Earliest evidence for social endogamy in the 9,000-year-old-population of Basta, Jordan.
The transition from mobile to sedentary life was one of the greatest social challenges of the human past. Yet little is known about the impact of this fundamental change on social interactions amongst early Neolithic communities, which are best recorded in the Near East. The importance of social processes associated with these economic and ecological changes has long been underestimated. However, ethnographic observations demonstrate that generalized reciprocity - such as open access to resources and land - had to be reduced to a circumscribed group before regular farming and herding could be successfully established. Our aim was thus to investigate the role of familial relationships as one possible factor within this process of segregation as recorded directly in the skeletal remains, rather than based on hypothetical correlations such as house types and social units. Here we present the revealing results of the systematically recorded epigenetic characteristics of teeth and skulls of the late Pre-Pottery Neolithic community of Basta in Southern Jordan (Figure S1). Additionally, mobility was reconstructed via a systematic strontium (Sr) isotope analysis of tooth enamel of the Basta individuals. The frequency of congenitally missing maxillary lateral incisors in the 9,000-year-old community of Basta is exceptionally high (35.7%). Genetic studies and a worldwide comparison of the general rate of this dental anomaly in modern and historic populations show that the enhanced frequency can only be explained by close familial relationships akin to endogamy. This is supported by strontium isotope analyses of teeth, indicating a local origin of almost all investigated individuals. Yet, the accompanying archaeological finds document far-reaching economic exchange with neighboring groups and a population density hitherto unparalleled. We thus conclude that endogamy in the early Neolithic village of Basta was not due to geographic isolation or a lack of exogamous mating partners but a socio-cultural choice.


Mammalian exocrine secretions XV. Constituents of secretion of ventral gland of male dwarf hamster, Phodopus sungorus sungorus.
In a study aimed at the chemical characterization of constituents of the ventral gland secretion of the male dwarf hamster, Phodopus sungorus sungorus, 48 compounds, including saturated alcohols, saturated and unsaturated ketones, saturated and unsaturated straight-chain carboxylic acids, iso- and anteisocarboxylic acids, 3-phenylpropanoic acid, hydroxyesters, 2-piperidone, and some steroids were identified in the secretion. The position of the double bonds in gamma-icosadienyl-gamma-butyrolactone and gamma-henicosadienyl-gamma-butyrolactone, and the position of methylbranching in seven C16-C21 saturated ketones could not be established. Several constituents with typically steroidal mass spectra also remained unidentified. The female dwarf hamster's ventral gland either does not produce secretion or produced so little secretion that it was impossible to collect enough material for analysis.


The Effect of Flaxseed Supplementation on Hormonal Levels Associated with Polycystic Ovarian Syndrome: A Case Study.
Flaxseed is a rich source of lignan and has been shown to reduce androgen levels in men with prostate cancer. Polycystic ovarian syndrome (PCOS), a common endocrine disorder among women in their reproductive years, also is associated with high levels of androgens and is frequently accompanied by hirsutism, amenorrhea and obesity. This clinical case study describes the impact of flaxseed supplementation (30 g/day) on hormonal levels in a 31-year old woman with PCOS. During a four month period, the patient consumed 83% of the flaxseed dose. Heights, weights, and fasting blood samples taken at baseline and 4-month follow-up indicated the following values: BMI (36.0 vs. 35.7m/kg(2)); insulin (5.1 vs. 7.0 uIU/ml); total serum testosterone (150 ng/dl vs. 45 ng/dl); free serum testosterone (4.7 ng/dl vs. 0.5 ng/dl); and % free testosterone (3.1% vs. 1.1%). The patient also reported a decrease in hirsutism at the completion of the study period. The clinically-significant decrease in androgen levels with a concomitant reduction in hirsutism reported in this case study demonstrates a need for further research of flaxseed supplementation on hormonal levels and clinical symptoms of PCOS.


Interaction according to urinary sodium excretion level on the association between ATP2B1 rs17249754 and incident hypertension: the Korean genome epidemiology study.
We examined an interaction according to the estimated 24-h urinary sodium excretion on the association between ATP2B1 rs17249754 and incident hypertension. We assessed the incidence of hypertension in 1780 participants aged 45 to 75 years without cardiovascular diseases. DNA genotyping was performed using the Affymetrix Single Nucleotide Polymorphism (SNP) array 5.0. Because of previously reported associations with hypertension in various populations including Koreans, ATP2B1 rs17249754 was determined. Sodium intake was assessed by estimating the 24-h urinary sodium excretion with a Kawasaki formula from a spot urine sample. We utilized Cox proportional hazard models to test an interaction according to urinary sodium excretion on the association between ATP2B1 rs17249754 and incident hypertension. The incident hypertension was increased as sodium excretion level was increased. We confirmed that the ATP2B1 rs17249754 polymorphism had significant association with hypertension. We found that the association was modified by urinary sodium excretion level (p-value = 0.006); the mutant type (AA allele, previously recognized as a protective allele) with <4 g/day urinary sodium excretion had an inverse association on hypertension compared with the wild types (GG+GA) (HR = 0.39, 95% confidence interval (CI) 0.17-0.90), whereas the mutant type with ≥6 g/day urinary sodium demonstrated a significantly increased risk of hypertension (HR = 1.89, 95% CI 1.05-3.43). In this 6-year longitudinal study, our findings suggest that excessive sodium intake estimated from urinary sodium excretion significantly modified the risk of developing hypertension associated with ATP2B1 rs17249754 genetic trait. That is, carriers with ATP2B1 rs17249754 homozygote mutant allele may be at higher risk of hypertension, when they consume excessive sodium intake.


Requiem for Nigro or is anal squamous carcinoma still a surgical problem: Abdominoperineal excision rather than a defunctioning stoma?
Combined multimodal treatment (CMT) is the preferred treatment for anal squamous carcinoma with radical surgery reserved for treatment failure. Some patients require a defunctioning stoma prior to CMT. Successful closure of such a stoma is unlikely. Abdominoperineal excision (APE) may be suitable as primary treatment in these patients. A retrospective review of all patients with anal squamous carcinoma was undertaken. Patients who required defunctioning colostomies prior to CMT were analysed for potential resectability of tumour prior to CMT and rate of permanent stoma. To evaluate organ preservation in the treatment of anal squamous cancer and the closure rate of pre-treatment, temporary diverting colostomy, thereby assessing whether APE could be offered as primary treatment in those requiring a pre-treatment colostomy. One hundred and twenty-five patients were included of which 58 were males. The mean age was 56 years. 107 were treated with curative intent. Six received primary APE and 12 salvage APE. Thirty (22 males) required pretreatment diverting colostomies. Three (10%) stomas were successfully reversed. Forty-eight (38%) of the 125 completed treatment with a permanent colostomy. Six patients who needed a stoma prior to CMT were deemed resectable. Organ preservation was not possible in about a third of patients. Defunctioning stomas prior to CMT were likely to be permanent. We propose that APE could be considered as an alternative in selective cases where the tumour is resectable with low morbidity and a stoma is indicated.


The yin and yang of 15-lipoxygenase-1 and delta-desaturases: dietary omega-6 linoleic acid metabolic pathway in prostate.
One of the major components in high-fat diets (Western diet) is the omega (omega, n)-6 polyunsaturated fatty acid (PUFA) called linoleic acid (LA). Linoleic acid is the precursor for arachidonic acid (AA). These fatty acids are metabolized to an array of eicosanoids and prostaglandins depending upon the enzymes in the pathway. Aberrant expression of the catabolic enzymes such as cyclooxygenases (COX-1 and/or -2) or lipoxygenases (5-LO, 12-LO, 15-LO-1, and 15-LO-2) that convert PUFA either AA and/or LA to bioactive lipid metabolites appear to significantly contribute to the development of PCa. However, PUFA and its cellular interactions in PCa are poorly understood. We therefore examined the mRNA levels of key enzymes involved in the LA and AA pathways in 18 human donor (normal) prostates compared to 60 prostate tumors using the Affymetrix U95Av2 chips. This comparative (normal donor versus prostate cancer) study showed that: 1) the level of 15-LO-1 expression (the key enzyme in the LA pathway) is low (P < 0.001), whereas the levels of delta-5 desaturase (P < 0.001, the key enzyme in the AA pathway), delta-6 desaturase (P = 0.001), elongase (P = 0.16) and 15-lipoxygenase-2 (15-LO-2, P = 0.74) are higher in donor (normal) prostates, and 2) Contrary to the observation in the normal tissues, significantly high levels of only 15-LO-1; whereas low levels of delta-6 desaturase, elongase, delta-5 desaturase and 15-LO-2 respectively, were observed in PCa tissues. Although the cyclooxygenase (COX)-1 and COX-2 mRNA levels were high in PCa, no significant differences were observed when compared in donor tissues. Our study underscores the importance of promising dietary intervention agents such as the omega-3 fatty acids as substrate competitors of LA/AA, aimed primarily at high 15-LO-1 and COX-2 as the molecular targets in PCa initiation and/or progression.


Reconstitution of membrane proteins: a GPCR as an example.
Membrane proteins are the gatekeepers to the cell and are essential to the function of all cells, controlling the flow of molecules and information across the cell membrane. Much effort has been put into the development of systems for studying membrane proteins in simplified environments that nevertheless mimic their native lipid environment. After isolation and production of purified membrane proteins in detergent, it is often necessary to reconstitute them into a lipid structure such as liposome, nanodisc, or lipodisq. Each of these has the advantage of returning the protein to a defined lipid environment, and the choice of system depends on the application. Regardless of the system to be used, the fundamental process involves the removal of detergent and incorporation of the protein into a stable lipid system. This chapter details methodologies we have developed, mainly focussed on the model G protein-coupled receptor (GPCR) neurotensin receptor 1, and the GPCR-homologue and model, bacteriorhopdopsin.


