Effect of Repeated Wuniu Early Tea Administration on the CYP450 Activity Using a Cocktail Method.
Wuniu early tea (Camellia sinensis) is an important beverage consumed in China. Up to date, a lot of methods for identifying and chemical analysing have been done. However, there is no report on the effects of Wuniu early tea on cytochrome P450 isozymes. Therefore, the present objective of our study was to evaluate the potential effects of Wuniu early tea on cytochrome P450 isozymes P2C9, P1A2, P2C19 and P2B6 in rats with a cocktail approach including, matching probe drugs of tolbutamide, phenacetin, omeprazole and bupropion. These four probe drugs were simultaneously administered to rats after repeated Wuniu early tea administration. The pharmacokinetics of the probes in the plasma was simultaneous determined by high-performance liquid chromatography-mass spectrometry. The t1/2 and AUC(0-∞) of tolbutamide increased significantly and CLz decreased remarkably in test rats after repeated Wuniu early tea administration. However, the main pharmacokinetic parameters of the other three probe drugs were not significantly different between control and test rats. The findings in this study suggested that Wuniu early tea could inhibit cytochrome P2C9 while did not influence on cytochrome P1A2, cytochrome P2C19 and cytochrome P2B6.


Precision health equity for racialized communities.
In the last three decades, a cohort of genomicists have intentionally sought to include more racially diverse people in their research in human genomics and precision medicine. How such efforts to be inclusive in human genomic research and precision medicine are modeled and enacted, specifically if the terms of inclusion are equitable for these communities remains to be explored. In this commentary, we review the historical context in which issues of racial inclusion arose with early genome and genetics projects. We then discuss attempts to include racialized peoples in more recent human genomics research. In conclusion, we raise critical issues to consider in the future of equitable human genomics and precision medicine research involving racialized communities, particularly as it concerns working towards what we call Precision Health Equity (PHE). Specifically, we examine issues of genetic data governance and the terms of participation in inclusive human genomics and precision health research. We do so by drawing on insights and protocols developed by researchers investigating Indigenous Data Sovereignty and propose exploring their application and adaptation to precision health research involving racialized communities.


Household composition and risk of fatal child maltreatment.
Approximately 2000 children die annually in the United States from maltreatment. Although maternal and child risk factors for child abuse have been identified, the role of household composition has not been well-established. Our objective was to evaluate household composition as a risk factor for fatal child maltreatment. Population-based, case-control study using data from the Missouri Child Fatality Review Panel system, 1992-1994. Households were categorized based on adult residents' relationship to the deceased child. Cases were all maltreatment injury deaths among children <5 years old. Controls were randomly selected from natural-cause deaths during the same period and frequency-matched to cases on age. The main outcome measure was maltreatment death. Children residing in households with adults unrelated to them were 8 times more likely to die of maltreatment than children in households with 2 biological parents (adjusted odds ratio [aOR]: 8.8; 95% confidence interval [CI]: 3.6-21.5). Risk of maltreatment death also was elevated for children residing with step, foster, or adoptive parents (aOR: 4.7; 95% CI: 1.6-12.0), and in households with other adult relatives present (aOR: 2.2; 95% CI: 1.1-4.5). Risk of maltreatment death was not increased for children living with only 1 biological parent (aOR: 1.1; 95% CI: 0.8-2.0). Children living in households with 1 or more male adults that are not related to them are at increased risk for maltreatment injury death. This risk is not elevated for children living with a single parent, as long as no other adults live in the home.


An improved algorithm for learning long-term dependency problems in adaptive processing of data structures.
Many researchers have explored the use of neural-network representations for the adaptive processing of data structures. One of the most popular learning formulations of data structure processing is backpropagation through structure (BPTS). The BPTS algorithm has been successful applied to a number of learning tasks that involve structural patterns such as logo and natural scene classification. The main limitations of the BPTS algorithm are attributed to slow convergence speed and the long-term dependency problem for the adaptive processing of data structures. In this paper, an improved algorithm is proposed to solve these problems. The idea of this algorithm is to optimize the free learning parameters of the neural network in the node representation by using least-squares-based optimization methods in a layer-by-layer fashion. Not only can fast convergence speed be achieved, but the long-term dependency problem can also be overcome since the vanishing of gradient information is avoided when our approach is applied to very deep tree structures.


Management of Patellar Tendinopathy Through Monitoring, Load Control, and Therapeutic Exercise: A Systematic Review.
Patellar tendinopathy presents with persistent tendon pain located in the lower pole of the patella and loss of function related to mechanical load. Although its pathogenesis is not completely clear, conservative treatment including exercise is the main intervention of patellar tendinopathy treatment. To describe the efficacy of patellar tendinopathy management through therapeutic exercise, and control and monitoring of loads. MEDLINE, WoS, Cochrane Plus, PEDro, and the gray literature were searched from inception to July 2021. Based on the PICO strategy, the inclusion criteria were clinical trials published in English or Spanish; outcomes of function, pain, and strength; patients with patellar tendinopathy with no age or gender limitations; using an active intervention; and at least a methodological quality equal to or greater than 3 points on the Jadad scale. All data were analyzed by 2 independent reviewers (P.N.-M. and D.H.-G.). Studies were qualitatively synthesized using a descriptive synthesis. The methodological quality and risk of bias assessment were performed with the PEDro and Jadad scale, respectively. A total of 136 articles were identified, of which 12 met the eligibility criteria. All of them were regarded as presenting a moderate risk of bias and their methodological quality was considered acceptable to good. Recovering patellar tendinopathy with therapeutic exercise seems to significantly improve function, pain, and strength after intervention and even lasted over time. A treatment based on load monitoring and physical exercise has proven to be effective in rehabilitating patellar tendinopathy, with positive results in the short and medium term.


Cortical Folding Development Study based on Over-Complete Spherical Wavelets.
We introduce the use of over-complete spherical wavelets for shape analysis of 2D closed surfaces. Bi-orthogonal spherical wavelets have been shown to be powerful tools in the segmentation and shape analysis of 2D closed surfaces, but unfortunately they suffer from aliasing problems and are therefore not invariant under rotations of the underlying surface parameterization. In this paper, we demonstrate the theoretical advantage of over-complete wavelets over bi-orthogonal wavelets and illustrate their utility on both synthetic and real data. In particular, we show that over-complete spherical wavelets allow us to build more stable cortical folding development models, and detect a wider array of regions of folding development in a newborn dataset.


Neurological update: non-motor symptoms in atypical parkinsonian syndromes.
Among people with Parkinson's disease (PD), non-motor symptoms (NMS) are a well-recognised cause of significant morbidity and poor quality of life. Yet, it is only more recently that NMS have been recognised to affect the lives of patients with atypical parkinsonian syndromes in a similar fashion. The aim of this article is to highlight and compare the relative prevalence of NMS among patients with atypical parkinsonian syndromes in the published literature, which largely remain underreported and unaddressed in routine clinical practice. All NMS that are recognised to occur in PD are also found to commonly occur in atypical parkinsonian syndromes. In particular, excessive daytime sleepiness is more prevalent among atypical parkinsonian syndromes (94.3%) compared to PD (33.9%) or normal controls (10.5%) (p < 0.001). Urinary dysfunction (not limited to urinary incontinence) is not only found to occur in MSA (79.7%) and PD (79.9%), but has also been reported in nearly half of the patients with PSP (49.3%), DLB (42%) and CBD (53.8%) (p < 0.001). Apathy is significantly more common among the atypical parkinsonian syndromes [PSP (56%), MSA (48%), DLB (44%), CBD (43%)] compared to PD (35%) (p = 0.029). Early recognition and addressing of NMS among atypical parkinsonian syndromes may help improve the holistic patient care provided and may encompass a range of conservative and pharmacotherapeutic treatments to address these symptoms.


Optimal management of older people with frailty non-weight bearing after lower limb fracture: a scoping review.
Patients with lower limb fractures who are non-weight bearing are at risk of the complications of the associated immobility and disability, particularly people with frailty, but there is lack of clarity about what constitutes optimal care for such patients. A scoping literature review was conducted to explore what evidence is available for the management of this patient group. MEDLINE (PubMed) CINAHL, EMBASE and the Cochrane databases of published literature and the HMIC and SIGLE sites for grey literature were searched for primary research studies and expert reports, using an iterative approach initially including the key term 'non-weight bearing'. All study types were included. Analysis was by narrative synthesis. No papers were identified from a search using the key phrase 'non-weight bearing'. With this term removed, 11 indirectly relevant articles on lower limb fractures were retrieved from the searches of the electronic databases comprising three observational studies, five non-systematic review articles, a systematic review, an opinion piece and a survey of expert opinion that had relevance to restricted weight bearing patients. The observational studies indicated depression, cognition and nutrition affect outcome and hence have indirect relevance to management. The non-systematic reviews articles emphasised the importance of maintaining strength and range of movement during immobilisation and advised an orthogeriatric model of care. Fourteen UK and 97 non-UK guidelines relevant to fragility fractures, falls and osteoporosis management were found in the grey literature, but none made specific recommendations regarding the management of any period of non-weight bearing. These findings provide a summary of the evidence base that can be used in the development of a clinical guideline for these patients but is not sufficient. We propose that, a guideline should be developed for these patients using an expert consensus process.


Leading Diverse Workforces: Perspectives from Managers and Employers about Dyslexic Employees in Australian Workplaces.
Dyslexia is a specific learning disability affecting around 1 in 10 Australian adults. It presents unique challenges for employees in the workforce, yet community and workplace awareness of the challenges of dyslexia is limited. The aim of this preliminary research was to explore the experiences and perspectives of Australian employers and managers responsible for supervising employees with dyslexia in the workplace. Using a qualitative research design, we conducted in-depth interviews with four managers who had current or previous experience managing employees with dyslexia. We used a deductive approach to analyse the data and categorise responses to the study questions. Participant responses indicated that there is a lack of awareness and understanding of dyslexia within Australian workplaces. Participants identified challenges facing employees with dyslexia in the workplace including, differing personal levels of confidence and comfort in disclosing disability; the possibility of discrimination, and a lack of inclusive organisational practices and processes. Suggestions for ways to improve workplaces for dyslexic employees included: additional support for leaders and managers to drive inclusive leadership, and additional training for leaders and managers on how to best support employees with dyslexia. While only a small sample size, this study indicates that further research is needed to better understand the working environment of Australian leaders and managers. It appears that leaders and mangers need skills and knowledge to better support employees with dyslexia and in doing so create more inclusive workplaces.


