Toward improving Caenorhabditis elegans phenome mapping with an ORFeome-based RNAi library.
The recently completed Caenorhabditis elegans genome sequence allows application of high-throughput (HT) approaches for phenotypic analyses using RNA interference (RNAi). As large phenotypic data sets become available, "phenoclustering" strategies can be used to begin understanding the complex molecular networks involved in development and other biological processes. The current HT-RNAi resources represent a great asset for phenotypic profiling but are limited by lack of flexibility. For instance, existing resources do not take advantage of the latest improvements in RNAi technology, such as inducible hairpin RNAi. Here we show that a C. elegans ORFeome resource, generated with the Gateway cloning system, can be used as a starting point to generate alternative HT-RNAi resources with enhanced flexibility. The versatility inherent to the Gateway system suggests that additional HT-RNAi libraries can now be readily generated to perform gene knockdowns under various conditions, increasing the possibilities for phenome mapping in C. elegans.


Genetic diversity in the 3' terminal 4.7-kb region of grapevine leafroll-associated virus 3.
Grapevine leafroll-associated virus 3 (GLRaV-3; Ampelovirus, Closteroviridae), associated with grapevine leafroll disease, is an important pathogen found across all major grape-growing regions of the world. The genetic diversity of GLRaV-3 in Napa Valley, CA, was studied by sequencing 4.7 kb in the 3' terminal region of 50 isolates obtained from Vitis vinifera 'Merlot'. GLRaV-3 isolates were subdivided into four distinct phylogenetic clades. No evidence of positive selection was observed in the data set, although neutral selection (ratio of nonsynonymous to synonymous substitution rates = 1.1) was observed in one open reading frame (ORF 11, p4). Additionally, the four clades had variable degrees of overall nucleotide diversity. Moreover, no geographical structure among isolates was observed, and isolates belonging to different phylogenetic clades were found in distinct vineyards, with one exception. Considered with the evidence of purifying selection (i.e., against deleterious mutations), these data indicate that the population of GLRaV-3 in Napa Valley is not expanding and its effective population size is not increasing. Furthermore, research on the biological characterization of GLRaV-3 strains might provide valuable insights on the biology of this species that may have epidemiological relevance.


Development, evolution and pathology of neocortical subplate neurons.
Subplate neurons have an essential role in cortical circuit formation. They are among the earliest formed neurons of the cerebral cortex, are located at the junction of white and grey matter, and are necessary for correct thalamocortical axon ingrowth. Recent transcriptomic studies have provided opportunities for monitoring and modulating selected subpopulations of these cells. Analyses of mouse lines expressing reporter genes have demonstrated novel, extracortical subplate neurogenesis and have shown how subplate cells are integrated under the influence of sensory activity into cortical and extracortical circuits. Recent studies have revealed that the subplate is involved in neurosecretion and modification of the extracellular milieu.


Surgical Treatment of Adolescent Acetabular Dysplasia With a Periacetabular Osteotomy: Does Obesity Increase the Risk of Complications?
The Bernese periacetabular osteotomy (PAO) is frequently used to treat symptomatic acetabular dysplasia in the adolescent age group. Despite encouraging results, factors predictive of the development of postoperative complications remain poorly understood. The purpose of this study was to investigate whether obesity is a risk factor for complications following PAO in adolescents. A retrospective cohort study design was used to collect data from 3 different institutions. Children and adolescents (below 19 y of age) who underwent PAO and were followed for minimum of 12 months were included. Obesity was defined as a body mass index ≥95 percentile. The modified Clavien-Dindo classification was used to grade complications. A logistic regression analysis was used to identify factors related to the development of a complication that required treatment outside of routine postoperative care (complication grades II to V). Changes in radiographic parameters including Tönnis acetabular roof angle, anterior center-edge angle, and lateral center-edge angle among obese versus nonobese subjects were also evaluated. The mean age at surgery among the 84 adolescents included in the study was 16.5 years (range, 12 to 19 y). A total of 11% of the population was considered obese. Obesity (P=0.0047) was the only variable significantly associated with the development of a complication. After controlling for study site, the odds of an obese subject developing a complication were 10 [95% confidence interval (CI), 1.89-59.8] times the odds of a nonobese subject developing a complication. There was no difference in the magnitude of change in anterior center-edge angle (P=0.1251), lateral center-edge angle (P=0.9774), or Tönnis (P=0.5770) angular correction that was achieved among the obese versus nonobese subjects following surgery. The Bernese PAO allows for adequate radiographic correction of acetabular dysplasia among obese and nonobese adolescents. However, the hip preservation surgeon should be aware of the higher risk of complications among obese adolescents undergoing PAO for the treatment of symptomatic acetabular dysplasia. Level III-retrospective study.


Postoperative pain management in patients with chronic kidney disease.
Chronic kidney disease (CKD) is a health care problem with increasing prevalence worldwide. Pain management represents one of the challenges in providing perioperative care for this group of patients. Physicians from different specialties may be involved in pain management of CKD patients, especially in advanced stages. It is important to understand the clinical staging of kidney function in CKD patients as the pharmacotherapeutic pain management strategies change as kidney function becomes progressively impaired. Special emphasis should be placed on dose adjustment of certain analgesics as well as prevention of further deterioration of renal function that could be induced by certain classes of analgesics. Chronic pain is a common finding in CKD patients which may be caused by the primary disease that led to kidney damage or can be a direct result of CKD and hemodialysis. The presence of chronic pain in some of the CKD patients makes postoperative pain management in these patients more challenging. This review focuses on the plans and challenges of postoperative pain management for patient at different stages of CKD undergoing surgical intervention to provide optimum pain control for this patient population. Further clinical studies are required to address the optimal medication regimen for postoperative pain management in the different stages of CKD.


Myeloid cell responses after spinal cord injury.
The past decade has revealed much about the complexity of the local inflammatory response after spinal cord injury (SCI). A major challenge is to distinguish between microglia and monocyte-derived macrophages (MDMs) to determine their phenotype and function. Transcriptome studies have revealed microglia-selective genes but are still limited in scope because many markers are downregulated after injury. Additionally, new genetic reporter mice are available to study microglia and MDMs. There is more evidence now for the plasticity and heterogeneity of microglia and MDMs. We also discuss the role of neutrophils that are the first peripheral cells to enter the injured CNS.


Melatonin is a safe and effective treatment for chronic pulmonary and extrapulmonary sarcoidosis.
Chronic sarcoidosis (CS) is often unresponsive to usual treatments. Melatonin, an immunoregulatory drug, was employed in CS patients in whom usual treatments were ineffective or induced severe side effects. Melatonin was given for 2 yr (20 mg/day in the first year, 10 mg/day in the second year) to 18 CS patients. Pulmonary function tests, chest X rays, pulmonary computed tomography, Ga(67) scintigraphy and angiotensin-converting enzyme (ACE) were assayed at baseline and in the follow-up. Normalization of ACE, improvement of pulmonary parameters and resolution of skin involvement were found in the patients given melatonin. After 24 months of melatonin therapy, hylar adenopathy completely resolved in eight patients and parenchymal lesions were markedly improved in all patients; in the five patients with reduced diffusion capacity of the lung for carbon monoxide, the values normalized after 6 months of therapy and remained stable until month 24. After 24 months, Ga(67) pulmonary and extra-pulmonary uptake was totally normalized in seven patients and, at month 12 months, ACE was normalized in six patients in which the values were high at the baseline. Skin lesions, present in three patients, completely disappeared at month 24 months. No side effects were experienced and no disease relapse was observed during melatonin treatment. Melatonin may be an effective and safe therapy for CS when other treatments fail or cause side effects.


Using Occupational Justice as a Linchpin of International Educational Collaborations.
When designing international educational collaborations, occupational science and occupational therapy educators must consider how occupational justice can be a linchpin for students' learning. This article describes an international collaboration involving 52 undergraduate occupational science students in the United States and 41 undergraduate occupational therapy students in South Africa. The students participated in six synchronous video conferences in 2016, during which they gave group presentations about four occupational science constructs and engaged in general question-and-answer sessions. Forty percent of the students provided feedback about the interactions using a six-item open-ended electronic questionnaire, which we analyzed using directed content analysis. Our findings suggest that the collaboration helped the students develop more nuanced understandings of disciplinary constructs, international peers, and themselves, providing a platform from which to engage with the big idea of occupational justice. Refinements to this collaboration are aimed at drawing on students' increased critical consciousness to further develop their knowledge about occupational justice.


Mitochondria-Targeted Fluorescence/Photoacoustic Dual-Modality Imaging Probe Tailored for Visual Precise Diagnosis of Drug-Induced Liver Injury.
The multispectral optoacoustic tomography (MSOT) technique can be used to perform high-resolution molecular imaging under deep tissues, which gives the technology significant prospective for clinical application. Here, we developed a superoxide anion (O2•-)-activated MSOT and fluorescence dual-modality imaging probe (APSA) for early diagnosis of drug-induced liver injury (DILI). APSA can respond quickly to O2•-, resulting in an absorption peak blueshift from 845 to 690 nm, which also leads to the photoacoustic (PA) signal at 690 nm and the fluorescence signal at 748 nm increases linearly with increasing O2•- concentration, which can be utilized to assess the extent of liver damage. The developed MSOT imaging method can eliminate background interference from hematopoietic tissue by collecting the PA signals excited at 680, 690, 740, 760, 800, 845, and 900 nm wavelengths to achieve noninvasive in situ visual diagnosis of DILI. The developed fluorescence imaging method can be used for the imaging of endogenous O2•- in living cells and anatomic diagnosis of liver injury. The developed probe has broad application prospects in the early diagnosis of DILI.


Have we left some behind? Trends in socio-economic inequalities in breastfeeding initiation: a population-based epidemiological surveillance study.
Breastfeeding is associated with improved health. Surveillance data show that breastfeeding initiation rates have increased; however, limited work has examined trends in socio-economic inequalities in initiation. The study's research question was whether socio-economic inequalities in breastfeeding initiation have changed over the past 20 years. This population-based study is a project within PATHS Equity for Children. Analyses used hospital discharge data for Manitoba mother-infant dyads with live births, 1988-2011 (n=316,027). Income quintiles were created, each with ~20% of dyads. Three-year, overall and by-quintile breastfeeding initiation rates were estimated for Manitoba and two hospitals. Age-adjusted rates were estimated for Manitoba. Rates were modelled using generalized linear models. Three measures, rate ratios (RRs), rate differences (RDs) and concentration indices, assessed inequality at each time point. We also compared concentration indices with Gini coefficients to assess breastfeeding inequality vis-à-vis income inequality. Trend analyses tested for changes over time. Manitoba and Hospital A initiation rates increased; Hospital B rates did not change. Significant inequalities existed in nearly every period, across all three measures: RRs, RDs and concentration indices. RRs and concentration indices suggested little to no change in inequality from 1988 to 2011. RDs for Manitoba (comparing initiation in the highest to lowest income quintiles) did not change significantly over time. RDs decreased for Hospital A, suggesting decreasing socio-economic inequalities in breastfeeding; RDs increased for Hospital B. Income inequality increased significantly in Manitoba during the study period. Overall breastfeeding initiation rates can improve while inequality persists or worsens.