Children consuming milk cereal drink are at increased risk for overweight: The IDEFICS Sweden study, on behalf of the IDEFICS Consortium.
The aims of this study were to characterize milk cereal drink (MCD) consumption among Swedish children and to investigate the association between MCD and overweight in a longitudinally followed cohort of children over 2 years of age. In the Swedish cohort from IDEFICS (Identification and prevention of Dietary- and lifestyle-induced health EFfects In Children and infantS) we examined early feeding practices and weight status when children were aged 2-9 years (2007/2008) and at 2-year follow-up. Weight and height were measured at both time points in 1077 children. Characteristics of MCD consumers were explored with logistic regression. Body mass index (BMI) z-scores at both time points and weight status at follow-up were regressed on explanatory factors using mixed linear and logistic regression, respectively. Nearly 69% of children had consumed MCD. The MCD consumers were more likely than never-consumers to have two native Swedish parents, parents with less than 2 years of post-secondary education, and a shorter period of breastfeeding. MCD consumers had a higher BMI z-score at follow-up compared with baseline (difference in BMI z-score=0.12, 95% confidence interval (CI)=0.07, 0.17), while the average BMI z-score in non-consumers remained stable over time (0.00, 95% CI= -0.07, 0.07). MCD consumers were nearly five times more likely than non-consumers to become overweight during the follow-up (odds ratio (OR)=4.78, 95% CI=1.68, 13.59), independent of breastfeeding. MCD was consumed by the majority of children in this study. MCD consumption is associated with an increased risk for overweight and less exposure to breastfeeding. Our findings motivate future research aimed at investigating how MCD should be recommended.


At-line gas chromatographic-mass spectrometric analysis of fatty acid profiles of green microalgae using a direct thermal desorption interface.
Thermally assisted hydrolysis and methylation-gas chromatography (THM-GC) is an important tool to analyse fatty acid in complex matrices. Since THM-GC has major drawbacks such as isomerisation when applied to fatty acids in natural matrices, a direct thermal desorption (DTD) interface and an incubation time of 30 min were used to circumvent these problems. Using vegetable oils such as sunflower oil and triarachidonin, the conversion of triglycerides into their fatty acid methyl esters (FAMEs) was investigated. The yields using a DTD (and trimethylsulfonium hydroxide as a reagent) were found to be similar or even higher than when applying a conventional off-line method, while the FAME profiles were identical. When the procedure was applied to analyse the FAME profiles of microbial cells in a methanolic or aqueous suspension, it was found that accurate profiles are obtained for such samples. Thus, the present approach opens the route to analyse fatty acids in microbial cells in a fully automated fashion, which will allow high sample throughput.


Effectiveness of Taijiquan in treating insomnia: A systematic review and meta-analysis of randomized controlled studies.
Sleep efficiency of <80% based on actigraphy was defined as insomnia as self-reported difficulty falling asleep or waking up at night three to four times per week. It is known that adequate sleep is very important for human wellbeing, affecting people's work and life, insomnia will seriously damage our daily life. There is no recognized non-drug treatment. Studies have found that Taijiquan has a positive effect on insomnia patients. This systematic review and meta-analysis will evaluate the effect of Taijiquan on insomnia. To find all randomized controlled trials exploring the effects of Taijiquan on insomnia patients in Chinese and English, eight databases (Pubmed, Embase, Cochrane library, Web of Science, CNKI, CBM, VIP, and Wanfang Data) were searched. The retrieval time is from database construction to October 2021. Searches were conducted in both English and Chinese language. A meta-analysis by mean difference (MD) and 95% confidence interval (CI) was performed with RevMan 5.3. The risk of bias for each study was accounted for according to the Cochrane Handbook. Our primary outcome was Pittsburg Sleep Quality Index. We explored sources of heterogeneity by comparing effect sizes across different types of etiology, country, control group, and intervention type. The protocol was pre-registered with PROSPERO, CRD42021284511. Twenty-one RCTs published between 2004 and 2021 with 2,022 participants were included in this study. Twenty-one randomized controlled studies showed that Tai Chi significantly improved PSQI scores in patients with cancer, muscle fibrosis, and sub-health insomnia [MD = -1.16, 95% CI (-1.62, -0.71), P < 0.01]; There is insufficient evidence of improvement in patients with cerebrovascular disease [MD = -0.54, 95% CI (-1.58, 0.51), P = 0.31]; 8-form, 10-form or 24-form Yang's Taijiquan had the same effect in improving PSQI [MD = -1.33, 95% CI (-1.85, -0.81), P < 0.01]. When there is no treatment, exercise, exercise and health education as the control, taijiquan has a significant effect on insomnia treatment, and there is no difference in efficacy compared with cognitive behavioral therapy and health education (usual care) alone. The results of the study showed that Taijiquan significantly improved sleep quality in healthy adults and patients with chronic diseases, which suggests that Taijiquan may be considered as an alternative behavioral therapy in the treatment of insomnia. In the future, more high-quality, well-controlled randomized trials are needed to better inform clinical decisions.


Energy expenditure of nonexercise activity.
We found recently that changes in nonexercise activity thermogenesis (NEAT) mediate resistance to weight gain with overfeeding in sedentary adults. A potentially important, yet seldom investigated, component of NEAT is the energy expenditure of fidgeting-like activities. Our goal was to measure changes in energy expenditure with fidgeting-like activities. Energy expenditure was measured in 24 subjects (17 women and 7 men x+/- SD body weight: 76 +/- 21 kg) while recumbent at rest, sitting motionless, standing motionless, partaking of self-selected fidgeting-like movements while seated and while standing, and walking on a treadmill at 1.6, 3.2, and 4.8 km/h (1, 2, and 3 mph). Measurements were performed by using a high-precision, indirect calorimeter connected to the subject via a transparent, lightweight facemask that enabled almost unrestricted movement. Compared with metabolic rate in the supine position (5.4 +/- 1.5 kJ/min), energy expenditure increased while sitting motionless by 4 +/- 6%, while fidgeting while seated by 54 +/- 29% (P: < 0.0001), while standing motionless by 13 +/- 8% (P: < 0.0001), while fidgeting while standing by 94 +/- 38% (P: < 0.0001), while walking at 1.6 km/h by 154 +/- 38% (P: < 0.0001), while walking at 3.2 km/h by 202 +/- 45% (P: < 0.0001), and while walking at 4.8 km/h by 292 +/- 81% (P: < 0.0001). There was a significant, positive correlation between changes in energy expenditure and body weight for fidgeting-like activities while standing (r = 0.43, P: = 0.02) but not while seated. There is marked variance between subjects in the energy expenditure associated with self-selected fidgeting-like activities. The thermogenic potential of fidgeting-like and low-grade activities is sufficiently great to substantively contribute to energy balance.


Mobile phone text messaging interventions for HIV and other chronic diseases: an overview of systematic reviews and framework for evidence transfer.
Strong international commitment and the widespread use of antiretroviral therapy have led to higher longevity for people living with human immune deficiency virus (HIV). Text messaging interventions have been shown to improve health outcomes in people living with HIV. The objectives of this overview were to: map the state of the evidence of text messaging interventions, identify knowledge gaps, and develop a framework for the transfer of evidence to other chronic diseases. We conducted a systematic review of systematic reviews on text messaging interventions to improve health or health related outcomes. We conducted a comprehensive search of PubMed, EMBASE (Exerpta Medica Database), CINAHL (Cumulative Index to Nursing and Allied Health Literature), PsycINFO, Web of Science (WoS) and the Cochrane Library on the 17th April 2014. Screening, data extraction and assessment of methodological quality were done in duplicate. Our findings were used to develop a conceptual framework for transfer. Our search identified 135 potential systematic reviews of which nine were included, reporting on 37 source studies, conducted in 19 different countries. Seven of nine (77.7%) of these reviews were high quality. There was some evidence for text messaging as a tool to improve adherence to antiretroviral therapy. Text messages also improved attendance at appointments and behaviour change outcomes. The findings were inconclusive for self-management of illness, treatment of tuberculosis and communicating results of medical investigations. The geographical distribution of text messaging research was limited to specific regions of the world. Prominent knowledge gaps included the absence of data on long term outcomes, patient satisfaction, and economic evaluations. The included reviews also identified methodological limitations in many of the primary studies. Global evidence supports the use of text messaging as a tool to improve adherence to medication and attendance at scheduled appointments. Given the similarities between HIV and other chronic diseases (long-term medications, life-long care, strong link to behaviour and the need for home-based support) evidence from HIV may be transferred to these diseases using our proposed framework by integration of HIV and chronic disease services or direct transfer.


Blood Myeloid Dendritic Cells and slanDC in Antiretroviral Therapy- Suppressed HIV-Infected Patients.
Myeloid dendritic cells (mDCs) play a complex role in HIV infection regardless of viral replication. The aim of our study was to analyse mDCs in long term antiretroviral therapy (ART)- suppressed HIV-infected patients. We evaluated the numbers of mDCs and slanDC in the context of different degree of CD4+ T cell recovery, persistent T cell activation (as HLA-DR+/CD3+ expression) and monocyte-macrophage activation assessed in terms of circulating levels of both sCD14 and sCD163. We enrolled 72 aviremic patients under effective ART and 34 healthy donors (HD). Patients were divided into two groups on the bases of ΔCD4, indicating the difference between the value of CD4 at the time of sampling and CD4 nadir. Higher levels of mDCs and slanDC were found in patients with ΔCD4>200/mmc in comparison to HD. In those patients also an increased level of sCD14 was found, whereas sCD163 seemed to be at normal levels. An augmentation of activated CD4 T lymphocytes was found, although less pronounced in patients with ΔCD4<200/mmc. In conclusion, our findings showed an expansion of mDCs with a shift to inflammatory slanDC that could sustain both microbial translocation and HIV latency in CD4 T cells.


Youthful memory capacity in old brains: anatomic and genetic clues from the Northwestern SuperAging Project.
The Northwestern University SuperAging Project recruits community dwellers over the age of 80 who have unusually high performance on tests of episodic memory. In a previous report, a small cohort of SuperAgers was found to have higher cortical thickness on structural MRI than a group of age-matched but cognitively average peers. SuperAgers also displayed a patch of ACC where cortical thickness was higher than in 50- to 60-year-old younger cognitively healthy adults. In additional analyses, some SuperAgers had unusually low densities of age-related Alzheimer pathology and unusually high numbers of von Economo neurons in the anterior cingulate gyrus. SuperAgers were also found to have a lower frequency of the ɛ4 allele of apolipoprotein E than the general population. These preliminary results show that above-average memory capacity can be encountered in advanced age. They also offer clues to potential biological factors that may promote resistance to age-related involutional changes in the structure and function of the brain.