Assembly and secretion of recombinant chains of human inter-alpha-trypsin inhibitor in COS-7 cells.
The inter-alpha-trypsin inhibitor (ITI) family is a group of structurally related plasma serine protease inhibitors. The ITI family members consist of combinations of mature heavy chains named HC1, HC2, HC3 linked to bikunin (a Kunitz-type protease inhibitor) by a covalent interchain protein-glycosaminoglycan-protein cross-link. The biosynthesis of the ITI family members takes place in the liver. In this report we examine the biosynthesis of these proteins using transient transfected COS-7 cells expressing one or more combinations of human ITI chains. The processing and secretion of alpha1-microglobulin and bikunin does not require the ITI heavy chains. A small proportion of the H3 chain seems to be processed into the HC3 form in the absence of the other ITI chains. In contrast, the processing of H2 into HC2 needs the presence of the L chain. The COS-7 cells are able to link the HC2 and HC3 heavy chains with bikunin by means of a chondroitin sulfate bridge, and thus to generate 260-kDa ITI-like proteins as well as pre-alpha-trypsin inhibitor (PalphaI). However, the maturation of the Hl chain into HC1 and the assembly of HC1 inside multichain proteins may take place according to a mechanism which differs from that of the H2 and H3 chains. These results indicate that the assembly of the constituent chains of the ITI-like proteins and PalphaI is not dependent on the liver machinery.


Influence of Herbicide Exposure and Ranavirus Infection on Growth and Survival of Juvenile Red-Eared Slider Turtles (Trachemys scripta elegans).
Ranaviruses are an important wildlife pathogen of fish, amphibians, and reptiles. Previous studies have shown that susceptibility and severity of infection can vary with age, host species, virus strain, temperature, population density, and presence of environmental stressors. Experiments are limited with respect to interactions between this pathogen and environmental stressors in reptiles. In this study, we exposed hatchling red-eared slider turtles (Trachemys scripta elegans) to herbicide and ranavirus treatments to examine direct effects and interactions on growth, morbidity, and mortality. Turtles were assigned to one of three herbicide treatments or a control group. Turtles were exposed to atrazine, Roundup ProMax®, or Rodeo® via water bath during the first 3 weeks of the experiment. After 1 week, turtles were exposed to either a control (cell culture medium) or ranavirus-infected cell lysate via injection into the pectoral muscles. Necropsies were performed upon death or upon euthanasia after 5 weeks. Tissues were collected for histopathology and detection of ranavirus DNA via quantitative PCR. Only 57.5% of turtles exposed to ranavirus tested positive for ranaviral DNA at the time of death. Turtles exposed to ranavirus died sooner and lost more mass and carapace length, but not plastron length, than did controls. Exposure to environmentally relevant concentrations of herbicides did not impact infection rate, morbidity, or mortality of hatchling turtles due to ranavirus exposure. We also found no direct effects of herbicide or interactions with ranavirus exposure on growth or survival time. Results of this study should be interpreted in the context of the modest ranavirus infection rate achieved, the general lack of growth, and the unplanned presence of an additional pathogen in our study.


Developing novel antimicrobials by combining cancer chemotherapeutics with bacterial DNA repair inhibitors.
Cancer chemotherapeutics kill rapidly dividing cells, which includes cells of the immune system. The resulting neutropenia predisposes patients to infection, which delays treatment and is a major cause of morbidity and mortality. To tackle this problem, we have isolated several compounds that inhibit bacterial DNA repair, alone they are non-toxic, however in combination with DNA damaging anti-cancer drugs, they prevent bacterial growth. These compounds were identified through screening of an FDA-approved drug library in the presence of the anti-cancer compound cisplatin. Using a series of triage tests, the screen was reduced to a handful of drugs that were tested for specific activity against bacterial nucleotide excision DNA repair (NER). Five compounds emerged, of which three possess promising antimicrobial properties including cell penetrance, and the ability to block replication in a multi-drug resistant clinically relevant E. coli strain. This study suggests that targeting NER could offer a new therapeutic approach tailor-made for infections in cancer patients, by combining cancer chemotherapy with an adjuvant that targets DNA repair.


Inhibition of Ferroptosis Alleviates Early Brain Injury After Subarachnoid Hemorrhage In Vitro and In Vivo via Reduction of Lipid Peroxidation.
Subarachnoid hemorrhage (SAH) is a serious cerebrovascular disease with high mortality, and the mean age at morbidity is younger than in other types of stroke. Early brain injury (EBI) plays a key role in the poor prognoses of SAH. In EBI, multiple forms of cell death have been identified and well studied; however, the role of ferroptosis has not been elucidated. Hence, in this study, we developed an in vivo (SAH rat model) and in vitro model (SH-SY5Y oxyhemoglobin injury model) to understand the role of ferroptosis in EBI, then explored the protective mechanism of ferrostatin-1 (Fer-1). Firstly, we found that neurological scores, blood-brain barrier permeability, brain edema deteriorated after SAH in the in vivo model, cell viability was decreased after SAH in both cortex and SH-SY5Y cells. Further, iron content in cortex was increased after SAH, while transferrin receptor 1 and ferroportin (Fpn) were increased in oxyhemoglobin-treated in vitro model. Additionally, glutathione content and glutathione peroxidase 4 activity were reduced in SAH rats, and lipid peroxides were increased in the oxyhemoglobin-treated cells. Finally, administration of Fer-1 upregulated Fpn and decreased the iron content, then improved the lipid peroxidation and EBI. However, Fer-1 had no effect on the apoptosis. Our study indicated that the ferroptosis was involved in EBI of SAH, and the inhibitor Fer-1 provided neuroprotection against EBI by alleviating ferroptosis, the potential protective mechanism might be via suppressing lipid peroxidation.


Human suffering effects of nuclear tests at Semipalatinsk, Kazakhstan: established on the basis of questionnaire surveys.
The main objective of the present paper is to explore the effects of radiation exposure on the inhabitants near the Semipalatinsk Nuclear Tests Site (SNTS), Kazakhstan. Our research team of the Research Institute for Radiation Biology and Medicine, Hiroshima University, started in 2002 to conduct a field research study using questionnaire surveys. The present paper attempts to clarify health effects and mental problems on the inhabitants by using our questionnaire surveys. Among the responses to our survey, the present paper focuses upon responses to the questions concerning their health and mental problems. The data in Semipalatinsk have been compared with the results obtained in a similar survey conducted by Hiroshima and Nagasaki cities. The results show: (1) 33% of the residents replied that they felt bad or had very bad health conditions. (2) 70% of the residents strongly recognized a causal relationship between their bad health conditions and the nuclear tests. (3) The diseases that over 30% of respondents possessed are arthralgia/ lower back pain/ arthritis, high-blood pressure, heart disease and digestive system disease. (4) Acute radiation injuries from 1949 to 1962 that over 20% of respondents experienced were headaches and general malaise. (5) Concerning their mental condition, 22% of respondents felt easily frustrated and agitated and 21% experienced nightmare.


Dissecting the regulation of pollen tube growth by modeling the interplay of hydrodynamics, cell wall and ion dynamics.
Hydrodynamics, cell wall and ion dynamics are all important properties that regulate pollen tube growth. Currently, the two main pollen tube growth models, the cell wall model and the hydrodynamic model do not appear to be reconcilable. Here we develop an integrative model for pollen tube growth and show that our model reproduces key experimental observations: (1) that the hypertonic condition leads to a much longer oscillatory period and that the hypotonic condition halves the oscillatory period; (2) that oscillations in turgor are experimentally undetectable; (3) that increasing the extracellular calcium concentration or decreasing the pH decreases the growth oscillatory amplitude; (4) that knockout of Raba4d, a member of the Rab family of small GTPase proteins, decreases pollen tube length after germination for 24 h. Using the model generated here, we reveal that (1) when cell wall extensibility is large, pollen tube may sustain growth at different volume changes and maintain relatively stable turgor; (2) turgor increases if cell wall extensibility decreases; (3) increasing turgor due to decrease in osmolarity in the media, although very small, increases volume change. However, increasing turgor due to decrease in cell wall extensibility decreases volume change. In this way regulation of pollen tube growth by turgor is context dependent. By changing the osmolarity in the media, the main regulatory points are extracellular osmolarity for water flow and turgor for the volume encompassed by the cell wall. However, if the viscosity of cell wall changes, the main regulatory points are turgor for water flow and wall extensibility for the volume encompassed by the cell wall. The novel methodology developed here reveals the underlying context-dependent regulatory principle of pollen tube growth.


Role of nonselective cation channels in spontaneous and protein kinase A-stimulated calcium signaling in pituitary cells.
Several receptors linked to the adenylyl cyclase signaling pathway stimulate electrical activity and calcium influx in endocrine pituitary cells, and a role for an unidentified sodium-conducting channel in this process has been proposed. Here we show that forskolin dose-dependently increases cAMP production and facilitates calcium influx in about 30% of rat and mouse pituitary cells at its maximal concentration. The stimulatory effect of forskolin on calcium influx was lost in cells with inhibited PKA (cAMP-dependent protein kinase) and in cells that were haploinsufficient for the main PKA regulatory subunit but was preserved in cells that were also haploinsufficient for the main PKA catalytic subunit. Spontaneous and forskolin-stimulated calcium influx was present in cells with inhibited voltage-gated sodium and hyperpolarization-activated cation channels but not in cells bathed in medium, in which sodium was replaced with organic cations. Consistent with the role of sodium-conducting nonselective cation channels in PKA-stimulated Ca(2+) influx, cAMP induced a slowly developing current with a reversal potential of about 0 mV. Two TRP (transient receptor potential) channel blockers, SKF96365 and 2-APB, as well as flufenamic acid, an inhibitor of nonselective cation channels, also inhibited spontaneous and forskolin-stimulated electrical activity and calcium influx. Quantitative RT-PCR analysis indicated the expression of mRNA transcripts for TRPC1 >> TRPC6 > TRPC4 > TRPC5 > TRPC3 in rat pituitary cells. These experiments suggest that in pituitary cells constitutively active cation channels are stimulated further by PKA and contribute to calcium signaling indirectly by controlling the pacemaking depolarization in a sodium-dependent manner and directly by conducting calcium.