The epidemiology and management of self-harm amongst adults in England.
Previous research into the epidemiology and management of self-harm has been largely based in centres with a special interest in this behaviour or focused on hospital admissions only. There are no national data on the characteristics and management of people presenting to hospital following self-harm. Data were collected from 8-week service audits carried out in a stratified random sample of 31 general hospitals in England. 4033 episodes of self-harm resulting in presentation to Accident and Emergency Departments were identified. Overdose alone accounted for 79 per cent of episodes, 80 per cent of presentations were outside normal office hours (9 am - 5 pm, Monday to Friday) and the peak period of attendance was from 8 pm to 2 am. In only 56 per cent of episodes was a specialist psychosocial assessment conducted prior to discharge and less than half (46 per cent) led to admission to a hospital bed. Psychiatric admission occurred in 10 per cent. Episodes involving older subjects (>45 years) and those using methods other than laceration or overdose were the most likely to lead to assessment and admission. Non-fatal self-harm is one of the strongest predictors of suicide, yet nearly half of all hospital attendances in England following self-harm do not lead to a specialist assessment. Patterns of service provision should take account of the observation that most self-harm attendances occur outside normal working hours and those at greatest risk of repetition are the least likely to receive assessments.


Economic aspects of the association between diabetes and depression: a systematic review.
The importance of co-morbid diabetes and depression is gaining increased attention. Quantifying the socio-economic and clinical impacts of co-morbidity is important given the high costs of these diseases. This review synthesised evidence on the economic impact of co-morbidity and potential cost-effectiveness of prevention and treatment strategies. 11 databases from 1980 until June 2011 searched. In addition, websites and reference lists of studies scrutinised and hand search of selected journals performed. Reviewers independently assessed abstracts, with economic data extracted from relevant studies. 62 studies were identified. 47 examined the impact of co-morbidity on health care and other resource utilisation. 11 of these included productivity losses, although none quantified the impact of mortality. Most demonstrated an association between co-morbidity and increasing health service utilisation and cost. Adverse impacts on workforce participation and absenteeism were found. 15 economic evaluations were also identified. Most focused on primary care led collaborative and/or stepped care, suggesting actions may be cost effective. We did not identify any studies looking at actions to reduce the risk of diabetes in people with depression. Most studies are set in the US, which may be due to focus on English language databases. Few studies looked at impacts beyond one year or outside the health care system. There is an evidence base demonstrating the adverse economic impacts of co-morbid diabetes and depression and potential for cost effective intervention. This evidence base might be strengthened through modelling studies on cost effectiveness using different time periods, contexts and settings.


Cell death induced by 2-phenylethynesulfonamide uncovers a pro-survival function of BAX.
PES (2-phenylethynesulfonamide) was initially identified as an inhibitor of p53 translocation to mitochondria and named Pifithrin-µ. Further studies showed that PES selectively killed tumour cells and was thus a promising anticancer agent. PES-induced cell death was characterised by a non-apoptotic, autophagosome-rich phenotype. We observed this phenotype via electron microscopy in wild type (wt) and double Bax-/- Bak-/- (DKO) mouse embryonic fibroblasts (MEFs) treated with PES. We excluded the involvement of effector caspases, BAX and BAK, in causing PES-triggered cell death. Therefore, apoptosis was ruled out as the lethal mode of action of PES. Surprisingly, MEFs containing BAX were significantly protected from PES treatments. BAX overexpression in Bax-/- MEFs confirmed this pro-survival effect. Moreover, this protective effect required the ability of BAX to localise to mitochondrial membranes. Conversely, mitochondrial fusion induced by treatment with Mdivi-1 conferred increased resistance to MEFs subjected to PES treatment. The involvement of BAX in the regulation of mitochondrial dynamics has been reported. We propose the promotion of mitochondrial fusion by BAX to be the pro-survival function attributed to BAX.


Transcatheter embolization of acute non-variceal gastrointestinal hemorrhage.
To determine the efficacy and safety of transcatheter embolization of nonvariceal gastrointestinal hemorrhage. Descriptive analytical study. Radiology Department, The Aga Khan University Hospital, Karachi, Pakistan, from October 1999 to August 2004. The study included 27 patients who underwent angiography for suspected gastrointestinal hemorrhage. The presumptive diagnosis was based on the findings of endoscopy in 08 patients, scintigraphy in 05 patients and on clinical findings only in 14 patients. Nine patients had gastroduodenal hemorrhage, 04 patients had hemobilia and 14 patients had lower gastrointestinal bleeding. Five patients had comorbidities. One patient had uremia, 2 had hepatitis C, 1 had cirrhosis and 1 had coagulopathy. Technical success, clinical success, complications and patient survival were assessed. Nine patients had upper gastrointestinal hemorrhage, 4 patients had hemobilia and 14 patients had lower gastrointestinal bleeding. Etiology of bleeding was known in 15 patients and unknown in 12 patients. Clinical success was achieved in 23 (85.18%) of 27 patients. Two patients had early rebleeding. One of these was managed surgically and recovered. The other had severe coagulopathy and was unfit for surgery. Two patients had bowel infarction, one of these was managed surgically and recovered and the other died of complication of procedure. One patient had small splenic infarcts and was managed conservatively. Overall 85.18% success was achieved for the embolization procedure. Two of 27 patients died. One patient died because of recurrence of bleeding and other died because of infarction of right hemi-colon which occurred as complication of embolization. Transcatheter embolization is effective and safe in patients with nonvariceal gastrointestinal hemorrhage.


White Matter Microstructure Reflects Individual Differences in Music Reward Sensitivity.
People show considerable variability in the degree of pleasure they experience from music. These individual differences in music reward sensitivity are driven by variability in functional connectivity between the nucleus accumbens (NAcc), a key structure of the reward system, and the right superior temporal gyrus (STG). However, it is unknown whether a neuroanatomical basis exists for this variability. We used diffusion tensor imaging and probabilistic tractography to study the relationship between music reward sensitivity and white matter microstructure connecting these two regions via the orbitofrontal cortex (OFC) in 38 healthy human participants (24 females and 14 males). We found that right axial diffusivity (AD) in the STG-OFC connectivity inversely correlated with music reward sensitivity. Additionally, right mean diffusivity and left AD in the NAcc-OFC tract also showed an inverse correlation. Further, AD in this tract also correlated with previously acquired BOLD activity during music listening, but not for a control monetary reward task in the NAcc. Finally, we used mediation analysis to show that AD in the NAcc-OFC tract explains the influence of NAcc activation during a music task on music reward sensitivity. Overall, our results provide further support for the idea that the exchange of information among perceptual, integrative, and reward systems is important for musical pleasure, and that individual differences in the structure of the relevant anatomical connectivity influences the degree to which people are able to derive such pleasure.SIGNIFICANCE STATEMENT Music is one of the most important sources of pleasure for many people, but at the same time there are important individual differences in the sensitivity to musical reward. Previous studies have revealed the critical involvement of the functional connectivity between perceptual and subcortical brain areas in the enjoyment of music. However, it is unknown whether individual differences in music sensitivity might arise from variability in the structural connectivity among these areas. Here we show that structural connectivity between supratemporal and orbitofrontal cortices, and between orbitofrontal and nucleus accumbens, predict individual differences in sensibility to music reward. These results provide evidence for the critical involvement of the interaction between the subcortical reward system and higher-order cortical areas in music-induced pleasure.


Organic anion and cation SLC22 "drug" transporter (Oat1, Oat3, and Oct1) regulation during development and maturation of the kidney proximal tubule.
Proper physiological function in the pre- and post-natal proximal tubule of the kidney depends upon the acquisition of selective permeability, apical-basolateral epithelial polarity and the expression of key transporters, including those involved in metabolite, toxin and drug handling. Particularly important are the SLC22 family of transporters, including the organic anion transporters Oat1 (originally identified as NKT) and Oat3 as well as the organic cation transporter Oct1. In ex vivo cultures of metanephric mesenchyme (MM; the embryonic progenitor tissue of the nephron) Oat function was evident before completion of nephron segmentation and corresponded with the maturation of tight junctions as measured biochemically by detergent extractability of the tight junction protein, ZO-1. Examination of available time series microarray data sets in the context of development and differentiation of the proximal tubule (derived from both in vivo and in vitro/ex vivo developing nephrons) allowed for correlation of gene expression data to biochemically and functionally defined states of development. This bioinformatic analysis yielded a network of genes with connectivity biased toward Hnf4α (but including Hnf1α, hyaluronic acid-CD44, and notch pathways). Intriguingly, the Oat1 and Oat3 genes were found to have strong temporal co-expression with Hnf4α in the cultured MM supporting the notion of some connection between the transporters and this transcription factor. Taken together with the ChIP-qPCR finding that Hnf4α occupies Oat1, Oat3, and Oct1 proximal promoters in the in vivo differentiating rat kidney, the data suggest a network of genes with Hnf4α at its center plays a role in regulating the terminal differentiation and capacity for drug and toxin handling by the nascent proximal tubule of the kidney.


13-year long-term associations between changes in traditional cardiovascular risk factors and changes in fibrinogen levels: the Coronary Artery Risk Development in Young Adults (CARDIA) study.
Cross-sectional and prospective studies have linked cardiovascular events and traditional risk factors (TRFs) with higher plasma fibrinogen levels. In a young cohort, we sought to determine longitudinal associations between changes in/development of TRFs and fibrinogen levels over 13 years. We included 2525 adults from the CARDIA study, aged 25-37 with fibrinogen and TRFs measured at year 7 (study baseline; 1992-1993); and year 20 (follow-up). Multiple linear regressions were used to compare mean changes in fibrinogen to TRFs. Mean fibrinogen increased by 71 mg/dL vs. 70 mg/dL (p = NS) in black vs. white men, and 78 mg/dL vs. 68 mg/dL (p < 0.05) in black vs. white women, respectively over 13 years. After multivariable adjustments, fibrinogen generally rose with increasing BMI (p < 0.001; all sex/race groups), LDL cholesterol, log triglycerides and diastolic blood pressure; and fell with increasing HDL cholesterol and physical activity. 13-year increase in fibrinogen for persons who quit smoking or became non-obese were comparable (p = NS) to that of never-smokers and never-obese persons. Among young black and white men and women with few baseline cardiovascular risk factors, fibrinogen tracked longitudinally with changes in TRFs over 13 years through middle age. There was a strong inverse longitudinal relationship between modifiable risk factors (weight loss/smoking cessation) and 13-year change in fibrinogen. Our study helps provide some insight into the role of fibrinogen as a disease marker in the associations between fibrinogen and CVD.