Persistence at 12 months with denosumab in postmenopausal women with osteoporosis: interim results from a prospective observational study.
To determine persistence with subcutaneous denosumab every 6 months in women being treated for osteoporosis, we conducted a single-arm prospective, observational study in the United States and Canada. Among 935 patients enrolled, 12-month persistence was 82%, with 66 patients (7%) reporting serious adverse events and 19 patients (2%) reporting fractures. Increased persistence with osteoporosis therapy is associated with reduced fracture risk. Denosumab reduced fracture risk in clinical trials; persistence in community settings is undetermined. This study evaluates persistence with denosumab in community practice in the United States (US) and Canada. In a 24-month multicenter, prospective, single-arm, observational study, women being treated for osteoporosis were enrolled ≤4 weeks after the first subcutaneous injection of denosumab. For this 12-month prespecified interim analysis, endpoints include persistence (one injection at study entry and another within 6 months + 8 weeks), attributes associated with persistence (univariate analysis), and serious adverse events (SAEs). Among 935 patients (mean age 71 years), mean baseline T-scores were -2.18 (femoral neck) and -2.00 (lumbar spine); 50% of patients had experienced osteoporotic fracture(s). At 12 months, 82 % of patients were persistent with denosumab. Baseline factors significantly (p < 0.05) associated with higher persistence included use of osteoporosis medications >5 years previously, lumbar spine T-score > -2.5, and treatment by female physicians (US). Lower persistence was associated (p < 0.05) with psychiatric diagnoses including depression, southern US residence, being divorced, separated, or widowed (US), and prior hip fracture (Canada). SAEs were reported in 66 patients (7%); no SAEs of osteonecrosis of the jaw, atypical femoral fracture, fracture healing complications, hypocalcemia, eczema, or hypersensitivity were reported. Nineteen patients (2%) reported osteoporotic fractures. The 12-month persistence observed in this single-arm open-label study of US and Canadian community practice extends the evidence regarding denosumab's potential role in reducing fracture risk in postmenopausal women with osteoporosis.


Modelling strain localization in Ti-6Al-4V at high loading rate: a phenomenological approach.
A phenomenological approach, based on a combination of a damage mechanism and a crystal plasticity model, is proposed to model a process of strain localization in Ti-6AI-4V at a high strain rate of 103 s-1. The proposed model is first calibrated employing a three-dimensional representative volume element model. The calibrated parameters are then employed to investigate the process of onset of strain localization in the studied material. A suitable mesh size is chosen for the proposed model by implementing a mesh-sensitivity study. The influence of boundary conditions on the initiation of the strain localization is also studied. A variation of crystallographic orientation in the studied material after the deformation process is characterized, based on results for different boundary conditions. The study reveals that the boundary conditions significantly influence the formation of shear bands as well as the variation of crystallographic orientation in the studied material. Results also indicate that the onset of strain localization can affect considerably the material's behaviour. This article is part of the theme issue 'Modelling of dynamic phenomena and localization in structured media (part 2)'.


Targeting Fibroblast Activation Protein: Radiosynthesis and Preclinical Evaluation of an 18F-Labeled FAP Inhibitor.
Fibroblast activation protein (FAP) has emerged as an interesting molecular target used in the imaging and therapy of various types of cancers. 68Ga-labeled chelator-linked FAP inhibitors (FAPIs) have been successfully applied to PET imaging of various tumor types. To broaden the spectrum of applicable PET tracers for extended imaging studies of FAP-dependent diseases, we herein report the radiosynthesis and preclinical evaluation of an 18F-labeled glycosylated FAPI ([18F]FGlc-FAPI). Methods: An alkyne-bearing precursor was synthesized and subjected to click chemistry-based radiosynthesis of [18F]FGlc-FAPI by 2-step 18F-fluoroglycosylation. FAP-expressing HT1080hFAP cells were used to study competitive binding to FAP, cellular uptake, internalization, and efflux of [18F]FGlc-FAPI in vitro. Biodistribution studies and in vivo small-animal PET studies of [18F]FGlc-FAPI compared with [68Ga]Ga-FAPI-04 were conducted in nude mice bearing HT1080hFAP tumors or U87MG xenografts. Results: [18F]FGlc-FAPI was synthesized with a 15% radioactivity yield and a high radiochemical purity of more than 99%. In HT1080hFAP cells, [18F]FGlc-FAPI showed specific uptake, a high internalized fraction, and low cellular efflux. Compared with FAPI-04 (half maximal inhibitory concentration [IC50] = 32 nM), the glycoconjugate, FGlc-FAPI (IC50 = 167 nM), showed slightly lower affinity for FAP in vitro, whereas plasma protein binding was higher for [18F]FGlc-FAPI. Biodistribution studies revealed significant hepatobiliary excretion of [18F]FGlc-FAPI; however, small-animal PET studies in HT1080hFAP xenografts showed higher specific tumor uptake of [18F]FGlc-FAPI (4.5 percentage injected dose per gram of tissue [%ID/g]) than of [68Ga]Ga-FAPI-04 (2 %ID/g). In U87MG tumor-bearing mice, both tracers showed similar tumor uptake, but [18F]FGlc-FAPI showed a higher tumor retention. Interestingly, [18F]FGlc-FAPI demonstrated high specific uptake in bone structures and joints. Conclusion: [18F]FGlc-FAPI is an interesting candidate for translation to the clinic, taking advantage of the longer half-life and physical imaging properties of 18F. The availability of [18F]FGlc-FAPI may allow extended PET studies of FAP-related diseases, such as cancer, but also arthritis, heart diseases, or pulmonary fibrosis.


Incidence and Prevalence of Crohn's Disease and Ulcerative Colitis in Olmsted County, Minnesota From 1970 Through 2010.
The incidence and prevalence of inflammatory bowel diseases (IBD) continue to increase worldwide. We sought to update incidence rates of Crohn's disease (CD) and ulcerative colitis (UC) in a well-defined United States population, calculating values for Olmsted County, Minnesota through 2010. We also calculated prevalence values. The resources of the Rochester Epidemiology Project were used to identify county residents who were diagnosed with IBD (CD or UC), based on previously set criteria. Those with new diagnoses of CD or UC between 1970 and 2010 were identified as incidence cases, and those meeting diagnostic criteria on January 1, 2011, were identified as prevalence cases. Incidence rates were estimated (adjusted for age and sex to the US white population in 2010). Trends in incidence based on age at diagnosis, sex, and year of diagnosis were evaluated by Poisson regression. The incidence cohort included 410 patients with CD (51% female) and 483 individuals with UC (56% male). Median age of diagnosis was 29.5 years for persons with CD (range, 4-93 years) and 34.9 years for UC (range, 1-91 years). From 2000 through 2010, the adjusted annual incidence rate for CD was 10.7 cases per 100,000 person-years (95% confidence interval [CI], 9.1-12.3 person-years) and for UC was 12.2 per 100,000 (95% CI, 10.5-14.0 person-years). On January 1, 2011, there were 380 residents with CD, with an adjusted prevalence of 246.7 cases per 100,000 persons (95% CI, 221.7-271.8 cases per 100,000 persons), and 435 residents with UC, with an adjusted prevalence of 286.3 (95% CI, 259.1-313.5 cases per 100,000 persons). Male sex was significantly associated with a higher incidence rate of UC, and younger age was significantly associated with a higher incidence rate of CD. Estimated incidence rates for UC and CD in Olmsted County are among the highest in the United States. Extrapolating the adjusted prevalence to the most recent US Census, there could be approximately 1.6 million persons in the United States with IBD.


Prospective changes in alcohol use among hazardous drinkers in the absence of treatment.
Gaining a better understanding of the natural course of hazardous alcohol consumption could inform the development of brief interventions to encourage self-change. In the current study, hazardous drinkers (based on Alcohol Use Disorders Identification Test score) were recruited using advertisements to participate in a 2-year multiwave prospective study. Participants (n = 206) provided self-reports every six months during the study, including reports of daily alcohol consumption. The current investigation focuses on self-initiated change in participants' frequency of heavy drinking days (i.e., ≥ 5/4 drinks per day for men/women), as predicted by a number of demographic (e.g., age) and psychosocial (e.g., guilt-proneness) variables. Latent growth curve models of the change in percent heavy drinking days over the 2-year period provided an excellent fit to the observed data and indicated a significant decline in percent heavy drinking days over time. Reductions in heavy drinking frequency were predicted by younger age and higher guilt-proneness. The identification of these predictors of reductions in heavy drinking frequency provides information to guide future work investigating self-change among hazardous drinkers.


Co-production of "nature walks for wellbeing" public health intervention for people with severe mental illness: use of theory and practical know-how.
Interventions need to be developed in a timely and relatively low-cost manner in order to respond to, and quickly address, major public health concerns. We aimed to quickly develop an intervention to support people with severe mental ill-health, that is systematic, well founded both in theory and evidence, without the support of significant funding or resource. In this article we aim to open and elucidate the contents of the 'black box' of intervention development. A multidisciplinary team of seven academics and health practitioners, together with service user input, developed an intervention in 2018 by scoping the literature, face-to-face meetings, email and telephone. Researcher fieldnotes were analysed to describe how the intervention was developed in four iterative steps. In step 1 and 2, scoping the literature showed that, a) people with severe mental illness have high mortality risk in part due to high levels of sedentary behaviour and low levels of exercise; b) barriers to being active include mood, stress, body weight, money, lack of programmes and facilities and stigma c) 'nature walks' has potential as an intervention to address the problem. In Step 3, the team agreed what needed to be included in the intervention so it addressed the "five ways to mental wellbeing" i.e., help people to connect, be active, take notice, keep learning and give. The intervention was mapped to key behavioural change concepts such as, personal relevance, relapse prevention, self-efficacy. In Step 4, the team worked out how best to implement the intervention. The intervention would be delivered over 12 weeks by members of the hospital team and community walk volunteers. Participants would receive a nature walks booklet and text messages. We developed a theoretically-informed, evidence-based nature walks programme in a timely and relatively low-cost manner relevant in an era of growing mental illness and funding austerity. Further research is required to test if the intervention is effective and if this approach to intervention development works.