Community Evaluation of the National Diabetes Education Program's Diabetes HealthSense Website.
Purpose The purpose of this study was to assess the impact of Diabetes HealthSense on knowledge, attitudes, and behavior changes that prevent, delay, or manage diabetes among people at risk (PAR) for diabetes and people with diabetes (PWD). Methods Using a 2-group pretest-posttest design, 15 community sites were randomly assigned to either an intervention or comparison group. Intervention participants attended a group education session with a diabetes educator, followed by 4 weeks of independent use of the Diabetes HealthSense website. The comparison group received no intervention. A total of 311 adults (n = 135 intervention, n = 176 comparison) completed both a pretest and posttest. Outcome measures examined changes in self-reported knowledge, self-efficacy, and behaviors that support diabetes prevention or management. Results Statistically significant within-group pretest to posttest changes were found for almost all outcome measures in the intervention group, with no significant changes in the comparison group. Significant between-group differences were also found for almost all outcome measures at posttest, with the intervention group having more positive outcomes than the comparison group. Conclusions Patient referral to online tools is considered one key component of initial and ongoing diabetes self-management education and support (DSME/S) and is recommended as a way to enhance and extend the reach of in-person diabetes education. Positive outcomes were found for PWD/PAR who used Diabetes HealthSense following a guided education session. Study results suggested that with guided exploration, Diabetes HealthSense provided a valuable tool for educators to use with patients to support and extend the reach of DSME/S.


Evidence for deep regulatory similarities in early developmental programs across highly diverged insects.
Many genes familiar from Drosophila development, such as the so-called gap, pair-rule, and segment polarity genes, play important roles in the development of other insects and in many cases appear to be deployed in a similar fashion, despite the fact that Drosophila-like "long germband" development is highly derived and confined to a subset of insect families. Whether or not these similarities extend to the regulatory level is unknown. Identification of regulatory regions beyond the well-studied Drosophila has been challenging as even within the Diptera (flies, including mosquitoes) regulatory sequences have diverged past the point of recognition by standard alignment methods. Here, we demonstrate that methods we previously developed for computational cis-regulatory module (CRM) discovery in Drosophila can be used effectively in highly diverged (250-350 Myr) insect species including Anopheles gambiae, Tribolium castaneum, Apis mellifera, and Nasonia vitripennis. In Drosophila, we have successfully used small sets of known CRMs as "training data" to guide the search for other CRMs with related function. We show here that although species-specific CRM training data do not exist, training sets from Drosophila can facilitate CRM discovery in diverged insects. We validate in vivo over a dozen new CRMs, roughly doubling the number of known CRMs in the four non-Drosophila species. Given the growing wealth of Drosophila CRM annotation, these results suggest that extensive regulatory sequence annotation will be possible in newly sequenced insects without recourse to costly and labor-intensive genome-scale experiments. We develop a new method, Regulus, which computes a probabilistic score of similarity based on binding site composition (despite the absence of nucleotide-level sequence alignment), and demonstrate similarity between functionally related CRMs from orthologous loci. Our work represents an important step toward being able to trace the evolutionary history of gene regulatory networks and defining the mechanisms underlying insect evolution.


Cortisol, DHEAS, their ratio and the metabolic syndrome: evidence from the Vietnam Experience Study.
The aim of these analyses was to examine the association of cortisol, DHEAS and the cortisol:DHEAS ratio with the metabolic syndrome (MetS) and its components. Design The analyses were cross-sectional. Participants were 4255 Vietnam era US army veterans. From military service files, telephone interviews and a medical examination, occupational, socio-demographic and health data were collected. MetS was ascertained from data on body mass index; fasting blood glucose or a diagnosis of diabetes; blood pressure or a diagnosis of hypertension; high-density lipoprotein cholesterol; and triglyceride levels. Contemporary morning fasted cortisol and DHEAS concentrations were determined. The outcomes were MetS and its components. Analysis was by logistic regression, first adjusting for age and then additionally for an array of candidate confounders. Cortisol, although not in the fully adjusted analysis, and DHEAS were both related to MetS. Whereas high cortisol concentrations were associated with an increased risk of MetS, high DHEAS concentrations appeared protective. By far, the strongest associations with MetS were observed for the cortisol:DHEAS ratio; the higher the ratio, the greater the risk of having MetS. The ratio was also significantly related to four of the five MetS components. The cortisol:DHEAS ratio is positively associated with MetS. Prospective analyses are needed to help untangle direction of causality, but this study suggests that the cortisol:DHEAS ratio is worthy of further study in this and other health contexts.


A multi-target brain-computer interface based on code modulated visual evoked potentials.
The number of selectable targets is one of the main factors that affect the performance of a brain-computer interface (BCI). Most existing code modulated visual evoked potential (c-VEP) based BCIs use a single pseudorandom binary sequence and its circularly shifting sequences to modulate different stimulus targets, making the number of selectable targets limited by the length of modulation codes. This paper proposes a novel paradigm for c-VEP BCIs, which divides the stimulus targets into four target groups and each group of targets are modulated by a unique pseudorandom binary code and its circularly shifting codes. Based on the paradigm, a four-group c-VEP BCI with a total of 64 stimulus targets was developed and eight subjects were recruited to participate in the BCI experiment. Based on the experimental data, the characteristics of the c-VEP BCI were explored by the analyses of auto- and cross-correlation, frequency spectrum, signal to noise ratio and correlation coefficient. On the basis, single-trial data with the length of one stimulus cycle were classified and the attended target was recognized. The averaged classification accuracy across subjects was 88.36% and the corresponding information transfer rate was as high as 184.6 bit/min. These results suggested that the c-VEP BCI paradigm is both feasible and effective, and provides a new solution for BCI study to substantially increase the number of available targets.


Inflammation and epithelial alterations in rat prostate: impact of the androgen to oestrogen ratio.
Chronic non-bacterial prostatitis may offer new insights into the pathogenesis of human benign prostatic hyperplasia and prostate cancer and the strategies for their treatment and prevention. The potential significance of androgen replacement therapy in terms of the reversal of oestradiol (E(2))-induced inflammatory reaction was studied in the dorsolateral prostate (DLP) of the Noble rat. Castrated Noble rats were treated with E(2) and different doses of androgens [dihydrotestosterone (DHT) and testosterone (T)] to achieve an elevated concentration of E(2) and a wide range of the androgen-to-oestradiol ratios in serum. After the 3-week treatment, inflammatory changes in the DLP were classified and counted. Oestrogen receptor alpha (ER alpha), progesterone receptor (PR), fos-related antigen-2 (Fra2), Ki-67 and P63 were immunocytochemically stained. T, E(2) and prolactin concentrations in serum were measured and the relative weights of the seminal vesicles and pituitary glands and microscopic structures of the DLP and seminal vesicle ducts were determined. Hypoandrogenic doses of DHT (judged on the basis of seminal vesicle weight gain), dose-dependently increased the number of perivascular and stromal inflammatory infiltrates. T and DHT were anti-inflammatory at the doses which normalized or over stimulated the growth of the seminal vesicles. As signs of anti-oestrogenicity, androgens dose-dependently decreased the number and distribution of the ER alpha and PR-positive cells at proinflammatory concentrations. Anti-inflammatory concentrations were needed to reduce the expression of Fra2, E(2)-increased prolactin concentration in serum and pituitary weight. The androgen concentrations required to prevent proinflammatory and epithelial responses to E(2) in the presence of elevated E(2) concentrations may subject the accessory sex glands to more intense androgenic stimulation than is normal for the male. The androgen-resistant endpoints of oestrogen action (body weight reduction and hyperplasia of seminal vesicle ducts) further indicate limitations in the possible preventive effects of androgen-replacement therapy.


Environmental persistence of porcine coronaviruses in feed and feed ingredients.
Porcine Epidemic Diarrhea Virus (PEDV), Porcine Delta Corona Virus (PDCoV), and Transmissible Gastroenteritis Virus (TGEV) are major threats to swine health and contaminated feed plays a role in virus transmission. The objective of our study was to characterize inactivation of PEDV, PDCoV, and TGEV in various feed ingredient matrices. Samples of complete feed, spray dried porcine plasma, meat meal, meat and bone meal, blood meal, corn, soybean meal, and corn dried distillers grains with solubles were weighed (5 g/sample) into scintillation vials and inoculated with 1 mL of PEDV, PDCoV, or TGEV. Samples were incubated at room temperature for up to 56 days. Aliquots were removed at various time points followed by preparing serial 10-fold dilutions and inoculating in cell cultures to determine the amount of surviving virus. Inactivation kinetics were determined using the Weibull model, which estimates a delta value indicating the time necessary to reduce virus concentration by 1 log. Delta values of various ingredients were compared and analyzed as to their nutrient composition. Soybean meal had the greatest delta value (7.50 days) for PEDV (P < 0.06) as compared with all other ingredients. High delta values (P < 0.001) were observed in soybean meal for PDCoV (42.04 days) and TGEV (42.00 days). There was a moderate correlation between moisture content and the delta value for PDCoV (r = 0.49, P = 0.01) and TGEV (r = 0.41, P = 0.02). There was also a moderate negative correlation between TGEV survival and ether extract content (r = -0.51, P = 0.01). In conclusion, these results indicate that the first log reduction of PDCoV and TGEV takes the greatest amount of time in soybean meal. In addition to this, moisture and ether content appear to be an important determinant of virus survival in feed ingredients.