Hepatic gene transfer of the catalytic subunit of the apolipoprotein B mRNA editing enzyme results in a reduction of plasma LDL levels in normal and watanabe heritable hyperlipidemic rabbits.
Apolipoprotein (apo) B exists in two forms, the full length protein apoB-100 and the carboxyterminal-truncated apoB-48 that is synthesized in the intestine due to editing of the apoB mRNA which generates a premature stop codon. To determine whether gene transfer of the catalytic subunit of the apoB mRNA editing enzyme APOBEC-1 (apoB mRNA editing enzyme catalytic polypeptide 1) into the liver of rabbits reconstitutes hepatic apoB mRNA editing and how this affects the plasma levels of apoB-containing lipoproteins, we constructed an APOBEC-1 recombinant adenovirus (Ad APOBEC-1). After injection of Ad APOBEC-1 into normal New Zealand White (NZW) or Watanabe heritable hyperlipidemic (WHHL) rabbits, up to 50% of the hepatic apoB mRNA was edited and freshly isolated hepatocytes secreted predominantly apoB-48-containing lipoproteins. VLDL isolated from Ad APOBEC-1-treated NZW and WHHL rabbits contained both apoB-100 and apoB-48, whereas that from control rabbits infected with a beta-galactosidase recombinant adenovirus (Ad LacZ) contained exclusively apoB-100. VLDL from WHHL rabbits treated with Ad APOBEC-1 had the same particle size, lipid composition, and content of apolipoprotein E as VLDL from Ad LacZ-infected control animals. An increase of VLDL was observed in NZW and WHHL rabbits after infection with Ad APOBEC-1 as well as Ad LacZ. After injection of Ad APOBEC-1, LDL became undetectable in the plasma of NZW rabbits and was reduced by an average of 65% in the plasma of WHHL rabbits compared to Ad LacZ-infected controls. LDL from Ad APOBEC-1-infected WHHL rabbits contained only apoB-100. VLDL isolated from Ad APOBEC-1-infected WHHL rabbits were rapidly cleared from the circulation after injection into NZW rabbits. These results provide further evidence that the switch in the hepatic synthesis from exclusively apoB-100 to partly apoB-48 can result in a reduction of LDL formation that requires the full-length apoB-100.


[Breast-feeding, bottle-feeding, sucking habits and malocclusion in Brazilian preschool children].
This study was aimed at verifying the prevalence of nutritive (breast-feeding and bottle-feeding) and non-nutritive sucking habits and the presence of malocclusion in Brazilian preschool children. The study was a cross-sectional oral health survey of 342 children (196 boys and 146 girls) between the ages of 3 and 5 in Campina Grande, Brazil. The data was collected by interviews with the children's mothers or minders and by clinical examinations carried out by a calibrated examiner (kappa = 0,86). Descriptive statistics using the EPI-INFO Program (version 3.3) and Chi-square test at 0.05 probability level were produced. Sucking habit prevalence was very high in all groups, ranging from 70 % to 77,4 %. Malocclusion was present in 87 %, dummy use in 84,8 % and finger-sucking in 7,2 %. About 84,2 % of the children had a history of bottle-feeding and 79,9 % showed some evidence of malocclusion at the time of dental examination. There were significant differences for the following variables: sucking habits and malocclusion; breast-feeding time and sucking habits; breast-feeding time and malocclusion; type of feeding and sucking habits; and type of feeding and malocclusion. Dummy-sucking incidence was higher than that of finger-sucking in Brazilian children. Sucking habit incidence was higher in bottle-fed children than in breast-fed children. The relationship between incidence of habits and malocclusion was statistically significant.


Fluorescent chemosensors of carbohydrate triols exhibiting TICT emissions.
4-4'-Disubstituted biphenyl boronic acids (BBAs) are push-pull fluorophores with "turn-on" fluorescence properties. Upon carbohydrate triol binding, BBA boronate esters can participate in photon-induced electron transfer, giving a twisted intramolecular charge transfer (TICT) complex. The resulting TICT emissions distinguish between carbohydrates that bind to boron as a diol versus triol unit, thereby revealing stereochemical information about the carbohydrate.


Inferences of evolutionary history of a widely distributed mangrove species, Bruguiera gymnorrhiza, in the Indo-West Pacific region.
Inference of genetic structure and demographic history is fundamental issue in evolutionary biology. We examined the levels and patterns of genetic variation of a widespread mangrove species in the Indo-West Pacific region, Bruguiera gymnorrhiza, using ten nuclear gene regions. Genetic variation of individual populations covering its distribution range was low, but as the entire species it was comparable to other plant species. Genetic differentiation among the investigated populations was high. They could be divided into two genetic clusters: the West and East clusters of the Malay Peninsula. Our results indicated that these two genetic clusters derived from their ancestral population whose effective size of which was much larger compared to the two extant clusters. The point estimate of speciation time between B. gymnorrhiza and Bruguiera sexangula was two times older than that of divergence time between the two clusters. Migration from the West cluster to the East cluster was much higher than the opposite direction but both estimated migration rates were low. The past Sundaland and/or the present Malay Peninsula are likely to prevent gene flow between the West and East clusters and function as a geographical or land barrier.


Effect of prazosin on blood pressure and plasma renin activity in man.
1. The effects of oral administration of 4.5 mg of prazosin/day on blood pressure and on plasma renin activity were assessed in patients with essential hypertension and in healthy normotensive volunteer subjects. 2. Mean blood pressure in the hypertensive group fell significantly within 2 weeks of treatment, whereas heart rate was little affected. None of the parameters measured in the normotensive subjects during treatment with prazosin revealed significant changes. 3. Sub-classification of the hypertensive patients into low-, normal- and high-renin categories revealed significant decreases of renin in all six patients with high renin- and in four out of 12 patients with normal renin- but not in the two patients with low renin-essential hypertension. 4. The results indicate the prazosin exerts its hypotensive action and suppresses plasma renin activity particularly in patients with high renin-essential hypertension. These may be considered to have increased sympathetic drive. 5. Conceivably, the blood pressure-lowering effect of prazosin is affected by peripheral vasodilatation and also by a decreased venous return to the heart.


Somatostatin Analogs Treated Small Intestinal Neuroendocrine Tumor Patients Circulating MicroRNAs.
We previously detected and investigated nine altered microRNAs in small intestinal neuroendocrine tumor (SI-NET) tissues at different stages of disease. The aims of this study are to: 1) analyze whether SI-NET tissue microRNAs can be also detected in patient serum samples, 2) investigate a potential somatostatin analogs (SSAs) role on microRNA levels regulation in SSA-treated patient samples and 3) elucidate whether the serum microRNA levels in samples collected in different hospitals are predictable and steady. Our results show that tissue microRNAs are detectable in patient serum samples, and miR-96, -182, -183, -196a and -200a levels are lower in SI-NET untreated patients than in SSA-treated patients at all different stages. Conversely, miR-31, -129-5p, -133a and -215 levels do not show any difference in untreated SI-NET patients and SSA-treated patients at all different stages. Our findings also show that miR-200a exhibits an atypical behavior with high levels in both untreated and SSA-treated patients at liver metastasis stage, and unequivocally never at the earlier stages. Serum samples collected in two hospitals keep alike microRNA level pattern, elucidating that the results are not dependent on samples handling. In conclusion, SI-NET tissue microRNAs are always detectable in untreated and SSA-treated patient serum samples, SSAs play an unknown role in eliciting SSA-treated patients' microRNA levels higher than in untreated patients, and this study enlightens that miR-200a might be involved in the liver metastasis during SI-NET progression.


Scorpion envenomation-induced acute thrombotic inferior myocardial infarction.
The occurrence of a serious cardiac emergency following scorpion envenomation has rarely been reported and, when so, mostly presented as non-ST segment elevation myocardial infarction, cardiogenic shock, or myocarditis. Possible mechanisms include imbalance in blood pressure and coronary vasospasm caused by the combination of sympathetic excitation, scorpion venom-induced release of catecholamines, and the direct effect of the toxin on the myocardium. We report a case of a 55-year-old man who presented with acute inferior wall myocardial infarction (MI) within 2 h of being stung by a scorpion. Coronary angiogram revealed total thrombotic occlusion of the left circumflex artery, which was treated successfully with glycoprotein IIb/IIIa inhibitor, thrombus aspiration, antivenom serum, and supportive therapy. Therefore, life-threatening MI can complicate the clinical course during some types of scorpion envenomation and should be managed as an acute coronary syndrome.


Focal nodular hyperplasia of the liver in longterm survivors of neuroblastoma: how much diagnostic imaging is necessary?
Focal nodular hyperplasia of the liver is a tumor-like lesion, uncommon in children, but it has recently been more frequently observed in children treated for malignant diseases, especially neuroblastoma. The aetiology is unclear, the pathogenesis remains controversial. Focal nodular hyperplasia of the liver is suspected to be a sequela of tumor therapy. Besides the clinical data we evaluated the imaging modalities needed to diagnose focal nodular hyperplasia of the liver in children with neuroblastoma who have been followed in our institution for more than 5 years. Out of 60 children six developed focal nodular hyperplasia at a median time of 10.5 years after diagnosis of neuroblastoma and 9.4 years after the end of treatment. The diagnosis of focal nodular hyperplasia was based on imaging criteria which are variable in ultrasonography and specific in MRI. Only one child underwent surgical biopsies to rule out liver metastases. Longterm survivors of neuroblastoma are at risk of developing focal nodular hyperplasia, especially if they underwent toxic chemotherapy and/or radiotherapy to the liver during initial treatment. The recommended diagnostic imaging tools are ultrasonography for detecting liver lesions and MRI for confirming and characterizing these lesions as focal nodular hyperplasia.