Urinary Metabolic Profile of Patients with Transfusion-Dependent β-Thalassemia Major Undergoing Deferasirox Therapy.
Renal dysfunction is a frequent complication in patients suffering from β-thalassemia major (β-TM). The aim of this study was to analyze the renal function and urine metabolomic profile of β-TM patients undergoing transfusions and deferasirox (DFX) therapy, in order to better characterize and shed light on the pathogenesis of renal disease in this setting. 40 patients affected by β-TM treated with DFX and 35 age- and gender-matched healthy controls were enrolled in the study. Renal function was assessed. Glomerular filtration rate (GFR) was estimated with CKD-EPI and Schwartz formula for adults and children, respectively. Renal tubular function and maximal urine concentration ability were tested. Urine specimens were analyzed by nuclear magnetic resonance spectroscopy to identify the urinary metabolite profiles. The study of renal function in β-TM patients revealed normal estimated (e)GFR mean values and the albumin-to-creatinine ratio was <30 mg/g. The analysis of tubular function showed normal basal plasma electrolyte levels; 60% of patients presented hypercalciuria and many subjects showed defective urine concentration. Several amino acids, N-methyl compounds, and organic acids were overexcreted in the urine of thalassemic patients compared with controls. The major finding of this work is that β-TM patients and controls exhibit different concentrations of some metabolites in the urine. Early recognition of urinary abnormalities may be useful to detect and prevent kidney damage.


Non-fatal occupational injuries in British agriculture.
To investigate the incidence, nature and determinants of non-fatal occupational injuries in British agriculture. As part of a postal survey, data on lifetime histories of work in agriculture and occupational accidents were obtained from men born between 1933 and 1977 and residing in three rural areas of England and Wales. Incidence rates for different categories of accident were compared with those derived from statutory reporting. Associations with risk factors were explored by Poisson regression, and summarised by incidence rate ratios (IRRs). Of the 10 765 responders (response rate = 31%), 3238 (30%) reported at least one occupational accident at the ages of 14-64 years, leading to absence from work for >or=3 days, including 1492 accidents that could be linked to a specific job listed in the history of agricultural work. The reported incidence of injuries in agriculture was markedly higher than that derived from statutory reporting, particularly for self-employed farmers. During 1996-2003, the highest rates of agricultural accidents were from handling, lifting or carrying (4.9/1000 person-years), falls from a height (4.6/1000 person-years) and injury by animals (3.4/1000 person-years). After adjustment for calendar period and age, the risk of accidents was elevated in men who had only recently entered agricultural work (IRR 3.7, 95% CI 2.7 to 5.1 for men who had worked in agriculture for up to 1 year relative to those who had entered the industry >25 years earlier), and in those who carried out forestry (IRR 1.7, 95% CI 1.5 to 1.9). Our findings confirm the substantial underascertainment of serious accidental injuries in agriculture through statutory reporting, particularly for the self-employed. The risk of accidents is highest in new recruits to the industry and in those undertaking forestry, and these groups should be a target for further preventive action.


An absolute requirement for both the type II and type I receptors, punt and thick veins, for dpp signaling in vivo.
TGF beta elicits diverse cellular responses by signaling through receptor complexes formed by two distantly related transmembrane serine/threonine kinases called type II and type I receptors. Previous studies have indicated that the product of the Drosophila thick veins (tkv) gene is a type I receptor for decapentaplegic (dpp). Here, we show that the Drosophila gene punt encodes a homolog of a vertebrate type II receptor, and we demonstrate that punt, like tkv, is essential in vivo for dpp-dependent patterning processes. Because no dpp-related signalling is apparent in the absence of either the punt or tkv receptor, we infer that both receptors act in concert to transduce the dpp signal and that their functions cannot be replaced by the other extant type II and I receptors.


Kefir reduces insulin resistance and inflammatory cytokine expression in an animal model of metabolic syndrome.
There is growing evidence that kefir can be a promising tool in decreasing the risk of many diseases, including metabolic syndrome (MetS). The aim of the present study was to evaluate the effect of kefir supplementation in the diet of Spontaneously Hypertensive Rats (SHR) in which MetS was induced with monosodium glutamate (MSG), and to determine its effect on metabolic parameters, inflammatory and oxidation marker expression and glycemic index control. Thirty animals were used in this experiment. For the induction of MetS, twenty two-day-old male SHR received five consecutive intradermal injections of MSG. For the Negative Control, ten newborn male SHR received intradermal injections of saline solution (0.9% saline solution). After weaning, animals received standard diet and water ad libitum until reaching 3 months old, for the development of MetS. They were then divided into three groups (n = 10): negative control (NC, 1 mL saline solution per day), positive control (PC, 1 mL saline solution per day) and the Kefir group (1 mL kefir per day). Feeding was carried out by gavage for 10 weeks and the animals received standard food and water ad libitum. Obesity, insulin resistance, pro- and anti-inflammatory markers, and the histology of pancreatic and adipose tissues were among the main variables evaluated. Compared to the PC group, kefir supplementation reduced plasma triglycerides, liver lipids, liver triglycerides, insulin resistance, fasting glucose, fasting insulin, thoracic circumference, abdominal circumference, products of lipid oxidation, pro-inflammatory cytokine expression (IL-1β) and increased anti-inflammatory cytokine expression (IL-10). The present findings indicate that kefir has the potential to benefit the management of MetS.


Beam delivery and pulse compression to sub-50 fs of a modelocked thin-disk laser in a gas-filled Kagome-type HC-PCF fiber.
We present two experiments confirming that hypocycloid Kagome-type hollow-core photonic crystal fibers (HC-PCFs) are excellent candidates for beam delivery of MW peak powers and pulse compression down to the sub-50 fs regime. We demonstrate temporal pulse compression of a 1030-nm Yb:YAG thin disk laser providing 860 fs, 1.9 µJ pulses at 3.9 MHz. Using a single-pass grating pulse compressor, we obtained a pulse duration of 48 fs (FWHM), a spectral bandwidth of 58 nm, and an average output power of 4.2 W with an overall power efficiency into the final polarized compressed pulse of 56%. The pulse energy was 1.1 µJ. This corresponds to a peak power of more than 10 MW and a compression factor of 18 taking into account the exact temporal pulse profile measured with a SHG FROG. The compressed pulses were close to the transform limit of 44 fs. Moreover, we present transmission of up to 97 µJ pulses at 10.5 ps through 10-cm long fiber, corresponding to more than twice the critical peak power for self-focusing in silica.


NMR Structure Determination of Ion Pairs Derived from Quinine: A Model for Templating in Asymmetric Phase-Transfer Reductions by BH(4)(-) with Implications for Rational Design of Phase-Transfer Catalysts.
The solution structures of ion pairs formed by quarternary ammonium ions derived from quinine alkaloid with small hard anions (BH(4)(-) or Cl(-)) in CDCl(3) have been characterized by nuclear magnetic resonance methods. Structural observations have been correlated with the sense of asymmetric induction observed in the phase-transfer reduction of 9-anthryl trifluoromethyl ketone by borohydride (BH(4)(-)) when catalyzed by the quaternary N-benzylquinine ammonium ion. From interionic nuclear Overhauser effects (NOEs), it appears that the BH(4)(-) ion occupies two of the four trigonal pyramidal sites formed by substituents of the quarternary nitrogen of the catalyst cation. One of these sites is in close proximity to the cation's hydroxyl group that is strictly required for asymmetric induction in the model reaction, while the other site is near the vinyl group on the cation. The vinyl group does not appear to be important for determining the sense or extent of asymmetric induction. Using energy-minimized structures derived from NMR data, it was predicted that the N-(9-methyleneanthryl)quinine-quarternary ammonium catalyst would give improved asymmetric induction in the model reaction due to a preferred anion occupancy at the site near the hydroxyl group. An improvement in enantiomeric excess (ee) is observed using the anthryl-modified catalyst, and NMR studies on the modified catalyst confirm the predicted change in anion binding site occupancies. The changes in site occupancies determined by NMR can be fitted to a simple kinetic model that correctly predicts the extent of change in ee.


Morphology and innervation of the buccal glands of the Southern Hemisphere lamprey, Geotria australis.
The buccal glands of adults of the Southern Hemisphere lamprey Geotria australis consist of a pair of small, bean-shaped, hollow sacs, embedded within the basilaris muscle in the region below the eyes and to either side of the piston cartilage. Each gland, which is lined by a simple columnar epithelium and surrounded by an incomplete layer of skeletal muscle, discharges its contents into the oral cavity via a long, narrow duct. In downstream migrating young adults, the epithelial cells are low columnar, intermediate in electron density, and contain dark-staining inclusions and numerous lipid-like droplets. After saltwater acclimation, the epithelial cells become taller and the numbers of dark-staining inclusions increase whereas those of lipid-like droplets decline. By the end of the marine phase, the epithelium is more folded and now also contains dark and light cells. The ultrastructure of the epithelium shows the characteristics of both apocrine and merocrine secretion. Although intra-epithelial nerve endings were not observed, axons and occasional neurons are present in the lamina propria. Since the skeletal muscle capsule is also well innervated and contains neurons, a local feed-back mechanism may regulate the release of buccal gland fluid by monitoring the luminal pressure. Contractions of the skeletal muscle capsule and movements of the basilaris muscle during feeding would presumably assist the movement of secretion along the duct. The secretion possesses anticoagulating and haemolytic properties.


Impact of Worsened Metabolic Syndrome on the Risk of Dementia: A Nationwide Cohort Study.
The relationship of alteration of metabolic syndrome (MetS) with dementia remains unclear. The purpose of study was to evaluate the association between dynamic change in MetS status around a 5-year period and dementia. The cohort study was conducted from the Taiwanese Survey on Prevalence of Hypertension, Hyperglycemia, and Hyperlipidemia in 2002, with follow-up in 2007. The sample was subsequently linked to the National Health Insurance Research Database. Participants were divided into 3 groups: persistent MetS (MetS both in 2002 and 2007); nonpersistent MetS (MetS either in 2002 or 2007); and non-MetS (MetS neither in 2002 nor 2007). Furthermore, the individuals with nonpersistent MetS were categorized as improved MetS (MetS in 2002 but not in 2007) and worsened MetS (MetS not in 2002 but in 2007). Each participant was tracked until the end of 2011 to identify the development of dementia. In total, 3458 participants aged 40 to 80 years were included. Up to 10 years and 31 741 person-years of follow-up, 76 patients developed dementia. Only a relationship was found between the nonpersistent MetS and dementia (adjusted hazard ratio=1.93; 95% confidence interval =1.17-3.19; P=0.010). Moreover, a significantly higher dementia risk was observed in patients with worsened MetS (adjusted hazard ratio=2.22; 95% confidence interval=1.32-3.72; P=0.003), but not those with persistent (P=0.752) or improved (P=0.829) MetS. Similar results were detected in participants aged ≥65 years. Patients with worsened MetS had an increased dementia risk during the 10-year follow-up period in a population-based sample.


