalpable. The present study aimed to analyze the benefits and outcomes of close observation for treating pediatric supracondylar humeral fractures with a pink pulseless hand. Thirteen consecutive children presenting with a pink pulseless hand following supracondylar humeral fracture were enrolled in this study. Preoperative and postoperative color-flow Duplex ultrasound detection was used to assess brachial artery compromise in most cases. Urgent closed reduction and percutaneous pinning of the fractures were attempted first. Close observation was carried out when the hand was pink and pulseless with an absent radial pulse. Preoperative color-flow Duplex ultrasound showed no disruption of the brachial artery in cases detected. Compression of the artery by the proximal fragment was observed in most cases, with one case of entrapment of the artery between fragments, and thrombus considered in two cases. All cases underwent urgent surgery, after which nine experienced immediate return of the radial pulse. The remaining four without a palpable pulse were managed with close observation and no deterioration of the vascular status was observed; therefore, no surgical exploration was performed. Postoperative color-flow Duplex ultrasound revealed continuity of the artery and rich collateral circulation. Patients completed an average of 4.5 years of follow-up, during which no major complications occurred. All patients achieved excellent limb function. Our study demonstrates that close observation after urgent closed reduction and percutaneous pinning is a sufficient approach for the treatment of pediatric supracondylar humeral fractures accompanied with a pink pulseless hand. Surgical exploration is not necessary as long as the hand is warm and well perfused. Color-flow Duplex ultrasound is beneficial for assessing vascular compromise and determining treatment strategies.


Wave energy and intertidal productivity.
In the northeastern Pacific, intertidal zones of the most wave-beaten shores receive more energy from breaking waves than from the sun. Despite severe mortality from winter storms, communities at some wave-beaten sites produce an extraordinary quantity of dry matter per unit area of shore per year. At wave-beaten sites of Tatoosh Island, WA, sea palms, Postelsia palmaeformis, can produce > 10 kg of dry matter, or 1.5 x 10(8) J, per m(2) in a good year. Extraordinarily productive organisms such as Postelsia are restricted to wave-beaten sites. Intertidal organisms cannot transform wave energy into chemical energy, as photosynthetic plants transform solar energy, nor can intertidal organisms "harness" wave energy. Nonetheless, wave energy enhances the productivity of intertidal organisms. On exposed shores, waves increase the capacity of resident algae to acquire nutrients and use sunlight, augment the competitive ability of productive organisms, and protect intertidal residents by knocking away their enemies or preventing them from feeding.


High-resolution structure of myo-inositol monophosphatase, the putative target of lithium therapy.
Inositol monophosphatase is a key enzyme of the phosphatidylinositol signalling pathway and the putative target of the mood-stabilizing drug lithium. The crystal structure of bovine inositol monophosphatase has been determined at 1.4 A resolution in complex with the physiological magnesium ion ligands. Three magnesium ions are octahedrally coordinated at the active site of each of the two subunits of the inositol monophosphatase dimer and a detailed three-metal mechanism is proposed. Ligands to the three metals include the side chains of Glu70, Asp90, Asp93 and Asp220, the backbone carbonyl group of Ile92 and several solvent molecules, including the proposed nucleophilic water molecule (W1) ligated by both Mg-1 and Mg-3. Modelling of the phosphate moiety of inositol monophosphate to superpose the axial phosphate O atoms onto three active-site water molecules orientates the phosphoester bond for in-line attack by the nucleophilic water which is activated by Thr95. Modelling of the pentacoordinate transition state suggests that the 6-OH group of the inositol moiety stabilizes the developing negative charge by hydrogen bonding to a phosphate O atom. Modelling of the post-reaction complex suggests a role for a second water molecule (W2) ligated by Mg-2 and Asp220 in protonating the departing inositolate. This second water molecule is absent in related structures in which lithium is bound at site 2, providing a rationale for enzyme inhibition by this simple monovalent cation. The higher resolution structural information on the active site of inositol monophosphatase will facilitate the design of substrate-based inhibitors and aid in the development of better therapeutic agents for bipolar disorder (manic depression).


Blautia faecicola sp. nov., isolated from faeces from a healthy human.
An obligately anaerobic, Gram-stain-positive, non-motile and coccoid- or oval-shaped bacterium, designated strain KGMB01111T, was isolated from faeces from a healthy Korean. Comparative analysis of 16S rRNA gene sequences indicated that KGMB01111T was closely related to Ruminococcus gauveauii CCRI-16110T (93.9 %) and Blautia stercoris GAM6-1T (93.7 %), followed by Clostridium nexile DSM 1787T (93.5 %), Blautia producta ATCC 27340T (93.4 %), Blautia hydrogenotrophica DSM 10507T (93.1 %) and Blautia coccoides ATCC 29236T (93.1 %) within the family Lachnospiraceae (Clostridium rRNA cluster XIVa). Phylogenetic analysis based on the 16S rRNA gene sequences indicated that KGMB01111T formed a separate branch with species in the genus Blautia. The major cellular fatty acids (>10.0 %) were C16 : 0 and C18 : 1 cis 9 dimethyl acetal (DMA), and the major polar lipids were aminophospholipids and lipids. KGMB01111T contained meso-diaminopimelic acid in cell-wall peptidoglycan. The predominant end product of fermentation produced by KGMB01111T was acetic acid. Based on the whole-genome sequence, the DNA G+C content of the isolate was 44.7 mol%. On the basis of the phenotypic, chemotaxonomic and phylogenetic characteristics, KGMB01111T represents a novel species within the genus Blautia for which the name Blautia faecicola sp. nov. is proposed. The type strain is KGMB01111T (=KCTC 15706T=DSM 107827T).