Kikuchi-Fujimoto disease: retrospective study of 91 cases and review of the literature.
Kikuchi-Fujimoto disease (KFD) is a rare cause of lymphadenopathy, most often cervical. It has been mainly described in Asia. There are few data available on this disease in Europe. We conducted this retrospective, observational, multicenter study to describe KFD in France and to determine the characteristics of severe forms of the disease and forms associated with systemic lupus erythematosus (SLE). We included 91 cases of KFD, diagnosed between January 1989 and January 2011 in 13 French hospital centers (median age, 30 ± 10.4 yr; 77% female). The ethnic origins of the patients were European (33%), Afro-Caribbean (32%), North African (15.4%), and Asian (13%). Eighteen patients had a history of systemic disease, including 11 with SLE. Lymph node involvement was cervical (90%), often in the context of polyadenopathy (52%), and it was associated with hepatomegaly and splenomegaly in 14.8% of cases. Deeper sites of involvement were noted in 18% of cases. Constitutional signs consisted mainly of fever (67%), asthenia (74.4%), and weight loss (51.2%). Other manifestations included skin rash (32.9%), arthromyalgia (34.1%), 2 cases of aseptic meningitis, and 3 cases of hemophagocytic lymphohistiocytosis. Biological signs included lymphocytopenia (63.8%) and increase of acute phase reactants (56.4%). Antinuclear antibodies (ANAs) and anti-DNA antibodies were present in 45.2% and 18% of the patients sampled, respectively. Concomitant viral infection was detected in 8 patients (8.8%). Systemic corticosteroids were prescribed in 32% of cases, hydroxychloroquine in 17.6%, and intravenous immunoglobulin in 3 patients. The disease course was always favorable. Recurrence was observed in 21% of cases. In the 33 patients with ANA at diagnosis, SLE was known in 11 patients, diagnosed concomitantly in 10 cases and in the year following diagnosis in 2 cases; 6 patients did not have SLE, and 4 patients were lost to follow-up (median follow-up, 19 mo; range, 3-39 mo). The presence of weight loss, arthralgia, skin lesions, and ANA was associated with the development of SLE (p < 0.05). Male sex and lymphopenia were associated with severe forms of KFD (p < 0.05). KFD can occur in all populations, irrespective of ethnic origin. Deep forms are common. An association with SLE should be investigated. A prospective study is required to determine the risk factors for the development of SLE.


Difficult-to-treat gout flares: eligibility for interleukin-1 inhibition in private practice is uncommon according to current EMA approval.
The objective was to determine the proportion of patients with difficult-to-treat or difficult-to-prevent acute gout attacks eligible for IL-1 inhibition. Participants included in the French cross-sectional GOSPEL cohort (n = 1003 gout patients) were examined for contraindications and intolerance to standard of care (SoC) drugs of gout flares (colchicine, non-steroidal anti-inflammatory drugs and systemic glucocorticoids). Patients were classified as definitely eligible for first-line IL-1 inhibition (canakinumab) according to European summary of product characteristics (contraindications/intolerance to SoC and at least three flares per year) without any other anti-inflammatory options (contraindications/intolerance only), or potentially eligible (precaution of use). Eligibility to receive IL-1 during an on-going flare related to insufficient efficacy was assessed (second-line eligibility). Definite first-line eligibility for IL-1 therapy was found in 10 patients (1%) and contraindication to all SoC therapies in nine patients who had presented <3 flares in the past 12 months. At least precaution of use for SoC therapies was noted for 218/1003 patients (21.7%). Of 487 patients experiencing flares at baseline, 114 (23.4%) were still experiencing pain scored ⩾4/10 numeric scale on day 3, one of whom could not receive further SoC drugs. Only nine of them had three or more flares in the past year and were eligible for second-line IL-1 inhibition. Despite significant numbers of patients without any SoC anti-inflammatory therapeutic options for gout flares, eligibility for IL-1 inhibition therapy according to current European approval is rare.


Impact of a randomized campus/community trial to prevent high-risk drinking among college students.
High-risk drinking by college students continues to pose a significant threat to public health. Despite increasing evidence of the contribution of community-level and campus-level environmental factors to high-risk drinking, there have been few rigorous tests of interventions that focus on changing these interlinked environments. The Study to Prevent Alcohol Related Consequences (SPARC) assessed the efficacy of a comprehensive intervention using a community organizing approach to implement environmental strategies in and around college campuses. The goal of SPARC was to reduce high-risk drinking and alcohol-related consequences among college students. Ten universities in North Carolina were randomized to an Intervention or Comparison condition. Each Intervention school was assigned a campus/community organizer. The organizer worked to form a campus-community coalition, which developed and implemented a strategic plan to use environmental strategies to reduce high-risk drinking and its consequences. The intervention was implemented over a period of 3 years. Primary outcome measures were assessed using a web-based survey of students. Measures of high-risk drinking included number of days alcohol was consumed, number of days of binge drinking, and greatest number of drinks consumed (all in the past 30 days); and number of days one gets drunk in a typical week. Measures of alcohol-related consequences included indices of moderate consequences due to one's own drinking, severe consequences due to one's own drinking, interpersonal consequences due to others' drinking, and community consequences due to others' drinking (all using a past 30-day time frame). Measure of alcohol-related injuries included (i) experiencing alcohol-related injuries and (ii) alcohol-related injuries caused to others. We found significant decreases in the Intervention group compared with the Comparison group in severe consequences due to students' own drinking and alcohol-related injuries caused to others. In secondary analyses, higher levels of implementation of the intervention were associated with reductions in interpersonal consequences due to others' drinking and alcohol-related injuries caused to others. A community organizing approach promoting implementation of environmental interventions can significantly affect high-risk drinking and its consequences among college students.


Delayed/back up antibiotic prescriptions: what do the public think?
To describe the general public's understanding, acceptance and use of delayed antibiotics. Face to face computer-assisted survey using an Ipsos MORI Capibus survey. Randomly selected households in England using multistage sampling. A representative sample of 1625 adults aged over 15 years and recruited from household visits in England, using age and gender quotas for each area. The survey was undertaken in January 2014. Weights based on gender, age, ethnicity, working status, social grade, housing tenure and Government Office Region corrected for selection biases, so that results are broadly representative of the population. Proportion of respondents; understanding the meaning of the term delayed antibiotic prescription and how the strategy is used in general practice; in favour of, or opposed to clinicians offering them a delayed antibiotic; reporting receipt, use and acceptability of delayed antibiotic prescriptions in the past year. 17% reported fully understanding the meaning of delayed antibiotic prescription and strategy use in general practice;72% were unaware of the term or strategy; 36-39% were in favour of, and 28-30% opposed to clinicians offering them a delayed antibiotic for throat, urine, ear or chest infections. Half of those who were fully aware of the term and practice were in favour of delayed antibiotics. Women, and older respondents, were more strongly opposed to delayed prescribing. Only 4% of all respondents, and 15% of those prescribed an antibiotic, reported being offered a delayed antibiotic in the last year. Wider understanding and acceptance of delayed prescribing may facilitate increased uptake. Further research is needed to determine why groups are so strongly in favour or opposed to delayed prescribing.


Rapid identification of Chikungunya and Dengue virus by a real-time reverse transcription-loop-mediated isothermal amplification method.
Both Chikungunya and Dengue virus belong to the acute arthropod-borne viruses. Because of the lack of specific symptoms, it is difficult to distinguish the two infections based on clinical manifestations. To identify and quantitatively detect Chikungunya and Dengue viruses, a real-time accelerated reverse-transcription-loop-mediated isothermal amplification (RT-LAMP) platform was developed, and 26-confirmed RNA samples, 42 suspects, and 18 healthy serum samples were evaluated by the method. The RT-polymerase chain reaction (PCR) and cDNA sequencing were used as references. The results showed that it could identify the Chikungunya and Dengue virus RNA correctly in all antibody-positive samples within 1 hour, without any cross-reactions. The virus load of the positive samples was quantitatively detected with a turbidimeter. The sensitivity was 100% and specificity was 95.25%. The findings indicate that the RT-LAMP is an effective method for rapid quantity detection of Chikungunya virus and Dengue virus in serum samples with convenient operation, high specificity, and high sensitivity.


A General Sparse Tensor Framework for Electronic Structure Theory.
Linear-scaling algorithms must be developed in order to extend the domain of applicability of electronic structure theory to molecules of any desired size. However, the increasing complexity of modern linear-scaling methods makes code development and maintenance a significant challenge. A major contributor to this difficulty is the lack of robust software abstractions for handling block-sparse tensor operations. We therefore report the development of a highly efficient symbolic block-sparse tensor library in order to provide access to high-level software constructs to treat such problems. Our implementation supports arbitrary multi-dimensional sparsity in all input and output tensors. We avoid cumbersome machine-generated code by implementing all functionality as a high-level symbolic C++ language library and demonstrate that our implementation attains very high performance for linear-scaling sparse tensor contractions.


Response to temozolomide and bevacizumab in a patient with poorly differentiated neuroendocrine carcinoma.
Poorly differentiated endocrine carcinomas (PDEC) are usually treated with cisplatin-based chemotherapy regimens. We here present a case with a dramatic response (both radiologically and biochemically) to the combination of temozolomide and bevacizumab, after failure of cisplatin and etoposide, with continued tumor shrinkage at 5 months. Temozolomide combined with bevacizumab might be a good treatment option in PDEC, perhaps even in a first-line setting. Prospective studies to answer this are warranted.


Survey for incidence of cancer as a measure of outcome in the JACC study.
As endpoint of cohort studies on cancer, the incidence, rather than the mortality is preferable. Of 45 areas in the Japan Collaborative Cohort Study (JACC Study), surveys for incidence of cancer were conducted in 24. The proportion of the study subjects aged 40 to 79 years in areas of survey for the incidence of cancer (65,184 persons) was 58.2% of the total subjects of the JACC Study (110,792 persons). Among the 24 areas of survey for the incidence of cancer (ASI), 10 areas were combined because of similarity. Then, we present the incidence rate of cancer among 15 ASI unified from the 24 ASI by gender according to area. We also report the completeness of the survey for cancer incidence presenting the mortality-incidence ratio (MI ratio) among the ASI. Where a population-based cancer registry was utilized, the MI ratio deviated from 0.31 to 0.61 in the male subjects and from 0.15 to 0.53 in the female subjects. However, where a population-based cancer registry was not used, the MI ratio deviated from 0.25 to 0.72 in the male subjects and from 0.13 to 0.79 in the female subjects, and there was an area where the MI ratio exceeded 0.70 in both of the male and female subjects. Establishment of population-based cancer registries is strongly desired throughout Japan to assess risk factors of cancer development for primary prevention of cancer.