Molecular characterization of Tasmanian aquabirnaviruses from 1998 to 2013.
Tasmanian aquabirnaviruses (TABVs) have been isolated intermittently since 1998 from healthy Atlantic salmon Salmo salar and rainbow trout Oncorhynchus mykiss farmed in Macquarie Harbour, Tasmania, Australia. However, beginning in 2011, TABVs have been isolated from rainbow trout in association with mortality events. To determine if recent molecular changes in TABV were contributing to increased mortalities, next generation sequencing was undertaken on 14 TABVs isolated from 1998 to 2013. Sequencing of both genome segments and analysis of the 5 viral proteins they encode revealed that minimal changes had occurred in the past 15 yr. Of the amino acid changes detected only 1, alanine to aspartic acid at position 139 of the minor structural VP3 protein, was unique to the recent disease events. The most dramatic changes observed were in the length of the non-structural VP5 protein varying from 43 to 133 amino acids. However, the amino acid substitution in VP3 and variable VP5 length were unlikely to have resulted in increased TABV pathogenicity. The genome of a novel Australian aquabirnavirus, Victorian trout aquabirnavirus (VTAB) was also sequenced and compared to TABV isolates.


Strategies for waste management in small and medium towns of developing countries: a case study of India.
This paper evaluates the issues of waste management in small and medium towns (SMTs) (with population in the range of 10,000-100,000) of India, and identifies the need for a multi-disciplinary approach encompassing technological, economic and financial aspects of the issues to effect improvements. A comprehensive set of cross-disciplinary strategies is suggested to improve the prevailing conditions with environmentally appropriate, economically efficient and financially self-sustaining waste management services. Based on a case study of four SMTs in the State of Tamil Nadu in India, this paper evaluates the application of the suggested strategies and offers policy recommendations.


Wild plants, pregnancy, and the food-medicine continuum in the southern regions of Ghana and Benin.
In West Africa, women utilize wild plant species to maintain and enhance their health throughout the duration of pregnancy. These plants are a culturally resilient and financially accessible form of nourishment for pregnant women in the region, many of whom are malnourished, yet studies that identify both the nutritional and medicinal properties of these plants are limited. The objective of this study was to analyze women's knowledge of plants consumed in pregnancy in the southern regions of Ghana and Benin from a food-medicine continuum perspective. We gathered data in two fieldwork periods in West Africa (Ghana 2010 and Benin 2011) through herbal market surveys and 56 questionnaires with women and then conducted a literature review on known properties of the plants. Ghanaian women reported consuming wild greens such as iron-rich Nephrolepis biserrata and tree barks such as protein-rich Ricinodendron heudelotii in a soup based on the African oil palm fruit (Elaeis guineensis), a source of fatty acids. In Benin, participants frequently reported ingesting plants during pregnancy in the form of herbal teas. Commonly cited species included Securidaca longipedunculata, Dichapetalum madagascariense, and Schwenckia americana. Several of the plants demonstrated antioxidant, anti-malarial and anti-inflammatory activity in pharmacological studies, yet the majority has incomplete nutritional and pharmacological profiles. In total, informants cited 105 species that were consumed during pregnancy. Although Ghanaian and Beninese women mentioned different species and different forms of consumption, in both countries women cited "strengthening" as the most common motivation to consume wild plants during pregnancy. Strengthening is a concept that resonates within the food-medicine continuum, bridging the local diet and herbal pharmacopoeia of women's plant use during pregnancy. Ethnobotanical studies of this nature highlight the multidimensional use of plants and can improve health and nutritional programs in the region.


Bone Mineral Density in Sjögren Syndrome Patients with and Without Distal Renal Tubular Acidosis.
Primary Sjögren's syndrome (pSS) can be complicated by distal renal tubular acidosis (dRTA), which may contribute to low bone mineral density (BMD). Our objective was to evaluate BMD in pSS patients with and without dRTA as compared with healthy controls. BMD of lumbar spine (LS) and femoral neck (FN) was measured in 54 pSS patients and 162 healthy age- and sex-matched controls by dual-energy X-ray absorptiometry (DXA). dRTA was defined as inability to reach urinary pH <5.3 after an ammonium chloride (NH4Cl) test. LS- and FN-BMD were significantly higher in pSS patients compared with controls (1.18 ± 0.21 g/cm(2) for patients vs. 1.10 ± 0.18 g/cm(2) for controls, P = 0.008 and 0.9 ± 0.16 g/cm(2) for patients vs. 0.85 ± 0.13 g/cm(2) for controls, P = 0.009, respectively). After adjustment for BMI and smoking, the LS- and FN-BMD remained significantly higher. Patients with dRTA (N = 15) did not have a significantly different LS- and FN-BMD compared with those without dRTA (N = 39) after adjustment for BMI, age, and gender. Thirty-seven (69 %) pSS patients were using hydroxychloroquine (HCQ). Unexpectedly, pSS patients had a significantly higher LS- and FN-BMD compared with healthy controls. Patients with dRTA had similar BMD compared with patients without dRTA. We postulate that an explanation for the higher BMD in pSS patients may be the frequent use of HCQ.


Light propagation characteristics for arbitrary wavevector directions in biaxial media by a coordinate-free approach.
The general case of light propagation in lossless anisotropic media occurs in crystals that are biaxial, either naturally so or by induced means (e.g., by electrooptic effect). In these crystals the optical properties, such as the refractive indices, change with propagation direction and are conveniently described by the two-sheeted wavevector surface. Most published work treats light propagation only in the principal planes of the crystal, where the wavevector surface reduces to a circle and an ellipse and the mathematics is simplified. Commonly, however, a biaxial bulk or waveguide device, especially an active device, will be oriented so that the light propagation is not in a principal plane. A complete and concise coordinate-free approach is presented for isolating each sheet, thereby providing a convenient means for calculating the directional optical properties of the two decoupled waves for arbitrary wavevector directions and birefringence levels. The versatility of this approach coupled with available graphics software is demonstrated by displaying numerous cross sections of the wavevector surfaces.


Effects of Conjugated Linoleic Acid Associated With Endurance Exercise on Muscle Fibres and Peroxisome Proliferator-Activated Receptor γ Coactivator 1 α Isoforms.
Conjugated linoleic acid (CLA) has been reported to improve muscle hypertrophy, steroidogenesis, physical activity, and endurance capacity in mice, although the molecular mechanisms of its actions are not completely understood. The aim of the present study was to identify whether CLA alters the expression of any of the peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) isoforms, and to evaluate the possible existence of fibre-type-specific hypertrophy in the gastrocnemius and plantaris muscles. Mice were randomly assigned to one of four groups: placebo sedentary, CLA sedentary, placebo trained, or CLA trained. The CLA groups were gavaged with 35 μl per day of Tonalin® FFA 80 food supplement containing CLA throughout the 6-week experimental period, whereas the placebo groups were gavaged with 35 μl sunflower oil each day. Each administered dose of CLA corresponded to approximately 0.7 g/kg or 0.5%, of the dietary daily intake. Trained groups ran 5 days per week on a Rota-Rod for 6 weeks at increasing speeds and durations. Mice were sacrificed by cervical dislocation and hind limb posterior muscle groups were dissected and used for histological and molecular analyses. Endurance training stimulated mitochondrial biogenesis by PGC1α isoforms (tot, α1, α2, and α3) but CLA supplementation did not stimulate PGC1α isoforms or mitochondrial biogenesis in trained or sedentary mice. In the plantaris muscle, CLA supplementation induced a fibre-type-specific hypertrophy of type IIx muscle fibres, which was associated with increased capillary density and was different from the fibre-type-specific hypertrophy induced by endurance exercise (of types I and IIb muscle fibres). J. Cell. Physiol. 232: 1086-1094, 2017. © 2016 Wiley Periodicals, Inc.


Pharmacological intervention in prediabetes: considering the risks and benefits.
The impact of the diabetes epidemic will be staggering in terms of costs to individuals and society. Social educational initiatives are imperative to altering the lifestyle trends that drive the growth of the epidemic. Targeted lifestyle or drug interventions aimed at preventing progression from prediabetes to type 2 diabetes mellitus carry costs and risks that need to be considered in the context of expected benefits, which also need to be carefully defined. In terms of pharmacological intervention as part of a primary prevention programme, the risk/benefit assessment must include the potential for adverse effects in a large population of asymptomatic individuals, a significant proportion of whom would not progress to diabetes in the absence of treatment and in whom impaired glucose regulation may reflect different underlying pathogenetic mechanisms. Improving the balance of risks and benefits in drug interventions will require a greater ability to determine which treatments are likely to safely improve glucose regulation and prevent diabetes and its adverse cardiovascular outcomes in individual patients.


Ribosomal proteins as biomarkers for bacterial identification by mass spectrometry in the clinical microbiology laboratory.
Whole-cell matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is a rapid method for identification of microorganisms that is increasingly used in microbiology laboratories. This identification is based on the comparison of the tested isolate mass spectrum with reference databases. Using Neisseria meningitidis as a model organism, we showed that in one of the available databases, the Andromas database, 10 of the 13 species-specific biomarkers correspond to ribosomal proteins. Remarkably, one biomarker, ribosomal protein L32, was subject to inter-strain variability. The analysis of the ribosomal protein patterns of 100 isolates for which whole genome sequences were available, confirmed the presence of inter-strain variability in the molecular weight of 29 ribosomal proteins, thus establishing a correlation between the sequence type (ST) and/or clonal complex (CC) of each strain and its ribosomal protein pattern. Since the molecular weight of three of the variable ribosomal proteins (L30, L31 and L32) was included in the spectral window observed by MALDI-TOF MS in clinical microbiology, i.e., 3640-12000 m/z, we were able by analyzing the molecular weight of these three ribosomal proteins to classify each strain in one of six subgroups, each of these subgroups corresponding to specific STs and/or CCs. Their detection by MALDI-TOF allows therefore a quick typing of N. meningitidis isolates.


