Organophosphate Triesters and Diester Degradation Products in Municipal Sludge from Wastewater Treatment Plants in China: Spatial Patterns and Ecological Implications.
Little is known about the occurrences, distributions, sources, and potential risks of organophosphate (OP) triesters and diester degradation products in municipal sludge from wastewater treatment plants (WWTPs). In this study, we conducted the first nationwide survey to simultaneously determine a suite of 11 OP triesters and six diester degradation products in sludge from WWTPs across China. All OP triesters were detected and three diesters were identified for the first time in sludge samples. Total concentrations of OP triesters and diester degradation products were in the ranges of 43.9-2160 and 17.0-1300 ng (g of dry weight)-1, respectively, indicating relatively low pollution levels in China compared with those of several developed countries. A distinct geographical variation of higher concentrations of OP triesters and diesters in East China than in Central and West China was observed, suggesting that regional levels of organophosphate esters are associated with the magnitudes of regional economic development. Source analysis revealed nonchlorinated OP diesters are mainly derived from degradation in WWTPs, while chlorinated OP diesters were largely sourced from outside WWTPs. The estimated total emission fluxes of OP triesters and diesters via land-application sludge in China were approximately 330 and 134 kg/year, respectively. Further risk assessment based on risk quotient values in sludge-applied soils indicated low to medium risks for most OP triesters and diesters except tris(methylphenyl) phosphate. The significant accumulation of OP triesters and widespread occurrence of diester degradation products in sludge raise environmental concerns about these contaminants.


Single-cell RNA counting at allele and isoform resolution using Smart-seq3.
Large-scale sequencing of RNA from individual cells can reveal patterns of gene, isoform and allelic expression across cell types and states1. However, current short-read single-cell RNA-sequencing methods have limited ability to count RNAs at allele and isoform resolution, and long-read sequencing techniques lack the depth required for large-scale applications across cells2,3. Here we introduce Smart-seq3, which combines full-length transcriptome coverage with a 5' unique molecular identifier RNA counting strategy that enables in silico reconstruction of thousands of RNA molecules per cell. Of the counted and reconstructed molecules, 60% could be directly assigned to allelic origin and 30-50% to specific isoforms, and we identified substantial differences in isoform usage in different mouse strains and human cell types. Smart-seq3 greatly increased sensitivity compared to Smart-seq2, typically detecting thousands more transcripts per cell. We expect that Smart-seq3 will enable large-scale characterization of cell types and states across tissues and organisms.


#WhyWeTweetMH: Understanding Why People Use Twitter to Discuss Mental Health Problems.
Use of the social media website Twitter is highly prevalent and has led to a plethora of Web-based social and health-related data available for use by researchers. As such, researchers are increasingly using data from social media to retrieve and analyze mental health-related content. However, there is limited evidence regarding why people use this emerging platform to discuss mental health problems in the first place. The aim of this study was to explore the reasons why individuals discuss mental health on the social media website Twitter. The study was the first of its kind to implement a study-specific hashtag for research; therefore, we also examined how feasible it was to circulate and analyze a study-specific hashtag for mental health research. Text mining methods using the Twitter Streaming Application Programming Interface (API) and Twitter Search API were used to collect and organize tweets from the hashtag #WhyWeTweetMH, circulated between September 2015 and November 2015. Tweets were analyzed thematically to understand the key reasons for discussing mental health using the Twitter platform. Four overarching themes were derived from the 132 tweets collected: (1) sense of community; (2) raising awareness and combatting stigma; (3) safe space for expression; and (4) coping and empowerment. In addition, 11 associated subthemes were also identified. The themes derived from the content of the tweets highlight the perceived therapeutic benefits of Twitter through the provision of support and information and the potential for self-management strategies. The ability to use Twitter to combat stigma and raise awareness of mental health problems indicates the societal benefits that can be facilitated via the platform. The number of tweets and themes identified demonstrates the feasibility of implementing study-specific hashtags to explore research questions in the field of mental health and can be used as a basis for other health-related research.


Antimicrobial activity of Uncaria tomentosa against oral human pathogens.
Uncaria tomentosa is considered a medicinal plant used over centuries by the peruvian population as an alternative treatment for several diseases. Many microorganisms usually inhabit the human oral cavity and under certain conditions can become etiologic agents of diseases. The aim of the present study was to evaluate the antimicrobial activity of different concentrations of Uncaria tomentosa on different strains of microorganisms isolated from the human oral cavity. Micropulverized Uncaria tomentosa was tested in vitro to determine the minimum inhibitory concentration (MIC) on selected microbial strains. The tested strains were oral clinical isolates of Streptococcus mutans, Staphylococcus spp., Candida albicans, Enterobacteriaceae and Pseudomonas aeruginosa. The tested concentrations of Uncaria tomentosa ranged from 0.25-5% in Müeller-Hinton agar. Three percent Uncaria tomentosa inhibited 8% of Enterobacteriaceae isolates, 52% of S. mutans and 96% of Staphylococcus spp. The tested concentrations did not present inhibitory effect on P. aeruginosa and C. albicans. It could be concluded that micropulverized Uncaria tomentosa presented antimicrobial activity on Enterobacteriaceae, S. mutans and Staphylococcus spp. isolates.