Sculpted landscapes: art & place in Cleveland's Cultural Gardens, 1916-2006.
Perhaps the world's first peace garden, the Cleveland Cultural Gardens embody the history of twentieth-century America and reveal the complex interrelations between art and place. This essay uses the Cleveland Cultural Gardens as a lens through which to explore how art and place have intersected over time. It explores how communities have negotiated questions of national, ethnic, and American identity and embedded those identities into the vernacular landscape. It considers how the particulars of place were embedded into a public garden and asks whether it is possible for public art to transcend its place—both in terms of geography and history. In some sense, the Gardens have transcended their place, but in others respects, their fortunes were bound inextricably to that place, to the economic, demographic, and cultural contours that shaped and reshaped Northern Ohio. As works of art, the Cleveland Cultural Gardens both have reflected the history of Cleveland and American industrial cities during the 20th century and revealed something of the dynamics that underscored the changing character of public art and gardens in American cities.


Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period.
To determine time trends in the epidemiology of rheumatoid arthritis (RA) in a population-based cohort. An inception cohort of residents of Rochester, Minnesota > or = 18 years of age who first fulfilled the American College of Rheumatology 1987 criteria between January 1, 1955 and December 31, 1994 (applied retrospectively, as appropriate) was assembled and followed up until January 1, 2000. Incidence rates were estimated and were age- and sex-adjusted to the 1990 white population of the US. A birth cohort analysis was performed, and survival rates over time were examined. The incidence cohort comprised 609 patients, 445 (73.1%) of whom were female and 164 (26.9%) were male, with a mean age at incidence of 58.0 years. The overall age- and sex-adjusted annual incidence of RA among Rochester, Minnesota, residents > or = 18 years of age was 44.6/100,000 population (95% confidence interval 41.0-48.2). While the incidence rate fell progressively over the 4 decades of study, from 61.2/100,000 in 1955-1964, to 32.7/100,000 in 1985-1994, there were indications of cyclical trends over time. Birth cohort analysis showed diminishing incidence rates through successive cohorts following a peak in the 1880-1890 cohorts. Incidence rates increased with age until age 85, but peaked earlier in women than in men. The survival rate in RA patients was significantly lower than the expected rate in the general population (P < 0.001), and no improvement was noted over time. The secular trends demonstrated in this study population, including the progressive decline in the incidence of RA over the last 40 years, suggest that an environmental factor may play a role in the etiology of RA.


Structure of a bacterial α2-macroglobulin reveals mimicry of eukaryotic innate immunity.
Alpha-2-macroglobulins (A2Ms) are plasma proteins that trap and inhibit a broad range of proteases and are major components of the eukaryotic innate immune system. Surprisingly, A2M-like proteins were identified in pathogenically invasive bacteria and species that colonize higher eukaryotes. Bacterial A2Ms are located in the periplasm where they are believed to provide protection to the cell by trapping external proteases through a covalent interaction with an activated thioester. Here we report the crystal structures and characterization of Salmonella enterica ser. Typhimurium A2M in different states of thioester activation. The structures reveal thirteen domains whose arrangement displays high similarity to proteins involved in eukaryotic immune defence. A structural lock mechanism maintains the stability of the buried thioester, a requirement for its protease-trapping activity. These findings indicate that bacteria have developed a rudimentary innate immune system whose mechanism mimics that of eukaryotes.


Seven-year longitudinal change in risk factors for non-communicable diseases in rural Kerala, India: The WHO STEPS approach.
Nearly three-quarters of global deaths from non-communicable diseases (NCDs) occur in low- and middle-income countries such as India. However, there are few data available on longitudinal change in risk factors for NCDs in India. We conducted a cohort study among 495 individuals (aged 15 to 64 years at baseline) in rural Kerala state, India, from 2003 to 2010. For the present analysis, data from 410 adults (aged 20 to 64 years at baseline) who participated at both baseline and follow-up studies were analyzed. We used the World Health Organization STEPwise approach to risk factor surveillance for data collection. Age-adjusted change in risk factors for NCDs was assessed using the mixed-effects linear regression for continuous variables and the generalized estimating equation for categorical variables. The mean age of participants at baseline was 41.6 years, and 53.9% were women. The mean follow-up period was 7.1 years. There were significant increases in weight (mean change +5.0 kg, 95% confidence interval [CI] 4.2 to 5.8), body mass index (mean change +1.8 kg/m2, 95% CI 1.5 to 2.1), waist circumference (mean change +3.9 cm, 95% CI 3.0 to 4.8), waist-to-height ratio (mean change +0.022, 95% CI 0.016 to 0.027), current smokeless tobacco use (men: odds ratio [OR] 1.6, 95% CI 1.1 to 2.2), alcohol use (men: OR 2.6, 95% CI 1.9 to 3.5; women: OR 4.8, 95% CI 1.8 to 12.6), physical inactivity (OR 2.0, 95% CI 1.3 to 3.0), obesity (OR 2.2, 95% CI 1.7 to 2.8), and central obesity (OR 1.9, 95% CI 1.5 to 2.3). Over a seven-year period, several NCD risk factors have increased in the study cohort. This calls for implementation of lifestyle intervention programs in rural Kerala.


SNX9 regulates tubular invagination of the plasma membrane through interaction with actin cytoskeleton and dynamin 2.
Dynamic membrane remodeling during intracellular trafficking is controlled by the intricate interplay between lipids and proteins. BAR domains are modules that participate in endocytic processes by binding and deforming the lipid bilayer. Sorting nexin 9 (SNX9), which functions in clathrin-mediated endocytosis, contains a BAR domain, however, the properties of this domain are not well understood. Here we show that SNX9 shares many properties with other BAR domain-containing proteins, such as amphiphysin and endophilin. SNX9 is able to deform the plasma membrane, as well as liposomes, into narrow tubules and recruit N-WASP and dynamin 2 to these tubules via its SH3 domain. SNX9-induced tubulation is antagonized by N-WASP and dynamin 2 while it is enhanced by perturbation of actin dynamics. However, SNX9 also has several unique properties. The tubulating activity requires the BAR and PX domains, as well as the low-complexity (LC) domain, which binds the Arp2/3 complex. SNX9 also binds to PtdIns(4)P-5-kinases via its PX domain and its tubulating activity is regulated by phosphoinositides. In addition, the kinase activity of PtdIns(4)P-5-kinases is stimulated by interaction with SNX9, suggesting a positive feedback interaction between SNX9 and PtdIns(4)P-5-kinases. These results suggest that SNX9 functions in the coordination of membrane remodeling and fission via interactions with actin-regulating proteins, endocytic proteins and PtdIns(4,5)P2-metabolizing enzymes.


Rising CO2 levels will intensify phytoplankton blooms in eutrophic and hypertrophic lakes.
Harmful algal blooms threaten the water quality of many eutrophic and hypertrophic lakes and cause severe ecological and economic damage worldwide. Dense blooms often deplete the dissolved CO2 concentration and raise pH. Yet, quantitative prediction of the feedbacks between phytoplankton growth, CO2 drawdown and the inorganic carbon chemistry of aquatic ecosystems has received surprisingly little attention. Here, we develop a mathematical model to predict dynamic changes in dissolved inorganic carbon (DIC), pH and alkalinity during phytoplankton bloom development. We tested the model in chemostat experiments with the freshwater cyanobacterium Microcystis aeruginosa at different CO2 levels. The experiments showed that dense blooms sequestered large amounts of atmospheric CO2, not only by their own biomass production but also by inducing a high pH and alkalinity that enhanced the capacity for DIC storage in the system. We used the model to explore how phytoplankton blooms of eutrophic waters will respond to rising CO2 levels. The model predicts that (1) dense phytoplankton blooms in low- and moderately alkaline waters can deplete the dissolved CO2 concentration to limiting levels and raise the pH over a relatively wide range of atmospheric CO2 conditions, (2) rising atmospheric CO2 levels will enhance phytoplankton blooms in low- and moderately alkaline waters with high nutrient loads, and (3) above some threshold, rising atmospheric CO2 will alleviate phytoplankton blooms from carbon limitation, resulting in less intense CO2 depletion and a lesser increase in pH. Sensitivity analysis indicated that the model predictions were qualitatively robust. Quantitatively, the predictions were sensitive to variation in lake depth, DIC input and CO2 gas transfer across the air-water interface, but relatively robust to variation in the carbon uptake mechanisms of phytoplankton. In total, these findings warn that rising CO2 levels may result in a marked intensification of phytoplankton blooms in eutrophic and hypertrophic waters.


Argininosuccinate lyase deficiency causes blood-brain barrier disruption via nitric oxide-mediated dysregulation of claudin expression.
Nitric oxide (NO) is a critical signaling molecule that has been implicated in the pathogenesis of neurocognitive diseases. Both excessive and insufficient NO production have been linked to pathology. Previously, we have shown that argininosuccinate lyase deficiency (ASLD) is a novel model system to investigate cell-autonomous, nitric oxide synthase-dependent NO deficiency. Humans with ASLD are at increased risk for developing hyperammonemia due to a block in ureagenesis. However, natural history studies have shown that individuals with ASLD have multisystem disease including neurocognitive deficits that can be independent of ammonia. Here, using ASLD as a model of NO deficiency, we investigated the effects of NO on brain endothelial cells in vitro and the blood-brain barrier (BBB) in vivo. Knockdown of ASL in human brain microvascular endothelial cells (HBMECs) led to decreased transendothelial electrical resistance, indicative of increased cell permeability. Mechanistically, treatment with an NO donor or inhibition of Claudin-1 improved barrier integrity in ASL-deficient HBMECs. Furthermore, in vivo assessment of a hypomorphic mouse model of ASLD showed increased BBB leakage, which was partially rescued by NO supplementation. Our results suggest that ASL-mediated NO synthesis is required for proper maintenance of brain microvascular endothelial cell functions as well as BBB integrity.


Optimistic bias and Facebook use: self-other discrepancies about potential risks and benefits of Facebook use.
Despite the accumulating evidence on the positive and negative outcomes of Facebook use, how people perceive themselves to be subject to these outcomes as well as the consequences and mechanisms of these perceptions are underexplored. According to optimistic bias, Facebook users may perceive that bad things are more likely to happen to others than to themselves, while good things are more likely to happen to them than to others. The findings from an online survey among Facebook users indicate that the negative psychological and social outcomes of using Facebook were perceived to be more likely to happen to other Facebook users than to themselves, p<0.001. These self-other discrepant perceptions toward negative social events (e.g., Facebook cyberbullying and scams) significantly mediated one's willingness to support Internet regulation, Sobel z=2.49, p=0.01. For positive outcomes of Facebook use, the direction of optimistic bias was reversed, t(235) = -5.52, p<0.01, indicating that people minimized the likelihoods of experiencing positive events from Facebook while assessing that other Facebook users are prone to encounter those positive events. This reversal pattern emerged among those with negative attitudes toward, and low involvement with, Facebook. These findings demonstrate important and novel self-other discrepant perceptions concerning the risks and benefits of Facebook use.