Effectiveness of copper oxide wire particles for Haemonchus contortus control in sheep.
To assess the efficacy of copper oxide wire particles (COWP) for the control of H contortus infections in grazing sheep. In experiment 1, 40 worm-free Merino hoggets (11 to 12 months of age) were divided into four equal groups and allocated to separate 0.8 ha pasture plots. Two groups then received 2.5 g COWP whereas the other two groups were untreated. From 1 week after COWP treatment all lambs received a weekly infection of 2000 H contortus larvae. At week 8, six sheep from the untreated group were then allocated to two groups and treated with either 2.5 or 5.0 g of COWP to establish therapeutic efficacy of treatment. Experiment 2 followed a similar protocol but was conducted with 40 worm-free Merino lambs (3 to 4 months of age) and no assessment of therapeutic efficacy was made. In experiment 1 no significant difference in faecal worm egg counts was observed between treatments and faecal worm egg counts remained less than 3000 epg in all animals. Total worm counts were reduced by 37% by COWP treatment (P = 0.055). Both 2.5 g and 5.0 g doses of COWP at 8 weeks of infection reduced faecal worm egg counts by > 85% with the higher dose giving an earlier response to treatment. In experiment 2, faecal worm egg counts at 4 and 6 weeks were reduced by more than 90% in the COWP treated lambs and worm numbers were 54% lower after 6 weeks when all remaining untreated lambs had to be treated for haemonchosis. Mean faecal worm egg counts in the COWP lambs remained below 3500 epg and clinical disease did not develop in the majority of lambs before the end of the experiment at 10 weeks. Treatment with COWPs appears to have the potential to reduce establishment and worm fecundity of Haemonchus spp for an extended period and may offer livestock producers a supplementary means of reducing larval contamination of pasture particularly in areas where anthelmintic resistance is a problem and copper supplementation is likely to be beneficial.


Integrated optofluidic system for monitoring particle mass concentrations based on planar emitter-receiver units.
We demonstrate an integrated optofluidic system for monitoring the particle mass concentration and the Sauter mean diameter of polydisperse flowing suspensions of water and standardized test dust. For optimum integration, a planar emitter-receiver unit is developed and fabricated on Si technology. A vertical cavity surface emitting laser at 850 nm serves as light source, and monolithically integrated segmented photodiodes detect both the attenuation of the primary light beam and the scattered light. The optical system is integrated into a planar transparent polymethylmethacrylate substrate by micromilling of an optical freeform surface and electron beam evaporation of reflective layers following the concept of planar integrated free-space optical systems. We are able to detect 1 mg/L of the standards ISO 12103-A2 (fine test dust), -A3 (medium test dust), and -A4 (coarse test dust) and to determine the Sauter mean diameter of the particle size distribution.


Cadmium fume inhalation and emphysema.
Lung function and chest radiographs of 101 men who had worked for 1 or more years manufacturing copper-cadmium alloy were compared with those of a referent group matched for age, sex, and employment status. Cigarette consumption was similar in the two groups. The cadmium workers had an excess of abnormalities of lung function and of radiographic changes consistent with emphysema. Classification of the cadmium workers by exposure categories based on either estimated cumulative cadmium exposure or liver cadmium measured by neutron activation analysis showed that abnormalities of lung function were greatest in those with the highest cumulative cadmium exposure or liver cadmium. The difference in the transfer coefficient (KCO) between cadmium workers and referents increased linearly with increasing cumulative exposure without evidence for a threshold. The estimated mean decrement in KCO for a cadmium worker employed 5 or more years with a cumulative exposure of 2000 yr.microgram.m-3 (exposure to the current UK control limit of 50 micrograms.m-3 for a working lifetime of 40 yr) lies between 0.05 and 0.3 mmol.min-1.kPa-1.l-1 (95% confidence interval). This decrement is consistent with the functional and radiological changes of emphysema observed in this group of workers.


Genetic association and transcriptome integration identify contributing genes and tissues at cystic fibrosis modifier loci.
Cystic Fibrosis (CF) exhibits morbidity in several organs, including progressive lung disease in all patients and intestinal obstruction at birth (meconium ileus) in ~15%. Individuals with the same causal CFTR mutations show variable disease presentation which is partly attributed to modifier genes. With >6,500 participants from the International CF Gene Modifier Consortium, genome-wide association investigation identified a new modifier locus for meconium ileus encompassing ATP12A on chromosome 13 (min p = 3.83x10(-10)); replicated loci encompassing SLC6A14 on chromosome X and SLC26A9 on chromosome 1, (min p<2.2x10(-16), 2.81x10(-11), respectively); and replicated a suggestive locus on chromosome 7 near PRSS1 (min p = 2.55x10(-7)). PRSS1 is exclusively expressed in the exocrine pancreas and was previously associated with non-CF pancreatitis with functional characterization demonstrating impact on PRSS1 gene expression. We thus asked whether the other meconium ileus modifier loci impact gene expression and in which organ. We developed and applied a colocalization framework called the Simple Sum (SS) that integrates regulatory and genetic association information, and also contrasts colocalization evidence across tissues or genes. The associated modifier loci colocalized with expression quantitative trait loci (eQTLs) for ATP12A (p = 3.35x10(-8)), SLC6A14 (p = 1.12x10(-10)) and SLC26A9 (p = 4.48x10(-5)) in the pancreas, even though meconium ileus manifests in the intestine. The meconium ileus susceptibility locus on chromosome X appeared shifted in location from a previously identified locus for CF lung disease severity. Using the SS we integrated the lung disease association locus with eQTLs from nasal epithelia of 63 CF participants and demonstrated evidence of colocalization with airway-specific regulation of SLC6A14 (p = 2.3x10(-4)). Cystic Fibrosis is realizing the promise of personalized medicine, and identification of the contributing organ and understanding of tissue specificity for a gene modifier is essential for the next phase of personalizing therapeutic strategies.


Two Spatially Distinct Posterior Alpha Sources Fulfill Different Functional Roles in Attention.
Directing attention helps to extract relevant information and suppress distracters. Alpha brain oscillations (8-12 Hz) are crucial for this process, with power decreases facilitating processing of important information and power increases inhibiting brain regions processing irrelevant information. Evidence for this phenomenon arises from visual attention studies (Worden et al., 2000); however, the effect also exists in other modalities, including the somatosensory system (Haegens et al., 2011) and intersensory attention tasks (Foxe and Snyder, 2011). We investigated in human participants (10 females, 10 males) the role of alpha oscillations in focused (0/100%) versus divided (40/60%) attention, both across modalities (visual/somatosensory; Experiment 1) and within the same modality (visual domain: across hemifields; Experiment 2) while recording EEG over 128 scalp electrodes. In Experiment 1, participants divided their attention between visual and somatosensory modality to determine the temporal/spatial frequency of a target stimulus (vibrotactile stimulus/Gabor grating). In Experiment 2, participants divided attention between two visual hemifields to identify the orientation of a Gabor grating. In both experiments, prestimulus alpha power in visual areas decreased linearly with increasing attention to visual stimuli. In contrast, prestimulus alpha power in parietal areas was lower when attention was divided between modalities/hemifields compared with focused attention. These results suggest there are two alpha sources, one of which reflects the "visual spotlight of attention" and the other reflects attentional effort. To our knowledge, this is the first study to show that attention recruits two spatially distinct alpha sources in occipital and parietal brain regions, acting simultaneously but serving different functions in attention.SIGNIFICANCE STATEMENT Attention to one spatial location/sensory modality leads to power changes of alpha oscillations (∼10 Hz) with decreased power over regions processing relevant information and power increases to actively inhibit areas processing "to-be-ignored" information. Here, we used detailed source modeling to investigate EEG data recorded during separate unimodal (visual) and multimodal (visual and somatosensory) attention tasks. Participants either focused their attention on one modality/spatial location or directed it to both. We show for the first time two distinct alpha sources are active simultaneously but play different roles. A sensory (visual) alpha source was linearly modulated by attention representing the "visual spotlight of attention." By contrast, a parietal alpha source was modulated by attentional effort, showing lowest alpha power when attention was divided.


REM desensitization as a new therapeutic method for post-traumatic stress disorder: a randomized controlled trial.
to evaluate potential efficacy of a new therapeutic approach in posttraumatic stress disorder in comparison with eye movement desensitization and reprocessing (EMDR), a standard treatment approach and controls. the study was designed using a randomized controlled trial methodology. Participants were recruited from military servicemen aged between 25 to 50 years who were admitting hospitals of Bushehr, Iran, with the final diagnosis of PTSD. Finally 33 male patients were devided into three subgroups: G1: EMDR; G2: REM Desensitization; and group 3: controls who received no therapy. Mississippi Scale for Posttraumatic Stress Disorder, Pittsburgh Sleep Quality Index (PSQI) and a 37 item death anxiety questionnaire were used for measures. multiple comparisons showed that intrusive thoughts were significantly more likely to improve with REM Desensitization versus EMDR (P=0.03), while depression was more responsive to EMDR (p=0.03). Among the Pittsburgh scale for the quality of sleep items, sleep quality (p=0.02), sleep duration (p=0.001), and total sleep quality score (p=0.002) were significantly more likely to improve in the REM Desensitization group. Change in the absolute death anxiety scores was not different between subgroups excepting EMDR versus control group (p=0.05). REM, desensitization, the new therapeutic approach to PTSD is a highly effective strategy, even more than EMDR, the standard treatment, in most of the evaluated subjects, with special emphasis on sleep symptoms, and also in the management of intrusive thoughts. Depression is the only factor in which, REM Desensitization was significantly less likely to represent a superior therapeutic effect than EMDR.


Oculomotor control in children who were born very prematurely.
Preterm infants are at increased risk of a variety of cerebral lesions, involving the white matter, cortex, cerebellum, thalamus, and caudate nucleus, many of which could compromise the control of eye movement. Visual problems and disorders of binocularity and alignment have been reported, but little if any quantitative assessment of oculomotor control has been undertaken. The purpose of this study was to extend the initial pilot study and quantitatively examine the control of saccades, smooth pursuit, and antisaccades in children who were born very prematurely. A group of preterm (PT) children aged 8 to 11 years (<32 weeks' gestation), who had normal IQ (>or=85) and were free of major disabilities (cerebral palsy, blindness, or deafness), and full-term (FT) control subjects of similar age were recruited from a geographically defined cohort. Antisaccades were examined in 36 preterm and 33 full-term subjects and smooth pursuit and saccades in 21 preterm and 19 full-term subjects, by using infrared oculography. Saccade and antisaccade targets were presented at an amplitude of 5 degrees according to a standard synchronous paradigm, and pursuit was assessed by using a step-ramp paradigm with a target velocity of 14 deg/s. There were no statistically significant differences between the preterm and the full-term subjects in relation to saccade gain, latency, duration, peak velocity, or the proportion of express saccades. Smooth-pursuit latencies tended to be slightly longer in the preterm subjects (leftward: P = 0.17, rightward: P = 0.02), but there were no significant differences between them and the full-term subjects in pursuit acceleration, open-loop velocity, or peak slow-eye velocity. The main area of deficit in the preterm children occurred in the voluntary control of saccades, with significantly higher antisaccade directional error rates (PT: 73.3% +/- 18.1%, FT: 54.2% +/- 16.9%, mean +/- SD; P < 0.001). The latency of the antisaccade error tended to be shorter in preterm subjects (P = 0.065), with a greater proportion of errors with latency in the express range (P = 0.08). Despite the increased risk of cerebral lesions, the control of saccades and pursuit was largely normal in the preterm children, suggesting that pathways at the level of the brain stem were principally intact. However, the preterm children had difficulties with the voluntary control of saccades, particularly in the area of inhibition, which may be indicative of a deficit in the region of the dorsolateral prefrontal cortex. This finding is consistent with other reports in preterm children in whom executive function has been found to be compromised, and both these aspects of behavior are likely to share similar areas of cortical control.