Current evidence base of FDG-PET/CT imaging in the clinical management of malignant pleural mesothelioma: emerging significance of image segmentation and global disease assessment.
Increasingly, integrated positron emission tomography-computed tomography (PET/CT) imaging is playing a crucial role in the assessment of patients with known or suspected malignant pleural mesothelioma (MPM). Based on the data reported in the literature, this combined modality is likely to become the instrument of choice for examining patients of MPM. The research on this subject has focused on the following five domains: (1) differentiation of MPM from other benign pleural diseases, (2) preoperative staging for the selection of appropriate candidates for surgery, (3) evaluation for therapy response and post-treatment surveillance for recurrence, (4) prognostication based upon the intensity of 2-deoxy-2-[(18)F]fluoro-D-glucose (FDG) uptake, and (5) planning of radiotherapy. These represent the bases for critical decision making in the management of mesothelioma, and FDG-PET/CT offers potential advantages over conventional CT imaging and thus can play a pivotal role in this regard. Optimal characterization of this potentially fatal disease with a high negative predictive value for MPM, superior capability for cancer staging initially and at the later course of disease, and ability for measuring therapeutic response and the precise determination of the target volume for radiotherapy planning represent distinct advantages of this promising molecular imaging tool. In this communication, we have explored the promising role of integrated FDG-PET/CT in the overall management of this serious malignancy. From the available data, the major role of PET-CT at present appears to be in the preoperative disease staging, response to treatment assessment, and post-treatment disease surveillance of MPM. In all these three areas, PET-CT convincingly shows better results than conventional anatomical imaging alone and thereby can aid in exploring novel therapeutic approaches. Disease prognosis and radiotherapy planning are evolving areas where this modality has demonstrated significant promise, but this has to be investigated further. The differentiating of MPM from benign pleural disease is a challenging issue; though in limited studies, it has shown promising results, single standardized uptake value (SUV) cutoff technique cannot be the optimal way for this purpose. Dual time point and delayed imaging helps further in this setting; however, more data require to be accrued in this area. We, in this review, have also discussed the feasibility of a new method of image segmentation based on an iterative thresholding algorithm, which permits definition of the boundaries of lesions based on PET images alone to provide lesional metabolically active tumor volumes, lesional partial volume corrected SUV (PVC-SUV) measurements, lesional PVC metabolic burden (PVC-MB) (calculated as the product of lesional MVP and lesional PVC-SUV), and whole body metabolic burden (WBMB) (calculated as the sum of lesional PVC-MB of all lesions). This global disease assessment, we believe, will be the way forward for assessing this malignancy with a non-invasive imaging modality.


Family carers' involvement strategies in response to sub-optimal health services to older adults living with dementia - a qualitative study.
While dementia policy strategies emphasize the importance of partnerships between families and formal carers to provide tailored care and effectively allocate community resources, family carers often feel left out or excluded. Poor communication has been identified as one reason for the lack of good partnerships. Few studies have investigated how family carers seek to involve themselves when they experience sub-optimal services, and how their strategies may depend on different considerations and personal abilities. Qualitative in-depth interviews were conducted with 23 family carers to explore their experiences with, perspectives on, contributions to, and interactions with healthcare services provided to older adults living with dementia. To capture nuances and variations, a semi-structured interview guide was used. Interviews were audio-recorded and transcribed verbatim. A four-step analysis of the transcripts was conducted, informed by hermeneutic and phenomenological methodology. Two main involvement strategies were identified: 1) being "the hub in the wheel" and 2) getting the wheel rolling. The first strategy was used to support and complement health services, while the second was used to add momentum and leverage to arguments or processes. The two main strategies were used differently among participants, in part due to differences in personal resources and the ability to utilize these, but also in light of family carers' weighing conflicting concerns and perceived costs and benefits. Awareness and acknowledgment of family carers' strategies, personal resources, and considerations may help policymakers and healthcare personnel when they build or maintain good partnerships together with family carers. A better understanding of family carers' own perspectives on carer involvement is a necessary precursor to developing good care partnerships.


Regioselective and diastereoselective borono-Mannich reactions with pinacol allenylboronate.
The first documented study of the borono-Mannich (Petasis) reactions of pinacol allenylboronate is described. The reactions of salicylaldehyde and primary and secondary amines are highly regioselective and give homopropargylamine and α-allenylamine products, respectively. In contrast, glycoaldehyde and chiral α-hydroxyaldehydes give exclusively anti-β-amino-β-allenyl alcohol products, irrespective of the nature of the amine component. These reactions are highly regio- and diastereoselective and can be employed using an enantiomerically enriched α-hydroxyaldehyde without detectable racemization.


Supported Planar Mammalian Membranes as Models of in Vivo Cell Surface Architectures.
Emerging technologies use cell plasma membrane vesicles or "blebs" as an intermediate to form molecularly complete, planar cell surface mimetics that are compatible with a variety of characterization tools and microscopy methods. This approach enables direct incorporation of membrane proteins into supported lipid bilayers without using detergents and reconstitution and preserves native lipids and membrane species. Such a system can be advantageous as in vitro models of in vivo cell surfaces for study of the roles of membrane proteins as drug targets in drug delivery, host-pathogen interactions, tissue engineering, and many other bioanalytical and sensing applications. However, the impact of methods used to induce cell blebbing (vesiculation) on protein and membrane properties is still unknown. This study focuses on characterization of cell blebs created under various bleb-inducing conditions and the result on protein properties (orientation, mobility, activity, etc.) and lipid scrambling in this platform. The orientation of proteins in the cell blebs and planar bilayers is revealed using a protease cleavage assay. Lipid scrambling in both cell blebs and planar bilayers is indicated through an annexin V binding assay. To quantify protein confinement, immobility, etc., incorporation of GPI-linked yellow fluorescent protein (GPI-YFP) was used in conjunction with single-molecule tracking (SMT) microscopy. Finally, to investigate the impact of the bleb induction method on protein activity and expression level, cell blebs expressing human aminopeptidase N (hAPN) were analyzed by an enzyme activity assay and immunoblotting. This work enriches our understanding of cell plasma membrane bleb bilayers as a biomimetic platform, reveals conditions under which specific properties are met, and represents one of the few ways to make molecularly complete supported bilayers directly from cell plasma membranes.


Immunogenicity, durability, and safety of an mRNA and three platform-based COVID-19 vaccines as a third dose following two doses of CoronaVac in China: A randomised, double-blinded, placebo-controlled, phase 2 trial.
More effective vaccine candidates against variants of concern as a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. This randomised, double-blinded, investigator-initiated phase 2 trial aims to evaluate immunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and three other platform vaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinant protein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster. 250 eligible volunteers, who had received a prime two-dose CoronaVac (3 to 5 weeks apart) vaccination 100-270 days before, were randomly assigned in a 1:1:1:1:1 ratio to receive a third dose of RQ3013 (30 μg mRNA per 0.15 mL), ChAdTS-S (5×1010 viral particles per 0.5 mL), ZR202-CoV (25 μg prefusion-stabilized Spike ectodomain trimer per 0.5 mL), CoronaVac (3 μg inactivated CN02 strain of SARS-CoV-2 per 0.5 mL) or placebo (0.5 mL of 0.9% sodium chloride solution) via intramuscular injection into the upper arm at a single clinical site in Kunming, China. Participants, investigators, and immunogenicity laboratory were masked to group assignment. The primary immunogenicity outcomes were geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 (wild-type, delta and omicron) virus at day 0 (before vaccination), day 7, day 14 and day 28 after vaccination, as analysed in a modified intention-to-treat (mITT) population (all participants who completed their booster doses and had at least one post-dose immunogenicity data). Secondary outcomes include T cell responses against the wild-type and omicron SARS-CoV-2 Spike protein. The primary safety outcome was incidence of adverse events within 14 days after the booster vaccination. This trial is registered with ChiCTR.org.cn, ChiCTR2200057758. Between January 1, 2022, and February 28, 2022, 235 eligible participants were enrolled and vaccinated, and the primary analysis included 234 participants. At baseline, neutralising antibodies against wild-type virus, the delta, or omicron variants were low or undetectable in all groups. After the booster vaccination, GMTs of neutralising antibodies ranged from 75.4 (95% confidence interval [CI] 61.4-92.5) in CoronaVac to 950.1 (95% CI 785.4-1149.3) in RQ3013 against live wild-type SARS-CoV-2, and from 8.1 (95% CI: 6.1-10.7) in CoronaVac to 247.0 (95% CI 194.1-314.3) in RQ3013 against the omicron variant at day 14. Immunogenicities of all heterologous regimens were superior to that of homologous regimen in neutralisation against all tested SARS-CoV-2 strains, with RQ3013 showing the highest geometric mean ratios (GMRs) of 12.6, 14.7, and 31.3 against the wild-type, the delta variant and the omicron variant compared to CoronaVac at day 14 post-vaccination, respectively. Durability analysis at day 90 showed that >90% of participants in RQ3013 and ZR202-CoV were seropositive for the omicron variant while ZR202-CoV with adjuvants containing CpG showed a slightly better durability than RQ3013. T cell responses specific to the omicron variant were similar to that of the wild-type, with RQ3013 showing the highest boosting effect. Any solicited injection site or systemic adverse events reported within 14 days after vaccination were most commonly observed in RQ3013 (47/47, 100%), followed by ZR202-CoV (46/47, 97.9%) and ChAdTS-S (43/48, 89.6%), and then CoronaVac (37/46, 80.4%) and placebo (21/47, 44.7%). More than 90% of the adverse events were grade 1 (mild) or 2 (moderate) with a typical resolution time of 3 days. No grade 4 adverse events or serious adverse events were reported by study vaccines. Although all study vaccines boosted neutralising antibodies with no safety concerns, RQ3013 showed much stronger cross-neutralisation and cellular responses, adding more effective vaccine candidates against the omicron variant. Yunnan Provincial Science and Technology Department China (202102AA100051 and 202003AC100010), the Double First-class University funding to Yunnan University, National Natural Science Foundation of China (81960116, 82060368 and 82170711), Yunnan Natural Science Foundation (202001AT070085), High-level Health Technical Personnel Project of Yunnan Province (H-2018102) and Spring City Plan: The High-level Talent Promotion and Training Project of Kunming.


Eccentric viewing training.
Eccentric viewing training seeks to train subjects to utilize a paramacular area of the retina for seeing when the macular area is damaged. The present paper demonstrates two techniques for training eccentric viewing, as well as a method for measuring impovement in the use of the paramacular area. Both techniques are inexpensive, can be administered by a technician, and do not require an extensive training period. However, there are indications the two techniques are not comparable in effectiveness.