Toxoplasma gondii lysine acetyltransferase GCN5-A functions in the cellular response to alkaline stress and expression of cyst genes.
Parasitic protozoa such as the apicomplexan Toxoplasma gondii progress through their life cycle in response to stimuli in the environment or host organism. Very little is known about how proliferating tachyzoites reprogram their expressed genome in response to stresses that prompt development into latent bradyzoite cysts. We have previously linked histone acetylation with the expression of stage-specific genes, but the factors involved remain to be determined. We sought to determine if GCN5, which operates as a transcriptional co-activator by virtue of its histone acetyltransferase (HAT) activity, contributed to stress-induced changes in gene expression in Toxoplasma. In contrast to other lower eukaryotes, Toxoplasma has duplicated its GCN5 lysine acetyltransferase (KAT). Disruption of the gene encoding for TgGCN5-A in type I RH strain did not produce a severe phenotype under normal culture conditions, but here we show that the TgGCN5-A null mutant is deficient in responding to alkaline pH, a common stress used to induce bradyzoite differentiation in vitro. We performed a genome-wide analysis of the Toxoplasma transcriptional response to alkaline pH stress, finding that parasites deleted for TgGCN5-A fail to up-regulate 74% of the stress response genes that are induced 2-fold or more in wild-type. Using chromatin immunoprecipitation, we verify an enrichment of TgGCN5-A at the upstream regions of genes activated by alkaline pH exposure. The TgGCN5-A knockout is also incapable of up-regulating key marker genes expressed during development of the latent cyst form, and is impaired in its ability to recover from alkaline stress. Complementation of the TgGCN5-A knockout restores the expression of these stress-induced genes and reverses the stress recovery defect. These results establish TgGCN5-A as a major contributor to the alkaline stress response in RH strain Toxoplasma.


Intrusive memories and ruminations related to violent crime among young offenders: phenomenological characteristics.
Very little is known about the nature of perpetrator's memories of violent crime. The authors conducted semistructured interviews with a representative sample of 105 young offenders convicted of serious violence, assessing intrusive memories, ruminations, and symptoms of posttraumatic stress disorder related to their violent crime. Forty-eight (46%) participants described significant intrusive memories of the assault, and 38 (36%) reported ruminations related to the assault. Ethnic origin and historical variables explained 19% of the variance of posttraumatic stress disorder symptom severity; intrusion and rumination characteristics added an additional 48% explained variance. The intrusive memories tended to concern the moment when the event turned for the worse for the perpetrator. The findings have implications for risk assessment and therapeutic interventions for violent offenders.


Lymphatic transport of alpha-, gamma- and delta-tocotrienols and alpha-tocopherol in rats.
Lymphatic transport of alpha-, gamma- and delta-tocotrienols and alpha-tocopherol was measured in thoracic duct-cannulated rats. Animals were administered 3 ml of a test emulsion containing 200 mg sodium taurocholate, 50 mg fatty acid free-albumin, 200 mg fat and 100 mg of a mixture of tocotrienols and alpha-tocopherol (Exp. 1) or 10 mg of purified alpha-, gamma- or delta-tocotrienol or alpha-tocopherol (Exp. 2) through a gastric tube. Quantitative lymphatic recovery of oleic acid given as triolein was obtained in these experimental conditions. The 24-hours recovery of tocotrienols and alpha-tocopherol were 10-20% of the administered dose in Exp. 1. The recovery of alpha-tocotrienol was about 2-times higher than that of alpha-tocopherol, while that of gamma- and delta-tocotrienols was intermediate between these two alpha-forms. In Exp. 2, where these compounds were administered individually, the 24 hours recovery ranged from 22 to 37% of the administered dose. Again, the recovery of alpha-tocotrienol was significantly higher than that of the other tocotrienols and alpha-tocopherol, while that of gamma- and delta-tocotrienols and alpha-tocopherol was comparable. Thus, the results show the preferential absorption of alpha-tocotrienol compared to gamma- and delta-tocotrienols and alpha-tocopherol.


Hypervascular lesion in the head of the pancreas. Preoperative angiography and selective embolization results in bloodless operation.
Pancreatic neuroendocrine tumors (PNETs) are rare tumors. These tumors are hypervascular in nature. Their surgical management is well described and practiced. Although hypervascular in their nature, preoperative angioembolization of the primary tumor is usually not indicated. We describe a case of an extremely hypervascular PNET in the head of the pancreas that was managed with preoperative angioembolization that was followed by a Whipple operation that resulted in excellent recovery. Pre-operative angioembolization of pancreatic tumors, although previously reported, is exceedingly rare. The use of this technique prior to surgery is feasible and may result in bloodless surgery and better outcome.


Pharmacokinetics and safety profile of single-dose administration of an estrogen receptor β-selective phytoestrogenic (phytoSERM) formulation in perimenopausal and postmenopausal women.
Selected estrogen receptor β-selective phytoestrogen (phytoSERM), a preparation of genistein, daidzein, and S-equol, has an 83-fold selective affinity for estrogen receptor (ER) β, and may promote neuronal survival and estrogenic mechanisms in the brain without exerting feminizing activity in the periphery. The aim of this study was to assess the safety, tolerability, and single-dose pharmacokinetics of the phytoSERM formulation in perimenopausal and postmenopausal women. Eighteen women aged 45 to 60 years from a 12-week clinical trial evaluating cognitive performance and vasomotor symptoms were randomly assigned to placebo, 50 mg, or 100 mg phytoSERM treatment groups. Plasma levels of the three parent phytoestrogens and their metabolites were measured before and at 2, 4, 6, 8, and 24 hours after ingestion by isotope dilution high-performance liquid chromatography (HPLC) electrospray ionization tandem mass spectrometry. Plasma concentrations of genistein, daidzein, and S-equol peaked at 9, 6, and 4 hours, respectively, for the 50-mg dose, and at 6, 6, and 5 hours, respectively, for the 100-mg dose. The maximum concentration (Cmax) and area under the curve (AUC) for the three parent compounds were greater in the 100-mg dose group, indicating a dose-dependent change in concentration with the phytoSERM treatment. No adverse events were elicited. A single-dose oral administration of the phytoSERM formulation was well-tolerated and did not elicit any adverse events. It was rapidly absorbed, reached high plasma concentrations, and showed a linear dose-concentration response in its pharmacokinetics. These findings are consistent with previously reported parameters for each parent compound (Clinicaltrials.gov NCT01723917).


Toll4 (TLR4) expression in cardiac myocytes in normal and failing myocardium.
Expression of innate immune response proteins, including IL-1beta, TNF, and the cytokine-inducible isoform of nitric oxide synthase (iNOS), have been documented in the hearts of humans and experimental animals with heart failure regardless of etiology, although the proximal events leading to their expression are unknown. Noting that expression of a human homologue of Drosophila Toll, a proximal innate immunity transmembrane signaling protein in the fly, now termed human Toll-like receptor 4 (hTLR4), appeared to be relatively high in the heart, we examined TLR4 mRNA and protein abundance in isolated cellular constituents of cardiac muscle and in normal and abnormal murine, rat, and human myocardium. TLR4 expression levels in cardiac myocytes and in coronary microvascular endothelial cells could be enhanced by either LPS or IL-1beta, an effect inhibited by the oxygen radical scavenger PDTC. Transfection of a constitutively active TLR4 construct, CD4/hTLR4, resulted in activation of a nuclear factor-kappaB reporter construct, but not of an AP-1 or an iNOS reporter construct, in cardiac myocytes. In normal murine, rat, and human myocardium, TLR4 expression was diffuse, and presumably cytoplasmic, in cardiac myocytes. However, in remodeling murine myocardium remote from sites of ischemic injury and in heart tissue from patients with idiopathic dilated cardiomyopathy, focal areas of intense TLR4 staining were observed in juxtaposed regions of 2 or more adjacent myocytes; this staining was not observed in control myocardium. Increased expression and signaling by TLR4, and perhaps other Toll homologues, may contribute to the activation of innate immunity in injured myocardium.


Dynamic 4D MRI for Characterization of Parathyroid Adenomas: Multiparametric Analysis.
The hypervascular nature of parathyroid adenomas can be explored by proper dynamic imaging to narrow the target lesions for surgical exploration. The purpose of this study was to establish MR perfusion characteristics of parathyroid adenomas to differentiate them from their mimics, such as subjacent thyroid tissue and cervical lymph nodes. Preoperative high-spatial and -temporal resolution dynamic 4D contrast-enhanced MR imaging in 30 patients with surgically proved parathyroid adenomas was evaluated retrospectively. Using coregistered images, we placed ROIs over the parathyroid adenoma, thyroid gland, and a cervical lymph node (jugulodigastric) to obtain peak enhancement, time-to-peak, wash-in, and washout in each patient. Data were analyzed by logistic regression and analysis of variance. Receiver operating characteristic analysis was performed to determine the optimal parameters for determination of parathyroid adenomas versus thyroid tissue and cervical lymph nodes. Parathyroid adenomas showed significantly (P < .05) faster time-to-peak, higher wash-in, and higher washout compared with cervical lymph nodes and significantly (P < .05) higher peak enhancement, faster time-to-peak, higher wash-in, and higher washout compared with thyroid tissue. Logistic regression analysis indicated significant contribution from time-to-peak (P = .02), wash-in (P = .03), and washout (P = .008) for differentiation of parathyroid adenomas from thyroid and cervical lymph nodes. Using receiver operating characteristic analysis, we obtained the best diagnostic accuracy from a combination of time-to-peak/wash-in/washout in the differentiation of parathyroid adenomas versus lymph nodes (area under the curve, 0.96; sensitivity/specificity, 88%/90%) and in distinguishing parathyroid adenomas versus thyroid tissue (area under the curve, 0.96; sensitivity/specificity, 91%/95%). Dynamic 4D contrast-enhanced MR imaging can be used to exploit the hypervascular nature of parathyroid adenomas. Multiparametric MR perfusion can distinguish parathyroid adenomas from subjacent thyroid tissue or lymph nodes with diagnostic accuracies of 96%.


Anti-hypertensive effect of metoprolol in spontaneously hypertensive rats.
1. Oral and intravenous administration of metoprolol to adult spontaneously hypertensive rats (SHR) with established hypertension lowered arterial blood pressure within 4 days of treatment. 2. Steady state plasma concentrations of metoprolol were similar to those of patients during anti-hypertensive treatment with this drug. 3. The neuroeffector function of portal veins of SHR treated orally for 14 days or intravenously for 4 days was not impaired when studied in vitro. This is in contrast to previous findings after long-term treatment. 4. It is concluded that the anti-hypertensive effect of metoprolol in SHR in many respects resembles that observed in patients. It is suggested that impairment of vasomotor nerve control may contribute to the anti-hypertensive effect of beta-adrenoreceptor antagonists.