Clinical genetics of functionally mild non-coding GTP cyclohydrolase 1 (GCH1) polymorphisms modulating pain and cardiovascular risk.
Guanosine triphosphate cyclohydrolase 1 (GCH1) is the first enzyme in the tetrahydrobiopterin (BH4) biosynthesis, an important co-factor for the formation of nitric oxide, biogenic amines and serotonin. Hereditary diseases such as DOPA-responsive dystonia and atypical phenylketonuria are known to be caused by coding or splice-site mutations in the GCH1 gene, leading mostly to a dominant negative enzyme. However, recent evidence suggests a clinical genetics of GCH1 beyond these hereditary loss-of-function diseases. That is, a non-coding GCH1 haplotype has been associated with reduced pain hypersensitivity and with altered vascular endothelial function. Moreover, the presence of the non-coding c.*243C>T variant in the 3'-untranslated region (3'-UTR) of the GCH1 gene has been associated with mildly increased heart rate and blood pressure. Here, we show that carriers of the pain-protective GCH1 haplotype also carry the c.*243C>T variant and vice versa. We thus demonstrate that apart from the coding or splice-site variants causing DOPA-responsive dystonia and atypical phenylketonuria, there is a common clinically relevant GCH1 genetics that is so far known to be related to unfavorable changes of endothelial function and a reduced risk for chronic pain.


Antibiotic susceptibility of group A streptococci: a 6-year follow-up study.
The susceptibility patterns of group A streptococci over the last 6 years in our hospital were determined. Since our last study, carried out in 1987, all isolates have remained very susceptible in vitro to penicillin and all of the other beta-lactam agents tested. We observed resistance to erythromycin, clindamycin, tetracycline, and ofloxacin. The prevalence of erythromycin-resistant group A streptococci did not change appreciably throughout the study period.


Dopamine Targeting Drugs for the Treatment of Schizophrenia: Past, Present and Future.
Schizophrenia is a chronic and debilitating neuropsychiatric disorder affecting approximately 1% of the world's population. This disease is associated with considerable morbidity placing a major financial burden on society. Antipsychotics have been the mainstay of the pharmacological treatment of schizophrenia for decades. The traditional typical and atypical antipsychotics demonstrate clinical efficacy in treating positive symptoms, such as hallucinations and delusions, while are largely ineffective and may worsen negative symptoms, such as blunted affect and social withdrawal, as well as cognitive function. The inability to treat these latter symptoms may contribute to social function impairment associated with schizophrenia. The dysfunction of multiple neurotransmitter systems in schizophrenia suggests that drugs selectively targeting one neurotransmission pathway are unlikely to meet all the therapeutic needs of this heterogeneous disorder. Often, however, the unintentional engagement of multiple pharmacological targets or even the excessive engagement of intended pharmacological targets can lead to undesired consequences and poor tolerability. In this article, we will review marketed typical and atypical antipsychotics and new therapeutic agents targeting dopamine receptors and other neurotransmitters for the treatment of schizophrenia. Representative typical and atypical antipsychotic drugs and new investigational drug candidates will be systematically reviewed and compared by reviewing structure-activity relationships, pharmacokinetic properties, drug metabolism and safety, pharmacological properties, preclinical data in animal models, clinical outcomes and associated side effects.


A High-Pressure Polymorph of Troilite, FeS.
A new polymorph of FeS was produced in a diamond-anvil cell and observed at high pressure both optically and by x-ray diffraction. Fourteen x-ray reflections of the high-pressure FeS were recorded; however, the crystal structure is unknown. This form of FeS is stable at 25 degrees C only at pressures above approximately 55 kilobars. The transition to the lower pressure polymorph, troilite, is rapid and reversible.


National trends in utilization and in-hospital outcomes of mechanical versus bioprosthetic aortic valve replacements.
Substantial controversy surrounds the choice between a mechanical versus bioprosthetic prosthesis for aortic valve replacement (AVR), based on age. This study aims to investigate national trends and in-hospital outcomes of the 2 prosthesis choices. All patients aged >18 years in the National Inpatient Sample who received an AVR between 1998 and 2011 were considered. Valve-type use was examined by patient, procedural, and hospital characteristics, after which we matched patients based on their propensity score for receiving a bioprosthetic valve and compared their in-hospital outcomes. Bioprosthetic valves comprised 53.3% of 767,375 implanted valves, an increase in use from 37.7% in the period 1998 to 2001 to 63.6% in the period 2007 to 2011. The median age was 74 years for patients receiving bioprosthetic valves, and 67 years for those receiving mechanical valves. Use of bioprosthetic valves increased across all age groups, most markedly in patients age 55 to 64 years. Compared with patients receiving mechanical valves, these patients had a higher incidence of renal disease (8.0% vs 4.2%), coronary artery disease (58.5% vs 50.5%), concomitant coronary artery bypass grafting (46.7% vs 41.9%), and having surgery in a high-volume (>250 cases per year) center (31.3% vs 18.5%). Patients receiving bioprosthetic valves had a higher occurrence of in-hospital complications (55.9% vs 48.6%), but lower in-hospital mortality (4.4% vs 4.9%) than patients receiving mechanical valves. This difference was confirmed in propensity-matched analyses (complications: 52.7% vs 51.5%; mortality: 4.3% vs 5.2%). Use of bioprosthetic valves in AVR increased dramatically from 1998 to 2011, particularly in patients age 55 to 64 years. Prosthesis selection varied significantly by facility, with low-volume facilities favoring mechanical valves. Aortic valve replacement with a bioprosthetic valve, compared with a mechanical valve, was associated with lower in-hospital mortality.


A controlled study of psychological and social change after surgical gender reassignment in selected male transsexuals.
Of two groups of 20 patients accepted for gender reassignment surgery, one was offered early operation and therefore had had surgery by follow-up two years later, while the second was still awaiting operation at two-year follow-up. Although the groups were similar initially, significant differences between them emerged at follow-up in terms of neuroticism and social and sexual activity, with benefits being enjoyed by the operated group.


Single-Bond Association Kinetics Determined by Tethered Particle Motion: Concept and Simulations.
Tethered particle motion (TPM), the motion of a micro- or nanoparticle tethered to a substrate by a macromolecule, is a system that has proven to be extremely useful for its ability to reveal physical features of the tether, because the thermal motion of the bound particle reports sensitively on parameters like the length, the rigidity, or the folding state of its tether. In this article, we survey the applicability of TPM to probe the kinetics of single secondary bonds, bonds that form and break between the tethered particle and a substrate due, for instance, to receptor/ligand pairs on particle and substrate. Much like the tether itself affects the motion pattern, so do the presence and absence of such secondary connections. Keeping the tether properties constant, we demonstrate how raw positional TPM data may be parsed to generate detailed insights into the association and dissociation kinetics of single secondary bonds. We do this using coarse-grained molecular dynamics simulations specifically developed to treat the motion of particles close to interfaces.


Interaction of c-Abl and p73alpha and their collaboration to induce apoptosis.
c-Abl, a non-receptor tyrosine kinase, is activated by agents that damage DNA. This activation results in either arrest of the cell cycle in phase G1 or apoptotic cell death, both of which are dependent on the kinase activity of c-Abl. p73, a member of the p53 family of tumour-suppressor proteins, can also induce apoptosis. Here we show that the apoptotic activity of p73alpha requires the presence of functional, kinase-competent c-Abl. Furthermore, p73 and c-Abl can associate with each other, andthis binding is mediated by a PxxP motif in p73 and the SH3 domain of c-Abl. We find that p73 is a substrate of the c-Abl kinase and that the ability of c-Abl to phosphorylate p73 is markedly increased by gamma-irradiation. Moreover, p73 is phosphorylated in vivo in response to ionizing radiation. These findings define a pro-apoptotic signalling pathway involving p73 and c-Abl.


Reducing Urban Violence: A Contrast of Public Health and Criminal Justice Approaches.
Cities are investing millions in Cure Violence, a public health approach to reduce urban violence by targeting at-risk youth and redirecting conflict to nonviolent responses. The impact of such a program compared with criminal justice responses is unknown because experiments directly comparing criminal justice and public health approaches to violence prevention are infeasible with observational data. We simulated experiments to test the influence of two interventions on violence: (1) Cure Violence and (2) directed police patrol in violence hot spots. We used an agent-based model to simulate a 5% sample of the New York City (NYC) adult population, with agents placed on a grid representing the land area of NYC, with neighborhood size and population density proportional to land area and population density in each community district. Agent behaviors were governed by parameters drawn from city data sources and published estimates. Under no intervention, 3.87% (95% CI, 3.84, 3.90) of agents were victimized per year. Implementing the violence interrupter intervention for 10 years decreased victimization by 13% (to 3.35% [3.32, 3.39]). Implementing hot-spots policing and doubling the police force for 10 years reduced annual victimization by about 11% (to 3.46% [3.42, 3.49]). Increasing the police force by 40% combined with implementing the violence interrupter intervention for 10 years decreased violence by 19% (to 3.13% [3.09, 3.16]). Combined investment in a public health, community-based approach to violence prevention and a criminal justice approach focused on deterrence can achieve more to reduce population-level rates of urban violence than either can in isolation. See video abstract at, http://links.lww.com/EDE/B298.