[The effect of treatment of chrysotile with chloride iron (III) on the effect of genomic instability in cultured human lymphocytes].
All forms of asbestos are carcinogenic to humans, that caused the prohibition of its use in Europe, America, etc. However, the unique physical and chemical properties of asbestos and many opportunities for its applications in various industries and human activities require the creation of new technologies to. Analysis of genomic instability in human lymphocytes in a large range of doses (micronucleus test with cytochalasin B showed a decline of core indicators of genome instability (frequency of dividing cells with cytogenetic damage, asymmetry in the distribution of the genetic material in mitosis, proliferative activity) incubation of cells with asbestos modified chloride iron, as compared to the initial sample. These data are consistent with the results of analysis of the intensity of neutrophil chemiluminescence of luminol by exposure of human blood samples studied. Based on the findings made some practical recommendations to the protocol cytogenetic analysis of genomic instability of people exposed to asbestos.


Ca2+-induced changes in the secondary structure of a 60 kDa phosphoinositide-specific phospholipase C from bovine brain cytosol.
The purification to homogeneity of a 60 kDa phosphoinositide-specific phospholipase C from bovine brain cytosol is reported here. This enzyme exhibits the same properties, in terms of response to Ca2+, as does the cytosolic activity in a variety of cell types. We show here that Ca2+ does not appear to modulate the binding of the enzyme to the substrate, but induces dramatic changes in its secondary structure. Therefore we suggest that a decrease in the alpha-helix content of this enzyme correlates with its ability to be activated by Ca2+.


Magnetization Transfer Contrast and Chemical Exchange Saturation Transfer MRI. Features and analysis of the field-dependent saturation spectrum.
Magnetization Transfer Contrast (MTC) and Chemical Exchange Saturation Transfer (CEST) experiments measure the transfer of magnetization from molecular protons to the solvent water protons, an effect that becomes apparent as an MRI signal loss ("saturation"). This allows molecular information to be accessed with the enhanced sensitivity of MRI. In analogy to Magnetic Resonance Spectroscopy (MRS), these saturation data are presented as a function of the chemical shift of participating proton groups, e.g. OH, NH, NH2, which is called a Z-spectrum. In tissue, these Z-spectra contain the convolution of multiple saturation transfer effects, including nuclear Overhauser enhancements (NOEs) and chemical exchange contributions from protons in semi-solid and mobile macromolecules or tissue metabolites. As a consequence, their appearance depends on the magnetic field strength (B0) and pulse sequence parameters such as B1 strength, pulse shape and length, and interpulse delay, which presents a major problem for quantification and reproducibility of MTC and CEST effects. The use of higher B0 can bring several advantages. In addition to higher detection sensitivity (signal-to-noise ratio, SNR), both MTC and CEST studies benefit from longer water T1 allowing the saturation transferred to water to be retained longer. While MTC studies are non-specific at any field strength, CEST specificity is expected to increase at higher field because of a larger chemical shift dispersion of the resonances of interest (similar to MRS). In addition, shifting to a slower exchange regime at higher B0 facilitates improved detection of the guanidinium protons of creatine and the inherently broad resonances of the amine protons in glutamate and the hydroxyl protons in myoinositol, glycogen, and glucosaminoglycans. Finally, due to the higher mobility of the contributing protons in CEST versus MTC, many new pulse sequences can be designed to more specifically edit for CEST signals and to remove MTC contributions.


Gonopodial system review and a new fish record of Poeciliopsis infans (Cyprinodontiformes: Poeciliidae) for Lake Patzcuaro, Michoacan, central Mexico.
Since 1997, Poeciliopsis infans Woolman 1894 has been recognized as a new inhabitant of Lake Patzcuaro, Michoacan in Central Mexico. Between February 1997 and October 1998, nine fish samples were collected at Lake Patzcuaro. Morphometric and meristic counts were conducted on a random selection of 40 organisms of both sexes of Poeciliopsis infans. Males of these viviparous fish posses a modified anal fin called gonopodium. The characteristic hemal spine on the 18th caudal vertebra for this species is described herein and the bony components of the gonopodial structure and suspensoria that together comprise the gonopodial system, which is important for taxonomic studies at various levels of classification were reviewed. Poeciliopsis infans displays a high degree of sexual dimorphism in body shape and anal fin anatomy with the most conspicuous difference observed in anal fin height, which averages 40% of SI in males and 17% in females. Comparisons between male and female anal fins are described herein as well as the possible impacts of this species on Lake Patzcuaro fish fauna.


The tactics of large randomized trials.
Single-center studies and small randomized controlled trials often provide contradictory or inconclusive results. In contrast, large randomized controlled trials are designed to definitively answer a relevant and practice-changing research question. These studies rely on large sample sizes to gain adequate precision of the results and substantial funding to support the research infrastructure necessary to minimize bias. Tactics for successfully completing a large randomized controlled trial are outlined with examples from recent orthopaedic trials.


Normal cerebral arterial development and variations.
The cerebral vascular architecture is both unique and heterogeneous in its structure, organization, and function. For many years, it was believed that brain vasculature was dominated by nonanastomosing terminal or "end-arteries." This was primarily based upon the observation of discrete distribution of brain infarcts after embolic occlusion of particular vessels. It was not until the detailed anatomy work of Pfeiffer in 1928 that the new concept of an almost-uninterrupted vascular network of brain vasculature was proposed. Since then, the cerebral vascular anatomy and embryology has been studied in great detail. Its full description is beyond the scope of this article, and our aim is to provide a brief overview of the development of cranial arterial anatomy, with special emphasis on commonly encountered anatomical variations that may have clinical implications. The failure to recognize these can lead to misdiagnosis as well as otherwise-preventable iatrogenic injuries and complications. We describe the proposed underlying embryologic processes, pathology and clinical implications of these variations, including aberrant internal carotid arteries, carotid agenesis and hypoplasia, azygous anterior cerebral arteries, arterial fenestrations, and persistent embryonic vessels.


Bone remodeling.
The skeleton is a metabolically active organ that undergoes continuous remodeling throughout life. Bone remodeling involves the removal of mineralized bone by osteoclasts followed by the formation of bone matrix through the osteoblasts that subsequently become mineralized. The remodeling cycle consists of three consecutive phases: resorption, during which osteoclasts digest old bone; reversal, when mononuclear cells appear on the bone surface; and formation, when osteoblasts lay down new bone until the resorbed bone is completely replaced. Bone remodeling serves to adjust bone architecture to meet changing mechanical needs and it helps to repair microdamages in bone matrix preventing the accumulation of old bone. It also plays an important role in maintaining plasma calcium homeostasis. The regulation of bone remodeling is both systemic and local. The major systemic regulators include parathyroid hormone (PTH), calcitriol, and other hormones such as growth hormone, glucocorticoids, thyroid hormones, and sex hormones. Factors such as insulin-like growth factors (IGFs), prostaglandins, tumor growth factor-beta (TGF-beta), bone morphogenetic proteins (BMP), and cytokines are involved as well. As far as local regulation of bone remodeling is concerned, a large number of cytokines and growth factors that affect bone cell functions have been recently identified. Furthermore, through the RANK/receptor activator of NF-kappa B ligand (RANKL)/osteoprotegerin (OPG) system the processes of bone resorption and formation are tightly coupled allowing a wave of bone formation to follow each cycle of bone resorption, thus maintaining skeletal integrity.


Nurses' Perceptions of Pediatric Intensive Care Unit Environment and Work Experience After Transition to Single-Patient Rooms.
The architectural design of the pediatric intensive care unit may play a major role in optimizing the environment to promote patients' sleep while improving stress levels and the work experience of critical care nurses. To examine changes in nurses' perceptions of the environment of a pediatric critical care unit for promotion of patients' sleep and the nurses' work experience after a transition from multipatient rooms to single-patient rooms. A cross-sectional survey of nurses was conducted before and after the move to a new hospital building in which all rooms in the pediatric critical care unit were single-patient rooms. Nurses reported that compared with multipatient rooms, single-patient private rooms were more conducive to patients sleeping well at night and promoted a more normal sleep-wake cycle (P < .001). Monitors/alarms and staff conversations were the biggest factors that adversely influenced the environment for sleep promotion in both settings. Nurses were less annoyed by noise in single-patient rooms (33%) than in multipatient rooms (79%; P < .001) and reported improved exposure to sunlight. Use of single-patient rooms rather than multipatient rooms improved nurses' perceptions of the pediatric intensive care unit environment for promoting patients' sleep and the nurses' own work experience.


A new insight for ohmic contacts to MoS2: by tuning MoS2 affinity energies but not metal work-functions.
Two-dimensional (2D) transition metal dichalcogenides (TMDCs) have recently attracted tremendous interest for fundamental studies and applications. High contact resistances between the metal electrodes and the 2D TMDCs, usually composed of a tunneling barrier (TB) and a Schottky barrier (SB), are the key bottleneck to the realization of high performance devices based on such systems. Here, from van der Waals density functional theory calculations, we demonstrate that strain can provide a feasible means to reduce the contact resistances between, for example, 2D semiconductor MoS2 and metal surfaces, in both strong and weak coupling regimes. Both the SB and TB are lowered significantly with the increasing tensile strain in both the coupling regimes. Especially, the SB can reduce to zero in all configurations considered, with tensile strain increasing to ∼4% or above. The mechanism of SB reduction under tensile strain is attributed to the increase of the MoS2 affinity energy since the monolayer MoS2 conduction band minimum (CBm) is derived from anti-bonding states. Thus, the SB in other semiconducting TMDCs with an anti-bonding CBm (for n-type contact) could also be reduced to zero by tensile strain. Our discoveries thus shed a new and general light on minimizing the contact resistance of semiconducting TMDCs-metal based contacts and this can also prove applicable to other 2D semiconductors, e.g. phosphorene.