Genetic deletion of PKR abrogates TNF-induced activation of IkappaBalpha kinase, JNK, Akt and cell proliferation but potentiates p44/p42 MAPK and p38 MAPK activation.
Double-stranded RNA-dependent protein kinase (PKR), a ubiquitously expressed serine/threonine kinase, has been implicated in the regulation or modulation of cell growth through multiple signaling pathways, but how PKR regulates tumor necrosis factor (TNF)-induced signaling pathways is poorly understood. In the present study, we used fibroblasts derived from PKR gene-deleted mice to investigate the role of PKR in TNF-induced activation of nuclear factor-kappaB (NF-kappaB), mitogen-activated protein kinases (MAPKs) and growth modulation. We found that in wild-type mouse embryonic fibroblast (MEF), TNF induced NF-kappaB activation as measured by DNA binding but deletion of PKR abolished this activation. This inhibition was associated with suppression of inhibitory subunit of NF-kappaB (IkappaB)alpha kinase (IKK) activation, IkappaBalpha phosphorylation and degradation, p65 phosphorylation and nuclear translocation, and NF-kappaB-dependent reporter gene transcription. TNF-induced Akt activation needed for IKK activation was also abolished by deletion of PKR. NF-kappaB activation was diminished in PKR-deleted cells transfected with TNF receptor (TNFR) 1, TNFR-associated death domain and TRAF2 plasmids; NF-kappaB activated by NF-kappaB-inducing kinase, IKK or p65, however, was minimally affected. Among the MAPKs, it was interesting that whereas TNF-induced c-Jun N-terminal kinase (JNK) activation was abolished, activation of p44/p42 MAPK and p38 MAPK was potentiated in PKR-deleted cells. TNF induced the expression of NF-kappaB-regulated gene products cyclin D1, c-Myc, matrix metalloproteinase-9, survivin, X-linked inhibitor-of-apoptosis protein (IAP), IAP1, Bcl-x(L), A1/Bfl-1 and Fas-associated death domain protein-like IL-1beta-converting enzyme-inhibitory protein in wild-type MEF but not in PKR-/- cells. Similarly, TNF induced the proliferation of wild-type cells, but this proliferation was completely suppressed in PKR-deleted cells. Overall, our results indicate that PKR differentially regulates TNF signaling; IKK, Akt and JNK were positively regulated, whereas p44/p42 MAPK and p38 MAPK were negatively regulated.


Radial versus femoral access for coronary angiography and intervention in patients with acute coronary syndromes (RIVAL): a randomised, parallel group, multicentre trial.
Small trials have suggested that radial access for percutaneous coronary intervention (PCI) reduces vascular complications and bleeding compared with femoral access. We aimed to assess whether radial access was superior to femoral access in patients with acute coronary syndromes (ACS) who were undergoing coronary angiography with possible intervention. The RadIal Vs femorAL access for coronary intervention (RIVAL) trial was a randomised, parallel group, multicentre trial. Patients with ACS were randomly assigned (1:1) by a 24 h computerised central automated voice response system to radial or femoral artery access. The primary outcome was a composite of death, myocardial infarction, stroke, or non-coronary artery bypass graft (non-CABG)-related major bleeding at 30 days. Key secondary outcomes were death, myocardial infarction, or stroke; and non-CABG-related major bleeding at 30 days. A masked central committee adjudicated the primary outcome, components of the primary outcome, and stent thrombosis. All other outcomes were as reported by the investigators. Patients and investigators were not masked to treatment allocation. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT01014273. Between June 6, 2006, and Nov 3, 2010, 7021 patients were enrolled from 158 hospitals in 32 countries. 3507 patients were randomly assigned to radial access and 3514 to femoral access. The primary outcome occurred in 128 (3·7%) of 3507 patients in the radial access group compared with 139 (4·0%) of 3514 in the femoral access group (hazard ratio [HR] 0·92, 95% CI 0·72-1·17; p=0·50). Of the six prespecified subgroups, there was a significant interaction for the primary outcome with benefit for radial access in highest tertile volume radial centres (HR 0·49, 95% CI 0·28-0·87; p=0·015) and in patients with ST-segment elevation myocardial infarction (0·60, 0·38-0·94; p=0·026). The rate of death, myocardial infarction, or stroke at 30 days was 112 (3·2%) of 3507 patients in the radial group compared with 114 (3·2%) of 3514 in the femoral group (HR 0·98, 95% CI 0·76-1·28; p=0·90). The rate of non-CABG-related major bleeding at 30 days was 24 (0·7%) of 3507 patients in the radial group compared with 33 (0·9%) of 3514 patients in the femoral group (HR 0·73, 95% CI 0·43-1·23; p=0·23). At 30 days, 42 of 3507 patients in the radial group had large haematoma compared with 106 of 3514 in the femoral group (HR 0·40, 95% CI 0·28-0·57; p<0·0001). Pseudoaneurysm needing closure occurred in seven of 3507 patients in the radial group compared with 23 of 3514 in the femoral group (HR 0·30, 95% CI 0·13-0·71; p=0·006). Radial and femoral approaches are both safe and effective for PCI. However, the lower rate of local vascular complications may be a reason to use the radial approach. Sanofi-Aventis, Population Health Research Institute, and Canadian Network for Trials Internationally (CANNeCTIN), an initiative of the Canadian Institutes of Health Research.


Enzymatic approach to syntheses of unnatural beta-lactams.
Four enzymes associated with the transformation of the peptide delta-(L-alpha-aminoadipyl)-L-cysteinyl-D-valine (ACV) into the beta-lactam antibiotic desacetylcephalosporin C have been isolated from the prokaryotic organism Streptomyces clavuligerus and immobilized. Appropriate choice of the cofactors allows continuous and quantitative conversion of the peptide into either penicillins or cephalosporins at room temperature. The overall process includes four oxidations, two ring closures, and one epimerization. In contrast, cell-free transformations with the eukaryotic organism Cephalosporium acremonium do not proceed beyond the oxidation level of penicillin. The amino acids of the natural peptide ACV can be altered by chemical means; several of the resulting peptides are converted into novel antibiotics by the enzymes of Streptomyces clavuligerus.


When children cannot return home: adoption and guardianship.
Since the 1970s, finding alternative permanent families for children in foster care who could not return to their birth parents has been a primary goal of the child welfare system. Since that time, significant gains have been made in helping such children find permanent homes through adoption and guardianship. This article analyzes these trends and finds: A majority of states have doubled the number of adoptions from foster care over the 1995-97 baselines established by the federal government. Legal guardianship initiatives at the state level have been instrumental in helping thousands of children achieve permanence. Children who exit foster care to adoption tend to be younger than those who exit to guardianship. Postpermanency services and supports are important to the long-term success of these placements. Innovative efforts to find adoptive parents and legal guardians for children in foster care could transform the nature of foster care if the number of children permanently living with families who receive state subsidies begins to exceed the number of children living in foster care. Looking forward, these changes would require child welfare agencies to think creatively and thoughtfully about how best to serve families and the children in their care.


Cytotoxicological pathways induced after nanoparticle exposure: studies of oxidative stress at the 'nano-bio' interface.
Nanotechnology is advancing rapidly; many industries are utilizing nanomaterials because of their remarkable properties. As of 2017, over 1800 "nano-enabled products" (i.e. products that incorporate a nanomaterial feature and alter the product's performance) have been used to revolutionize pharmaceutical, transportation, and agriculture industries, just to name a few. As the number of nano-enabled products continues to increase, the risk of nanoparticle exposure to humans and the surrounding environment also increases. These exposures are usually classified as either intentional or unintentional. The increased rate of potential nanoparticle exposure to humans has required the field of 'nanotoxicology' to rapidly screen for key biological, biochemical, chemical, or physical signals, signatures, or markers associated with specific toxicological pathways of injury within in vivo, in vitro, and ex vivo models. One of the common goals of nanotoxicology research is to identify critical perturbed biological pathways that can lead to an adverse outcome. This review focuses on the most common toxicological pathways induced by nanoparticle exposure and provides insights into how these perturbations could aid in the development of nanomaterial specific adverse outcomes, inform nano-enabled product development, ensure safe manufacturing practices, promote intentional product use, and avoid environmental health hazards.


Genome-Wide Mapping and Interrogation of the Nmp4 Antianabolic Bone Axis.
PTH is an osteoanabolic for treating osteoporosis but its potency wanes. Disabling the transcription factor nuclear matrix protein 4 (Nmp4) in healthy, ovary-intact mice enhances bone response to PTH and bone morphogenetic protein 2 and protects from unloading-induced osteopenia. These Nmp4(-/-) mice exhibit expanded bone marrow populations of osteoprogenitors and supporting CD8(+) T cells. To determine whether the Nmp4(-/-) phenotype persists in an osteoporosis model we compared PTH response in ovariectomized (ovx) wild-type (WT) and Nmp4(-/-) mice. To identify potential Nmp4 target genes, we performed bioinformatic/pathway profiling on Nmp4 chromatin immunoprecipitation sequencing (ChIP-seq) data. Mice (12 w) were ovx or sham operated 4 weeks before the initiation of PTH therapy. Skeletal phenotype analysis included microcomputed tomography, histomorphometry, serum profiles, fluorescence-activated cell sorting and the growth/mineralization of cultured WT and Nmp4(-/-) bone marrow mesenchymal stem progenitor cells (MSPCs). ChIP-seq data were derived using MC3T3-E1 preosteoblasts, murine embryonic stem cells, and 2 blood cell lines. Ovx Nmp4(-/-) mice exhibited an improved response to PTH coupled with elevated numbers of osteoprogenitors and CD8(+) T cells, but were not protected from ovx-induced bone loss. Cultured Nmp4(-/-) MSPCs displayed enhanced proliferation and accelerated mineralization. ChIP-seq/gene ontology analyses identified target genes likely under Nmp4 control as enriched for negative regulators of biosynthetic processes. Interrogation of mRNA transcripts in nondifferentiating and osteogenic differentiating WT and Nmp4(-/-) MSPCs was performed on 90 Nmp4 target genes and differentiation markers. These data suggest that Nmp4 suppresses bone anabolism, in part, by regulating IGF-binding protein expression. Changes in Nmp4 status may lead to improvements in osteoprogenitor response to therapeutic cues.