Type 2 myocardial infarction: incidence, presentation, treatment and outcome in routine clinical practice.
The clinical definition and optimal treatment for myocardial infarction (MI) type 2 (T2MI) are not well established. We assessed differences in presentation, treatment and outcomes of patients with MI type 1 (T1MI) and T2MI. The data of MI patients enrolled in the AMIS Plus cohort with T2MI were compared with T1MI using propensity score matching. A total of 13 829 patients had T1MI and 1091 (7.3%) T2MI. Patients with T2MI were older, often female, with more risk factors and comorbidities, and less ST segment elevation. After matching for these differences (1091 per group), T2MI patients less often presented with typical chest pain but more frequently with atrial fibrillation (15.6 vs. 4.9%; P < 0.001) and anemia (33.5 vs. 23.3%; P < 0.001) than patients with T1MI. They less frequently received percutaneous coronary interventions (51.1 vs. 76.4%; P < 0.001) and antiplatelet treatment. No differences were found for in-hospital (5.8 vs. 5.6%; OR 1.04; 95% confidence interval 0.72-1.49) and 1-year mortality (11.2 vs. 7.2%; P = 0.38) between matched T2MI and T1MI patients. Patients who suffered a T2MI had less typical symptoms, were less aggressively treated with anticoagulants, platelet inhibitors or percutaneous coronary intervention, but had similar complications and mortality to those with T1MI. Patients with T2MI are a heterogeneous group that requires further investigation to better define optimal therapeutic approaches.


Competing sexual-asexual generic names of Pezizomycetes and recommendations for use.
Following the change that eliminated dual naming of sexual and asexual morphs of fungi, generic names of Pezizomycetes have been evaluated to determine which of the competing names should be recommended for use. Evaluation is based on congruence of type species to determine if the names are congeneric and which name is most commonly cited as well as priority. In the Pezizomycetes six pairs of generic names were determined to compete. In all cases the older name, representing the sexual morph, is recommended for use, specifically Caloscypha rather than Geniculodendron, Desmazierella rather than Verticicladium, Miladina rather than Actinosporella, Morchella rather than Costantinella, Sarcoscypha rather than Molliardiomyces, and Trichophaea rather than Dichobotrys.


On the mechanism of rapid metal exchange between thiolate-protected gold and gold/silver clusters: a time-resolved in situ XAFS study.
The fast metal exchange reaction between Au38 and AgxAu38-x nanoclusters in solution at -20 °C has been studied by in situ X-ray absorption spectroscopy (time resolved quick XAFS) in transmission mode. A cell was designed for this purpose consisting of a cooling system, remote injection and mixing devices. The capability of the set-up is demonstrated for second and minute time scale measurements of the metal exchange reaction upon mixing Au38/toluene and AgxAu38-x/toluene solutions at both Ag K-edge and Au L3-edge. It has been proposed that the exchange of gold and silver atoms between the clusters occurs via the SR(-M-SR)n (n = 1, 2; M = Au, Ag) staple units in the surface of the reacting clusters during their collision. However, at no point during the reaction (before, during, after) evidence is found for cationic silver atoms within the staples. This means that either the exchange occurs directly between the cores of the involved clusters or the residence time of the silver atoms in the staples is very short in a mechanism involving the metal exchange within the staples.


Combination therapy of rabies-infected mice with inhibitors of pro-inflammatory host response, antiviral compounds and human rabies immunoglobulin.
Recent studies demonstrated that inhibitors of pro-inflammatory molecular cascades triggered by rabies infection in the central nervous system (CNS) can enhance survival in mouse model and that certain antiviral compounds interfere with rabies virus replication in vitro. In this study different combinations of therapeutics were tested to evaluate their effect on survival in rabies-infected mice, as well as on viral load in the CNS. C57Bl/6 mice were infected with Silver-haired bat rabies virus (SHBRV)-18 at virus dose approaching LD50 and LD100. In one experimental group daily treatments were initiated 4 h before-, in other groups 48 or 96 h after challenge. In the first experiment therapeutic combination contained inhibitors of tumour necrosis factor-α (infliximab), caspase-1 (Ac-YVAD-cmk), and a multikinase inhibitor (sorafenib). In the treated groups there was a notable but not significant increase of survival compared to the virus infected, non-treated mice. The addition of human rabies immunoglobulins (HRIG) to the combination in the second experiment almost completely prevented mortality in the pre-exposure treatment group along with a significant reduction of viral titres in the CNS. Post-exposure treatments also greatly improved survival rates. As part of the combination with immunomodulatory compounds, HRIG had a higher impact on survival than alone. In the third experiment the combination was further supplemented with type-I interferons, ribavirin and favipiravir (T-705). As a blood-brain barrier opener, mannitol was also administered. This treatment was unable to prevent lethal consequences of SHBRV-18 infection; furthermore, it caused toxicity in treated mice, presumably due to interaction among the components. In all experiments, viral loads in the CNS were similar in mice that succumbed to rabies regardless of treatment. According to the findings, inhibitors of detrimental host response to rabies combined with antibodies can be considered among the possible therapeutic and post-exposure options in human rabies cases.


Continuous Peripheral Nerve Blocks: An Update of the Published Evidence and Comparison With Novel, Alternative Analgesic Modalities.
A continuous peripheral nerve block (CPNB) consists of a percutaneously inserted catheter with its tip adjacent to a target nerve/plexus through which local anesthetic may be administered, providing a prolonged block that may be titrated to the desired effect. In the decades after its first report in 1946, a plethora of data relating to CPNB was published, much of which was examined in a 2011 Anesthesia & Analgesia article. The current update is an evidence-based review of the CPNB literature published in the interim. Novel insertion sites include the adductor canal, interpectoral, quadratus lumborum, lesser palatine, ulnar, superficial, and deep peroneal nerves. Noteworthy new indications include providing analgesia after traumatic rib/femur fracture, manipulation for adhesive capsulitis, and treating abdominal wall pain during pregnancy. The preponderance of recently published evidence suggests benefits nearly exclusively in favor of catheter insertion using ultrasound guidance compared with electrical stimulation, although little new data are available to help guide practitioners regarding the specifics of ultrasound-guided catheter insertion (eg, optimal needle-nerve orientation). After some previous suggestions that automated, repeated bolus doses could provide benefits over a basal infusion, there is a dearth of supporting data published in the past few years. An increasing number of disposable infusion pumps does now allow a similar ability to adjust basal rates, bolus volume, and lockout times compared with their electronic, programmable counterparts, and a promising area of research is communicating with and controlling pumps remotely via the Internet. Large, prospective studies now document the relatively few major complications during ambulatory CPNB, although randomized, controlled studies demonstrating an actual shortening of hospitalization duration are few. Recent evidence suggests that, compared with femoral infusion, adductor canal catheters both induce less quadriceps femoris weakness and improve mobilization/ambulation, although the relative analgesia afforded by each remains in dispute. Newly published data demonstrate that the incidence and/or severity of chronic, persistent postsurgical pain may, at times, be decreased with a short-term postoperative CPNB. Few new CPNB-related complications have been identified, although large, prospective trials provide additional data regarding the incidence of adverse events. Lastly, a number of novel, alternative analgesic modalities are under development/investigation. Four such techniques are described and contrasted with CPNB, including single-injection peripheral nerve blocks with newer adjuvants, liposome bupivacaine used in wound infiltration and peripheral nerve blocks, cryoanalgesia with cryoneurolysis, and percutaneous peripheral nerve stimulation.


A rational review on the effects of sweeteners and sweetness enhancers on appetite, food reward and metabolic/adiposity outcomes in adults.
Numerous strategies have been investigated to overcome the excessive weight gain that accompanies a chronic positive energy balance. Most approaches focus on a reduction of energy intake and the improvement of lifestyle habits. The use of high intensity artificial sweeteners, also known as non-caloric sweeteners (NCS), as sugar substitutes in foods and beverages, is rapidly developing. NCS are commonly defined as molecules with a sweetness profile of 30 times higher or more that of sucrose, scarcely contributing to the individual's net energy intake as they are hardly metabolized. The purpose of this review is first, to assess the impact of NCS on eating behaviour, including subjective appetite, food intake, food reward and sensory stimulation; and secondly, to assess the metabolic impact of NCS on body weight regulation, glucose homeostasis and gut health. The evidence reviewed suggests that while some sweeteners have the potential to increase subjective appetite, these effects do not translate in changes in food intake. This is supported by a large body of empirical evidence advocating that the use of NCS facilitates weight management when used alongside other weight management strategies. On the other hand, although NCS are very unlikely to impair insulin metabolism and glycaemic control, some studies suggest that NCS could have putatively undesirable effects, through various indirect mechanisms, on body weight, glycemia, adipogenesis and the gut microbiota; however there is insufficient evidence to determine the degree of such effects. Overall, the available data suggests that NCS can be used to facilitate a reduction in dietary energy content without significant negative effects on food intake behaviour or body metabolism, which would support their potential role in the prevention of obesity as a complementary strategy to other weight management approaches. More research is needed to determine the impact of NCS on metabolic health, in particular gut microbiota.


IOP-induced lamina cribrosa displacement and scleral canal expansion: an analysis of factor interactions using parameterized eye-specific models.
To study the anterior-posterior lamina cribrosa deformation (LCD) and the scleral canal expansion (SCE) produced by an increase in IOP and identify the main factors and interactions that determine these responses in the monkey. Eye-specific baseline models of the LC and sclera of both eyes of three normal monkeys were constructed. Morphing techniques were used to generate 888 models with controlled variations in LC thickness, position and modulus (stiffness), scleral thickness and modulus, and scleral canal size and eccentricity. Finite element modeling was used to simulate an increase in IOP from 10 to 15 mm Hg. A two-level, full-factorial experimental design was used to select factor combinations and to determine the sensitivity of LCD and SCE to the eight factors, independently and in interaction. LCD was between 53.6 μm (posteriorly) and -12.9 μm (anteriorly), whereas SCE was between 0.5 and 15.2 μm (all expansions). LCD was most sensitive to laminar modulus and position (24% and 21% of the variance in LCD, respectively), whereas SCE was most sensitive to scleral modulus and thickness (46% and 36% of the variance in SCE, respectively). There were also strong interactions between factors (35% and 7% of the variance in LCD and SCE, respectively). IOP-related LCD and SCE result from a complex combination of factors, including geometry and material properties of the LC and sclera. This work lays the foundation for interpreting the range of individual sensitivities to IOP and illustrates that predicting individual ONH response to IOP will require the measurement of multiple factors.