Percutaneous pulmonary valvuloplasty.
At Guy's Hospital percutaneous pulmonary valvuloplasty has been performed in 30 children with pulmonary valve stenosis. In 24 cases the results were satisfactory. There was little change in the stenoses of six children; three of these were found to have dysplastic valves at surgery. One child had a valvuloplasty performed twice. Follow up in eight children has shown the long term success of the procedure with no complications. Before percutaneous pulmonary valvuloplasty was available the only treatment for pulmonary valvular stenosis was surgery. This entailed a lengthy stay in hospital, a long postoperative period and an unsightly midline chest scar. The average length of time spent in hospital for surgery is two weeks, and for valvuloplasty a few days. Percutaneous pulmonary valvuloplasty should be considered as the initial treatment of choice for most congenital pulmonary valve stenosis. It is safe, effective, can be performed at any age and can reduce the risks of surgery.


Perception of alcohol intoxication shows acute tolerance while executive functions remain impaired.
Several psychological constructs (e.g., subjective perception of intoxication, visuomotor speed) display acute tolerance to alcohol, that is, show improvement at declining blood alcohol concentrations (BACs) relative to equivalent rising BACs. However, methodological challenges emerge when attempting to make such comparisons across limbs of the BAC curve, which have proven a barrier to advancing research on acute tolerance. To date, no studies have made multiple comparisons across the entire BAC trajectory. This study employs experimental procedures that overcome some of these difficulties, offering a clearer picture of recovery of impairment for subjective perception of intoxication and cognitive performance and the relationship between them. Twenty participants were assessed at multiple time points over 2 days. Continuous subjective perception of intoxication ratings and cognitive data derived from a computerized measure were paired with a novel analytic paradigm, which allowed comparisons at identified BACs. Results showed acute tolerance for individuals' subjective perception of intoxication and for performance on cognitive tasks measuring visuomotor speed and learning efficiency (recovery from impairment). In contrast, performance on measures of executive function and short-term memory showed no significant difference between limbs at exact concentrations (no recovery from impairment). Therefore, despite participants feeling less intoxicated over time, many cognitive functions remained impaired. The implication for these findings in terms of drunken driving behavior are substantial, suggesting that people may be likely to drive once they subjectively perceive that they have recovered from the acute intoxicating effects of alcohol, despite the persistence of "higher order" cognitive impairments.


Cardiovascular Safety and Benefits of Noninsulin Antihyperglycemic Drugs for the Treatment of Type 2 Diabetes Mellitus-Part 1.
Cardiovascular disease (CVD) is a major contributor to the morbidity and mortality associated with type 2 diabetes mellitus (T2DM). With T2DM growing in pandemic proportions, there will be profound healthcare implications of CVD in person with diabetes. The ideal drugs to improve outcomes in T2DM are those having antiglycemic efficacy in addition to cardiovascular (CV) safety, which has to be determined in appropriately designed CV outcome trials as mandated by regulatory agencies. Available evidence is largely supportive of metformin's CV safety and potential CVD risk reduction effects, whereas sulfonylureas are either CV risk neutral or are associated with variable CVD risk. Pioglitazone was also associated with improved CVD risk in patients with diabetes. The more recent antihyperglycemic medications have shown promise with regards to CVD risk reduction in T2DM patients at a high CV risk. Glucagon-like peptide-1 receptor agonists, a type of incretin-based therapy, were associated with better CV outcomes and mortality in T2DM patients, leading to the Food and Drug Administration approval of liraglutide to reduce CVD risk in high-risk T2DM patients. Ongoing and planned randomized controlled trials of the newer drugs should clarify the possibility of class effects, and of CVD risk reduction benefits in low-moderate CV risk patients. While metformin remains the first-line antiglycemic therapy in T2DM, glucagon-like peptide-1 receptor agonists should be appropriately prescribed in T2DM patients with baseline CVD or in those at a high CVD risk to improve CV outcomes. Dipeptidyl peptidase-4 inhibitors and sodium-glucose cotransporter-2 inhibitors are discussed in the second part of this review.


Male competition drives song divergence along an ecological gradient in an avian ring species.
Sexual selection operates via female choice and male competition, which can act independently, in concert, or in opposition. Female choice is typically considered the stronger selective force, but how these two processes interact to shape phenotypic divergence is poorly understood. I tested the hypothesis that variation in sexual selection in different habitats drives song divergence in the greenish warbler ring species. I evaluated the strength, direction, and targets of female choice and male competition in three populations spanning 2400 km of latitude. Average song length increased with latitude, concomitant with a decline in population density. Within populations, males sang longer songs when females were fertile and shorter songs during territory establishment. Females consistently preferred males with longer songs and larger song repertoires. By contrast, playback experiments showed that males used short songs in territory defense. Songs were shortest at high densities, and in the highest density population only, song traits preferred by females correlated with male territoriality. Stronger male competition at high population densities likely constrains maximum song length, whereas weaker competition at low densities allows expression of female choice for long songs. Interactions between male competition and ecology may be a crucial but oft-overlooked component of phenotypic divergence and speciation.


Resting-State Functional Correlates of Social Cognition in Multiple Sclerosis: An Explorative Study.
Social cognition includes mental operations essential for functional social interactions, and several studies revealed an impairment of social cognition abilities in patients with Multiple Sclerosis (MS). These deficits have been related to global and focal gray matter atrophy as well as microstructural white matter damage. Although some studies reveal a correlation between social cognition and task-based functional magnetic resonance imaging (MRI), no studies to date have explored the association between brain resting-state functional connectivity (RS-FC) abnormalities and several measures of social cognition in MS. The aim of this explorative study was to assess the contribution of RS-FC abnormalities of major brain networks to social cognition in MS patients. Clinical, neuropsychological, and MRI data were collected from 41 non-depressed and cognitively preserved relapsing-remitting MS patients (mean disease duration = 8.8 ± 8.2 years; median Expanded Disability Status Scale = 1.5, range 0-6.5) and 25 matched healthy controls (HCs). The ToM Pictures Sequencing Task (TMPS) and the Reading the Mind in the Eyes Task were employed to evaluate social cognition. All participants underwent a structural MRI and RS functional MRI 3T protocol. Regional gray matter atrophy was measured, and FCs of the default mode (DMN), right and left fronto-parietal, executive (EN), salience, cerebellar, and limbic (LN) networks were evaluated by independent component analysis (ICA). Differences on TMPS were found between MS patients and HC (MS < HC). In the MS group, associations were found between right middle temporal gyrus FC (in the DMN) and reciprocity subscale of TMPS, posterior cingulate cortex (PCC) FC (in the DMN) and first-order false-belief subscale of TMPS, cingulate gyrus FC (in the EN) and TMPS as well as reciprocity subscale of TMPS, and right superior temporal gyrus (in the LN) and reciprocity subscale of TMPS. All detected RS-FC changes did not co-localize with regional gray matter atrophy. The results suggest an association between social cognition and RS-FC changes of DMN, EN, and LN in MS. Future studies should further explore the possible adaptive or maladaptive mechanisms of these FC abnormalities in MS.


Long-term outcomes of patients with propylthiouracil-induced anti-neutrophil cytoplasmic auto-antibody-associated vasculitis.
It was well known that propylthiouracil (PTU) could induce ANCA-associated vasculitis (AAV) and clinical evident vasculitis could resolve after cessation of PTU with or without immunosuppressive therapy. However, the treatment strategy for patients with PTU-induced AAV remained inconclusive and their long-term outcomes were lacking. The aim of our study was to summarize these data. Fifteen patients with PTU-induced AAV, receiving immunosuppressive agents for <12 months and following over 24 months, were selected in the current study. The clinical and pathological data, including treatment protocols and outcomes, were retrospectively investigated. All the patients were followed for a mean of 55.0 (25-98) months. PTU was discontinued upon diagnosis of PTU-induced AAV. Immunosuppressive therapy was administrated only for patients with vital organ involvements, such as lung and kidney, and lasted only 7.9 +/- 3.3 (0.27-12) months. No relapse of vasculitis occurred during follow-up, even after withdrawal of immunosuppressive therapy. Twelve (80%) patients remained in complete remission and one patient remained in partial remission at the latest follow-up. Two patients were treatment resistant due to late referral and late withdrawal of PTU, both of them progressed to end-stage renal disease. For uncontrolled hyperthyroidism on presentation, six patients switched to methimazole and none of them experienced relapse of vasculitis. The long-term outcomes of patients with PTU-induced AAV were relatively good. PTU should be discontinued immediately after diagnosis. Immunosuppressive therapy may be only used in patients with vital organ involvements, and a long-term maintenance therapy may not be necessary.


Genomic mutation characteristics and prognosis of biliary tract cancer.
The incidence of biliary system cancer is higher in the Chinese population than in the West. The overall prognosis of gallbladder cancer and cholangiocarcinoma is poor, and the current treatment is limited. In order to explore the pathogenesis of biliary tract cancers and potential targeted therapies, we mapped the mutation landscape of biliary tract cancer in the Chinese population and analyzed the molecular mechanism related to prognosis. A total of 59 formalin fixed paraffin-embedded (FFPE) tissue samples were obtained from patients with operable biliary tract cancer. We conducted targeted capture sequencing of 620 genes through high-throughput sequencing technology and analyzed the fusion information of 13 genes. Mutations were detected in 88% samples, and the most frequent mutation base was C>T. Genes with higher single nucleotide variations (SNV) and copy number variations (CNV) frequency are TP53, KRAS, ARID1A, VEGFA, cyclin family related genes and cyclin-dependent kinase genes. Actionable mutations were detected in 59.3% samples, and germline mutations were detected in 22% samples. Patients with KRAS mutations, VEGFA pathway mutations and higher tumor mutation burden (TMB) may have poor prognosis. We explored the mutation characteristics and prognostic mechanism of biliary tract cancers in the Chinese population. This study provides potential evidence for targeted therapy and immunotherapy of biliary tract cancers.