Life-Span Development of Brain Network Integration Assessed with Phase Lag Index Connectivity and Minimum Spanning Tree Graphs.
Graph analysis of electroencephalography (EEG) has previously revealed developmental increases in connectivity between distant brain areas and a decrease in randomness and increased integration in the brain network with concurrent increased modularity. Comparisons of graph parameters across age groups, however, may be confounded with network degree distributions. In this study, we analyzed graph parameters from minimum spanning tree (MST) graphs and compared their developmental trajectories to those of graph parameters based on full graphs published previously. MST graphs are constructed by selecting only the strongest available connections avoiding loops, resulting in a backbone graph that is thought to reflect the major qualitative properties of the network, while allowing a better comparison across age groups by avoiding the degree of distribution confound. EEG was recorded in a large (n = 1500) population-based sample aged 5-71 years. Connectivity was assessed using phase lag index to reduce effects of volume conduction. Connectivity in the MST graph increased significantly from childhood to adolescence, continuing to grow nonsignificantly into adulthood, and decreasing significantly about 57 years of age. Leaf number, degree, degree correlation, and maximum centrality from the MST graph indicated a pattern of increased integration and decreased randomness from childhood into early adulthood. The observed development in network topology suggested that maturation at the neuronal level is aimed to increase connectivity as well as increase integration of the brain network. We confirm that brain network connectivity shows quantitative changes across the life span and additionally demonstrate parallel qualitative changes in the connectivity pattern.


Feeding decreases the oral bioavailability of cannabidiol and cannabidiolic acid in hemp oil in New Zealand White rabbits (Oryctolagus cuniculus).
To determine the pharmacokinetics of a solution containing cannabidiol (CBD) and cannabidiolic acid (CBDA), administered orally in 2 single-dose studies (with and without food), in the domestic rabbit (Oryctolagus cuniculus). 6 healthy New Zealand White rabbits. In phase 1, 6 rabbits were administered 15 mg/kg CBD with 16.4 mg/kg CBDA orally in hemp oil. In phase 2, 6 rabbits were administered the same dose orally in hemp oil followed by a food slurry. Blood samples were collected for 24 hours to determine the pharmacokinetics of CBD and CBDA. Quantification of plasma CBD and CBDA concentrations was determined using a validated liquid chromatography-mass spectrometry (LC-MS) assay. Pharmacokinetics were determined using noncompartmental analysis. For CBD, the area under the curve extrapolated to infinity (AUC)0-∞ was 179.8 and 102 hours X ng/mL, the maximum plasma concentration (Cmax) was 30.4 and 15 ng/mL, the time to Cmax (tmax) was 3.78 and 3.25 hours, and the terminal half-life (t1/2λ) was 7.12 and 3.8 hours in phase 1 and phase 2, respectively. For CBDA, the AUC0-∞ was 12,286 and 6,176 hours X ng/mL, Cmax was 2,573 and 1,196 ng/mL, tmax was 1.07 and 1.12 hours, and t1/2λ was 3.26 and 3.49 hours in phase 1 and phase 2, respectively. Adverse effects were not observed in any rabbit. CBD and CBDA reached a greater Cmax and had a longer t1/2λ in phase 1 (without food) compared with phase 2 (with food). CBDA reached a greater Cmax but had a shorter t1/2λ than CBD both in phase 1 and phase 2. These data may be useful in determining appropriate dosing of cannabinoids in the domestic rabbit.


Tunneled Peritoneal Catheter Placement in Palliation of Malignant Ascites: A Study with Two Different Types of Catheters.
Malignant ascites (MA) is abnormal accumulation of fluid in the peritoneal cavity and has negative effects on the quality of life. The purpose of this retrospective study is to explore feasibility, safety and efficacy of tunneled peritoneal catheter placement using both peritoneal dialysis and hemodialysis catheters in the palliation of MA. Between October 2013-June 2016, thirty patients with resistent MA underwent tunneled peritoneal catheterisation in our interventional radiology department. Tunneled peritoneal catheter (TPC) was placed in 22 (n=22/30; %73) patients, tunneled hemodialysis catheter (THC) was placed in 8 patients (n=8/30; %27). Routine visits were scheduled for months 1, 3, 6, 9, and 12 of the catheterization, and the records were evaluated retrospectively. The overall duration of catheterization varied from 2 to 334 days (mean 66.4 ± 68.5, median: 57 days). Catheters remained intact in 29 patients (96.7%) until the endpoint. There was one (3.3%) malfunctioning catheter among both groups. Overall, four patients developed infection, which were classified into major (n=2/30, %6.7) and minor (n=2/30, %6.7) complications according to SIR criteria. Tunneled peritoneal catheterization using both TPCs and THCs provided a safe method with relatively high patency, and low infection and systemic complication rates in the palliation of MA.


Synthesis, processing, and oligomerization of bovine herpesvirus 1 gE and gI membrane proteins.
This study reports the identification and initial characterization of the precursors, modified forms, and oligomers of bovine herpesvirus 1 (BHV-1) gI and gE proteins with polyvalent rabbit serum specific for gI or gE. Our experiments used the Colorado strain of BHV-1 and mutant viruses with insertions of the Escherichia coli lacZ gene into the predicted gE and gI reading frames. We also translated the gE and gI open reading frames in vitro and expressed them in uninfected cells using eukaryotic expression vectors. Precursor-product relationships were established by pulse-chase analysis and endoglycosidase H and glycopeptidase F digestions. Like the homologous glycoproteins of herpes simplex virus type 1, pseudorabies virus, and varicella-zoster virus, BHV-1 gI and gE are modified by N-linked glycosylation and associate with each other soon after synthesis, forming a noncovalent complex in infected and transfected cells. An analysis of mutant and wild-type-virus-infected cells and transfected COS cells expressing gE or gI alone suggested that gE-gI complex formation is necessary for efficient processing of the gE precursor to its mature form. One new finding was that unlike the other alphaherpesvirus gI homologs, a fraction of pulse-labeled gI synthesized in BHV-1-infected cells apparently is cleaved into two relatively stable fragments 2 to 4 h after the pulse. Finally, we incubated BHV-1-infected cell extracts with nonimmune mouse, rabbit, horse, pig, and calf sera and found no evidence that gE or gI functioned as Fc receptors as reported for the herpes simplex virus type 1 and varicella-zoster virus homologs.


Second-harmonic generation of amplified femtosecond Ti:sapphire laser pulses.
We study theoretically and experimentally second-harmonic generation (SHG) of 150-fs-duration amplified Ti:sapphire laser pulses at a wavelength of 780 nm in the nonlinear crystal KDP of different lengths and at different power densities as high as 150 GW cm(-2). The experimentally observed SHG conversion efficiency does not exceed 50%. It is shown theoretically that one possible process limiting the SHG efficiency at low as well as at high intensities is the modulation of the phase of the fundamental wave. In addition, continuum generation is observed at high intensities and can decrease the SHG efficiency.


From research to practice: factors affecting implementation of prospective targeted injury-detection systems.
AIM This paper describes key factors that shaped implementation of prospective targeted injury-detection systems (TIDS) for adverse drug events (ADEs) and nosocomial pressure ulcers (PrU). METHODS Using case-study methodology, the authors conducted semistructured interviews with implementation champions and TIDS users at five hospitals. Interviews focused on implementation experiences, assessment of TIDS' effectiveness and utility, and plans for sustainability. The authors used content analysis techniques to compare implementation experiences within and across organisations and triangulated data for explanation and confirmation of common themes. FINDINGS Participating hospitals were more successful in implementing the low-complexity PrU-TIDS, as compared with high-complexity ADE-TIDS. This pattern reflected the greater complexity of ADE-TIDS, its higher costs and poorer alignment with existing workflows. Complexity affected the innovations' perceived usability, the time needed to learn and install the trigger systems, and their costs. Local factors affecting implementation and sustainability of both innovations included turnover affecting champions and other staff, shifting organisational priorities, changing information infrastructures, and institutional constraints on adapting existing IT to the electronic TIDS. CONCLUSIONS To facilitate implementation of complex healthcare innovations such as ADE-TIDS, staff in adopting organisations should give high priority to innovation implementation; allocate sufficient resources; effectively communicate with and involve local champions and users; and align innovations with workflows and information systems. In addition, they should monitor local factors, such as changes in organisational priorities and IT, availability of implementation staff and champions, and external regulations and constraints that may pose barriers to innovation implementation and sustainability.


Seasonal effects on human striatal presynaptic dopamine synthesis.
Past studies in rodents have demonstrated circannual variation in central dopaminergic activity as well as a host of compelling interactions between melatonin--a scotoperiod-responsive neurohormone closely tied to seasonal adaptation--and dopamine in the striatum and in midbrain neuronal populations with striatal projections. In humans, seasonal effects have been described for dopaminergic markers in CSF and postmortem brain, and there exists a range of affective, psychotic, and substance abuse disorders that have been associated with both seasonal symptomatic fluctuations and dopamine neurotransmission abnormalities. Together, these data indirectly suggest a potentially crucial link between circannual biorhythms and central dopamine systems. However, seasonal effects on dopamine function in the living, healthy human brain have never been tested. For this study, 86 healthy adults underwent (18)F-DOPA positron emission tomography scanning, each at a different time throughout the year. Striatal regions of interest (ROIs) were evaluated for differences in presynaptic dopamine synthesis, measured by the kinetic rate constant, K(i), between fall-winter and spring-summer scans. Analyses comparing ROI average K(i) values showed significantly greater putamen (18)F-DOPA K(i) in the fall-winter relative to the spring-summer group (p = 0.038). Analyses comparing voxelwise K(i) values confirmed this finding and evidenced intrastriatal localization of seasonal effects to the caudal putamen (p < 0.05, false-discovery rate corrected), a region that receives dopaminergic input predominantly from the substantia nigra. These data are the first to directly demonstrate a seasonal effect on striatal presynaptic dopamine synthesis and merit future research aimed at elucidating underlying mechanisms and implications for neuropsychiatric disease and new treatment approaches.


A survey of expert opinion on the effects of occupational exposures to trunk rotation and whole-body vibration.
We present a review of current expert opinion on the effects of combined exposures to trunk rotation and whole-body vibration (WBV), commonly experienced by operators of agricultural machinery. We evaluate the level of agreement between academic experts in the field of ergonomics, human response to WBV and agricultural operators, on the effects of exposure to WBV and trunk rotation. A total of 83 individuals responded to the paper-based questionnaire, which included questions on risk levels from individual and combined exposures, discomfort development, exposure duration limits and tasks within agriculture. The results showed that all groups considered exposure to WBV and trunk rotation as risk factors for the development of back pain. The experts were not in consensus regarding acceptable exposure durations, areas of discomfort experienced or recommendations for cab developments.