Blood transfusion is associated with increased morbidity and mortality after lower extremity revascularization.
Little is known about the significance of blood transfusion in patients with peripheral arterial disease. We queried the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database to examine the effect of intraoperative blood transfusion on the morbidity and mortality in patients who underwent lower extremity revascularization. We analyzed data from the participant use data file containing vascular surgical cases submitted to the ACS NSQIP in 2005, 2006, and 2007 by 173 hospitals. Current procedural terminology codes were used to select lower extremity procedures that were grouped into venous graft, prosthetic graft, or thromboendarterectomy. Thirty-day outcomes analyzed were (1) mortality, (2) composite morbidity, (3) graft/prosthesis failure, (4) return to the operating room within 30 days, (5) wound occurrences, (6) sepsis or septic shock, (7) pulmonary occurrences, and (8) renal insufficiency or failure. Intraoperative transfusion of packed red blood cells was categorized as none, 1 to 2 units, and 3 or more units. Outcome rates were compared between the transfused and nontransfused groups using the chi(2) test and multivariable regression adjusting for transfusion propensity, comorbid and procedural risk. A total of 8799 patients underwent lower extremity revascularization between 2005 and 2007. Mean age was 66.8 +/- 12.0 years and 5569 (63.3%) were male. Transfusion rates ranged from 14.5% in thromboendarterectomy patients to 27.1% in prosthetic bypass patients (P < .05). After adjustment for transfusion propensity and patient and procedural risks, transfusion of 1 or 2 units remained significantly predictive of mortality, composite morbidity, sepsis/shock, pulmonary occurrences, and return to the operating room. The adjusted odds ratios for 30-day mortality ranged from 1.92 (95% confidence interval [CI] 1.36-2.70) for 1 to 2 units to 2.48 (95% CI 1.55-3.98) for 3 or more units. In a large number of patients undergoing lower extremity revascularization, we have found that there is a higher risk of postoperative mortality, pulmonary, and infectious complications after receiving intraoperative blood transfusion. Additional studies are necessary to better define transfusion triggers that balance the risk/benefit ratio for blood transfusion.


Predictors of frequent use of amphetamine type stimulants among HIV-negative gay men in Sydney, Australia.
Rates of use of amphetamine type stimulants among gay men have raised questions about the role of these drugs in increases in HIV infections and risk behaviour, but the role risk behaviours play with regard to illicit drug use within this population has not been investigated. Health in men (HIM) is a cohort of 1427 HIV-negative men in Sydney, Australia. All participants undergo annual face-to-face interviews. We examined onset of use of methamphetamine and of ecstasy (MDMA) after their baseline interview. Among baseline non-frequent users who completed an annual follow-up interview, 67 commenced at least weekly use of ecstasy, while 71 commenced at least weekly use of methamphetamine. Factors independently associated with commencing more frequent use of these drugs included being younger, greater involvement in gay social life, and having engaged in unprotected anal intercourse with casual partners. The transition from non- or less-frequent drug use to more frequent drug use may be associated with changes in sexual behaviour. While it may be true that illicit drug use leads to unsafe sexual behaviour, it is equally true that illicit drugs are used to enhance sexual performance and pleasure. The relationship is bidirectional and complex and must be understood within the contexts of particular sexual sub-cultural practices: engaging in sexual risk behaviour may be an indicator of future drug use as much as the reverse.


The Induction of Oxalate Metabolism In Vivo Is More Effective with Functional Microbial Communities than with Functional Microbial Species.
For mammals, oxalate enters the body through the diet or is endogenously produced by the liver; it is removed by microbial oxalate metabolism in the gut and/or excretion in feces or urine. Deficiencies in any one of the these pathways can lead to complications, such as calcium oxalate urinary stones. While considerable research has been conducted on individual oxalate-degrading bacterial isolates, interactions between oxalate and the gut microbiota as a whole are unknown. We examined the reduction in oxalate excretion in a rat model following oral administration of fecal microbes from a mammalian herbivore adapted to a high oxalate diet or to fecal transplants consisting of two different formulations of mixed oxalate-degrading isolates. While all transplants elicited a significant reduction in oxalate excretion initially, the greatest effect was seen with fecal microbial transplants, which persisted even in the absence of dietary oxalate. The reduction in oxalate excretion in animals given fecal transplants corresponded with the establishment of diverse bacteria, including known oxalate-degrading bacteria and a cohesive network of bacteria centered on oxalate-degrading specialists from the Oxalobacteraceae family. Results suggested that the administration of a complete community of bacteria facilitates a cohesive balance in terms of microbial interactions. Our work offers important insights into the development of targeted bacteriotherapies intended to reduce urinary oxalate excretion in patients at risk for recurrent calcium oxalate stones as well as bacteriotherapies targeting other toxins for elimination. IMPORTANCE Oxalate is a central component in 80% of kidney stones. While mammals do not possess the enzymes to degrade oxalate, many gastrointestinal bacteria are efficient oxalate degraders. We examined the role of cohesive microbial networks for oxalate metabolism, using Sprague-Dawley rats as a model host. While the transplantation of oxalate-degrading bacteria alone to the Sprague-Dawley hosts did increase oxalate metabolism, fecal transplants from a wild mammalian herbivore, Neotoma albigula, had a significantly greater effect. Furthermore, the boost for oxalate metabolism persisted only in animals that received fecal transplants. Animals receiving fecal transplants had a more diverse and cohesive network of bacteria associated with the Oxalobacteraceae, a family known to consist of specialist oxalate-degrading bacteria, than did animals that received oxalate-degrading bacteria alone. Our results indicate that fecal transplants are more effective at transferring specific functions than are microbial specialists alone, which has broad implications for the development of bacteriotherapies.


Two-dimensional statistical model for regularized backprojection in SPECT.
In SPECT, both the noise affecting the data and the discretization of the inverse Radon transform are responsible for the ill-posed nature of the reconstruction. To constrain the problem, we propose a regularized backprojection method (RBP) which takes advantage of the relationships existing between the continuity properties of the projections and those of the reconstructed object. The RBP method involves two stages: first, a statistical model (the fixed-effect model) is used to estimate the noise-free part of the projections. Then, the filtered projections are reconstructed using a backprojection algorithm (spline filtered backprojection) which ensures that the reconstructed object belongs to a space consistent with that containing the projections. The method is illustrated using analytical simulations, and the RBP approach is compared to the conventional filtered backprojection. The effect on the reconstructed slices of the parameters involved in RBP is studied in terms of spatial resolution, homogeneity in uniform regions and quantification. It is shown that appropriate combinations of these parameters yield a better compromise between homogeneity and spatial resolution than conventional FBP, with similar quantification performances.


[A comparative study of epinephrine injection and beta 2-agonist inhalation in the treatment of childhood asthma].
A total of 29 cases were enrolled in this study and divided randomly into Group I (traditional epinephrine injection) and Group II (terbutaline nebulizer inhalation). If patients did not respond well to the initial therapy. a crossover therapeutic regimen was assigned and their pulmonary function, peak expiratory flow rate (PEFR) was measured every 10 minutes for half an hour. Both groups of patients revealed significant improvement post initial treatment P less than 0.0001). Within group difference was analysis by Wilcoxon signed rank test. All subgroups at 10 minutes, 20 minutes, and 30 minutes were compared in terms of their baseline pulmonary function, epinephrine group P value showed 0.0059, 0.0038, 0.0025; and terbutaline nebulizer inhalation group P value showed as 0.0007. 0.0003, 0.0003 respectively. An analysis of the group with an initial PEFR below 40% of the normal predicted or the more severely ill childhood acute asthmatic patients, the ten minutes post-treatment PEFR value of the epinephrine group showed P = 0.059; a significant P value of 0.0038 was noted for the terbutaline inhalation group, but both group P value was less than 0.05 at 20.30 minutes post-treatment, respectively. Between-group difference was analysed by Mann Whitney U test. Although all time interval mean data showed higher for the terbutaline inhalation group, statistically it showed P greater than 0.05. The above data suggest terbutaline inhalation therapy at the dosage noted will have early onset of action and better early clinical improvement than the traditional epinephrine injection regimen. There seemed to be no difference in degree of improvement between the two regimens. Observation of crossover treatment found a 50% re-response rate in both group of of patients who did not respond well to their initial regimen, and post crossover treatment PEFR all showed statistically significant improvement. However, still there was no significant difference between the two groups. This suggests that the terbutaline nebulizer inhalation method can not totally replace the more traditional method of acute asthma management, and emphasizes that a crossover therapeutic regimen should be kept in mind because the re-response rate is still encouraging. According to the variance analysis, the most important factor influencing the final outcome was the degree of severity of the initial asthmatic attack. The lower in initial PEFR value. The worse the clinical response. Other factors like age, sex, duration of asthma (year) and time interval between onset to arrival at the emergency room, showed as neither significant nor important.(ABSTRACT TRUNCATED AT 400 WORDS)


Effects of problem format on division and multiplication performance: division facts are mediated via multiplication-based representations.
In 2 experiments participants solved division problems presented in multiplication-based formats (e.g., 8 x _ = 72) more quickly than division problems presented in division-based formats (e.g., 72 / 8 = _). In contrast, participants solved multiplication problems presented in a division-based format (e.g., _ / 8 = 9) slowly and made many errors. In both experiments, the advantage for multiplication-based formats on division problems was found only for large problems (i.e., those with products or dividends greater than 25). These findings provide support for the view that large single-digit division facts are mediated via multiplication-based representations and that multiplication is the primary mode of representation for both division and multiplication facts.


Can Better Management of Periodontal Disease Delay the Onset and Progression of Alzheimer's Disease?
A risk factor relationship exists between periodontal disease and Alzheimer's disease (AD) via tooth loss, and improved memory following dental intervention. This links the microbial contribution from indigenous oral periodontal pathogens to the manifestation of chronic conditions, such as AD. Here, we use Porphyromonas gingivalis infection to illustrate its effect on mental health. P. gingivalis infection, in its primary sub-gingival niche, can cause polymicrobial synergy and dysbiosis. Dysbiosis describes the residency of select commensals from the oral cavity following co-aggregation around the dominant keystone pathogen, such as P. gingivalis, to gain greater virulence. The initial process involves P. gingivalis disturbing neutrophil mediated innate immune responses in the healthy gingivae and then downregulating adaptive immune cell differentiation and development to invade, and subsequently, establish new dysbiotic bacterial communities. Immune responses affect the host in general and functionally via dietary adjustments caused by tooth loss. Studies from animals orally infected with P. gingivalis confirm this bacterium can transmigrate to distant organ sites (the brain) and contribute toward peripheral and intracerebral inflammation, and compromise vascular and microvascular integrity. In another study, P. gingivalis infection caused sleep pattern disturbances by altering glial cell light/dark molecular clock activity, and this, in turn, can affect the clearance of danger associated molecular patterns, such as amyloid-β, via the glymphatic system. Since P. gingivalis can transmigrate to the brain and modulate organ-specific inflammatory innate and adaptive immune responses, this paper explores whether better management of indigenous periodontal bacteria could delay/prevent the onset and/or progression of dementia.


[Search for alternative secondary structures of RNA, regulating expression of bacterial genes].
Expression of many bacterial genes is regulated by formation of alternative secondary RNA structure within the leader mRNA sequence. Our algorithm designed to search for these structures (basing on analysis of one nucleotide sequence) was applied to analyze operons of amino acid biosynthesis in alpha- and gamma-proteobacteria. The attenuators of these operons are predicted for genomes of some poorly known gamma-proteobacteria including Shewanella putrefaciens, attenuators of the tryptophan operon in some alpha-proteobacteria are also predicted.


Comparison of Lateral Tooth Volume and Morphology Between Buccally and Palatally Localised Unilateral Impacted Maxillary Canine Cases on Cone-Beam Computed Tomography.
The aim of this study was to compare the lateral tooth volume and morphology differences between buccally and palatally localized unilateral impacted maxillary canine (IMC) patients with volumetric and linear measurements on cone-beam computed tomography (CBCT) records. CBCT records of 48 individuals with 24-buccally and 24-palatally localized unilateral IMCs were included to the study. The patients comprised 34 females, 14 males, with a mean age of 17.71 (±SD 6.63 years). This split-mouth, retrospective case-control, study consisted of buccally and palatally IMC group, and each group was categorized into 2 sub-groups as impacted and erupted side. Lateral tooth volume, tooth length, mesiodistal-buccolingual crown widths, mesiodistal- buccolingual root widths at cemento-enamel junction (CEJ), at 4 mm apical to CEJ, at 8 mm apical to CEJ, mesiodistal crown-root angle, arch perimeter measurements were performed on CBCT images. The data were analyzed by factorial design repeated measures ANOVA. Bonferroni test was used for post-hoc analysis. The total volume, mesiodistal - buccolingual crown widths, buccolingual root width of lateral incisor at CEJ were statistically smaller in palatally IMC group. The lateral incisor's length, and arch perimeter were statistically shorter, mesiodistal, buccolingual root widths at 8 mm apical to CEJ, and crown-root angle of the lateral were narrower on impacted side than erupted side. The volume and crown widths of lateral incisor are effective in sagittal localization of IMC. The shorter length, narrower apical root morphology and mesially inclined crown-root angle of lateral incisor are noteworthy on impacted sides, regardless of sagittal position of IMC.


Time-reversal-invariant topological superconductors and superfluids in two and three dimensions.
We construct time-reversal invariant topological superconductors and superfluids in two and three dimensions. These states have a full pairing gap in the bulk, gapless counterpropagating Majorana states at the boundary, and a pair of Majorana zero modes associated with each vortex. The superfluid 3He B phase provides a physical realization of the topological superfluidity, with experimentally measurable surface states protected by the time-reversal symmetry. We show that the time-reversal symmetry naturally emerges as a supersymmetry, which changes the parity of the fermion number associated with each time-reversal invariant vortex and connects each vortex with its superpartner.


Structural and functional characterisation of Tst2, a novel TRPV1 inhibitory peptide from the Australian sea anemone Telmatactis stephensoni.
Sea anemone venoms are complex mixtures of biologically active compounds, including disulfide-rich peptides, some of which have found applications as research tools, and others as therapeutic leads. Our recent transcriptomic and proteomic studies of the Australian sea anemone Telmatactis stephensoni identified a transcript for a peptide designated Tst2. Tst2 is a 38-residue peptide showing sequence similarity to peptide toxins known to interact with a range of ion channels (NaV, TRPV1, KV and CaV). Recombinant Tst2 (rTst2, which contains an additional Gly at the N-terminus) was produced by periplasmic expression in Escherichia coli, enabling the production of both unlabelled and uniformly 13C,15N-labelled peptide for functional assays and structural studies. The LC-MS profile of the recombinant Tst2 showed a pure peak with molecular mass 6 Da less than that of the reduced form of the peptide, indicating the successful formation of three disulfide bonds from its six cysteine residues. The solution structure of rTst2 was determined using multidimensional NMR spectroscopy and revealed that rTst2 adopts an inhibitor cystine knot (ICK) structure. rTst2 was screened using various functional assays, including patch-clamp electrophysiological and cytotoxicity assays. rTst2 was inactive against voltage-gated sodium channels (NaV) and the human voltage-gated proton (hHv1) channel. rTst2 also did not possess cytotoxic activity when assessed against Drosophila melanogaster flies. However, the recombinant peptide at 100 nM showed >50% inhibition of the transient receptor potential subfamily V member 1 (TRPV1) and slight (∼10%) inhibition of transient receptor potential subfamily A member 1 (TRPA1). Tst2 is thus a novel ICK inhibitor of the TRPV1 channel.


Effect of health insurance on the utilisation of allied health services by people with chronic disease: a systematic review and meta-analysis.
Allied health services benefit the management of many chronic diseases. The effects of health insurance on the utilisation of allied health services has not yet been established despite health insurance frequently being identified as a factor promoting utilisation of medical and hospital services among people with chronic disease. The objective of this systematic review and meta-analysis was to establish the effects of health insurance on the utilisation of allied health services by people with chronic disease. Medline (Ovid Medline 1948 to Present with Daily Update), EMBASE (1980 to 1 April 2011), CINAHL, PsychINFO and the Cochrane Central Register of Controlled Trials were searched to 12 April 2011 inclusive. Studies were eligible for inclusion if they were published in English, randomised controlled trials, quasi-experimental trials, quantitative observational studies and included people with one or more chronic diseases using allied health services and health insurance. A full-text review was performed independently by two reviewers. Meta-analyses were conducted. One hundred and fifty-eight citations were retrieved and seven articles were included in the meta-analyses. The pooled odds ratio (95% CI) of having insurance (versus no insurance) on the utilisation of allied health services among people with chronic disease was 1.33 (1.16-1.52; P<0.001). There was a significant effect of insurance on the utilisation of non-physiotherapy services, pooled odds ratio (95% CI) 4.80 (1.46-15.79; P=0.01) but having insurance compared with insurance of a lesser coverage was not significantly associated with an increase in physiotherapy utilisation, pooled odds ratio (95% CI) 1.53 (0.81-2.91; P=0.19). The presence of co-morbidity or functional limitation and higher levels of education increased utilisation whereas gender, race, marital status and income had a limited and variable effect, according to the study population. The review was limited by the considerable heterogeneity in the research questions being asked, sample sizes, study methodology (including allied health service), insurance type and dependent variables analysed. The presence of health insurance was generally associated with increased utilisation of allied health services; however, this varied depending on the population, provider type and insurance product.


Visualization of the antioxidative effects of melatonin at the mitochondrial level during oxidative stress-induced apoptosis of rat brain astrocytes.
Oxidative stress-induced mitochondrial dysfunction has been shown to play a crucial role in the pathogenesis of a wide range of diseases. Protecting mitochondrial function, therefore, is vital for cells to survive during these disease processes. In this study, we demonstrate that melatonin, a chief secretory product of the pineal gland, readily rescued mitochondria from oxidative stress-induced dysfunction and effectively prevented subsequent apoptotic events and death in rat brain astrocytes (RBA-1). The early protection provided by melatonin in mitochondria of intact living cells was investigated by the application of time-lapse conventional, confocal, and multiphoton fluorescent imaging microscopy coupled with noninvasive mitochondria-targeted fluorescent probes. In particular, we observed that melatonin effectively prevented exogenously applied H2O2-induced mitochondrial swelling in rat brain astrocytes at an early time point (within 10 min) and subsequently reduced apoptotic cell death (150 min later). Other early apoptotic events such as plasma membrane exposure of phosphatidyl serine and the positive YOPRO-1 staining of the early apoptotic nucleus were also prevented by melatonin. A mechanistic study at the mitochondrial level related to the early protection provided by melatonin revealed that the indole molecule significantly reduced mitochondrial reactive oxygen species (ROS) formation induced by H2O2 stress. Melatonin also prevented mitochondrial ROS generation caused by other organic hydroperoxides including tert-butyl hydroperoxide and cumene hydroperoxide. This antioxidative effect of melatonin is more potent than that of vitamin E. Via its ability to reduce mitochondrial ROS generation, melatonin prevented H2O2-induced mitochondrial calcium overload, mitochondrial membrane potential depolarization, and the opening of the mitochondrial permeability transition (MPT) pore. As a result, melatonin blocked MPT-dependent cytochrome c release, the downstream activation of caspase 3, the condensation and karyorrhexis of the nucleus and apoptotic fragmentation of nuclear DNA. Thus, the powerful mitochondrial protection provided by melatonin reinforces its therapeutic potential to combat a variety of oxidative stress-induced mitochondrial dysfunctions as well as mitochondria-mediated apoptosis in various diseases.


PTR3: An Instrument for Studying the Lifecycle of Reactive Organic Carbon in the Atmosphere.
We have developed and characterized the novel PTR3, a proton transfer reaction-time-of-flight mass spectrometer (PTR-TOF) using a new gas inlet and an innovative reaction chamber design. The reaction chamber consists of a tripole operated with rf voltages generating an electric field only in the radial direction. An elevated electrical field is necessary to reduce clustering of primary hydronium (H3O+) and product ions with water molecules present in the sample gas. The axial movement of the ions is achieved by the sample gas flow only. Therefore, the new design allows a 30-fold longer reaction time and a 40-fold increase in pressure compared to standard PTR-TOF-MS. First calibration tests show sensitivities of up to 18000 counts per second/parts per billion and volume (cps/ppbv) at a mass resolution of >8000 m/Δm (fwhm). The new inlet using center-sampling through a critical orifice reduces wall losses of low volatility compounds. Therefore, the new PTR3 instrument is sensitive to VOC typically present in the ppbv range as well as to semivolatile organic compounds (SVOC) and even highly oxidized organic molecules (HOMs) present in the parts per quadrillion per volume (ppqv) range in the atmosphere.