Randomized dose-ranging trial of tamoxifen at low doses in hormone replacement therapy users.
The combination of hormone replacement therapy (HRT) and low-dose tamoxifen may retain the benefits while reducing the risks of either agent. We assessed the optimal biologic dose and schedule of tamoxifen in HRT users using surrogate end point biomarkers and menopausal symptoms. Two hundred ten current or de novo HRT users were randomly assigned to one of the following four arms: tamoxifen 1 mg/day and placebo/week, placebo/day and tamoxifen 10 mg/week, tamoxifen 5 mg/day and placebo/week, or both placebos for 12 months. The primary end point was the change of plasma insulinlike growth factor 1 (IGF-I) through 12 months, and secondary end points were IGF-I/IGF binding protein-3 (IGFBP-3) ratio, fibrinogen, antithrombin III, C reactive protein, C-telopeptide, mammographic percent density, and endometrial thickness. Endometrial proliferation was assessed by Pipelle biopsy in superficial, deep glandular, and stromal compartments after 12 months. Compared with placebo, IGF-I declined in all tamoxifen arms (P = .005), with a greater change on 5 mg/day (P = .019 v 10 mg/week or 1 mg/day). Tamoxifen increased IGFBP-3 and lowered antithrombin-III, C reactive protein, and mammographic density, with greater effects of 5 mg/day. Tamoxifen increased endometrial thickness but not Ki-67 expression, which was lower on 5 mg/day among the three doses. Menopausal symptoms were not significantly worsened by tamoxifen. Doses of tamoxifen < or = 5 mg/day modulate favorably biomarkers of breast carcinogenesis and cardiovascular risk in HRT users with no increase of endometrial proliferation and menopausal symptoms. A dose of 5 mg/day was the most effective and has been selected for a phase III trial in HRT users.


Approach to biomarker testing: perspectives from various specialties.
Despite its importance for patient outcomes, biomarker testing for lung cancer is not uniformly integrated into the Canadian health care system. To better understand current practice patterns for lung cancer biomarker testing, we assessed physician perspectives by specialty and region. A national survey of Canadian lung cancer specialists was conducted to understand their perspectives on biomarker testing in lung cancer. The 11-item survey assessed the current practice and challenges of testing. The survey was sent to 375 specialists. The overall response rate for the survey was 36%. Nearly all specialists reported that knowing tumour genotyping results affects patient outcome and influences the treatment decision. Medical oncologists most commonly initiated molecular testing; however, most respondents suggested a shared model involving medical oncologists and pathologists. More than half of all responding specialists had the perception that fewer than 25% of test results are available for first-line treatment decisions. Identified barriers to routine testing for all lung cancer patients included cost, lack of funding, tissue availability, and sample quality. There was clear agreement that biomarker testing is important in determining appropriate treatment for patients. There is a need for general consensus on who should initiate molecular testing. Clear clinical guidance for pathologists has to be established for molecular testing, including defining the population to be tested, the timing of testing, and the tests to be performed. Testing could be facilitated by including more information on diagnostic sample requisitions, such as clinical suspicion of primary lung cancer, cancer history, and other samples already collected.


Intrinsic Functional Connectivity of the Brain in Adults with a Single Cerebral Hemisphere.
A reliable set of functional brain networks is found in healthy people and thought to underlie our cognition, emotion, and behavior. Here, we investigated these networks by quantifying intrinsic functional connectivity in six individuals who had undergone surgical removal of one hemisphere. Hemispherectomy subjects and healthy controls were scanned with identical parameters on the same scanner and compared to a large normative sample (n = 1,482). Surprisingly, hemispherectomy subjects and controls all showed strong and equivalent intrahemispheric connectivity between brain regions typically assigned to the same functional network. Connectivity between parts of different networks, however, was markedly increased for almost all hemispherectomy participants and across all networks. These results support the hypothesis of a shared set of functional networks that underlie cognition and suggest that between-network interactions may characterize functional reorganization in hemispherectomy.


Bacterial surface appendages as targets for novel antibacterial therapeutics.
The rise of multidrug resistant bacteria is a major worldwide health concern. There is currently an unmet need for the development of new and selective antibacterial drugs. Therapies that target and disarm the crucial virulence factors of pathogenic bacteria, while not actually killing the cells themselves, could prove to be vital for the treatment of numerous diseases. This article discusses the main surface architectures of pathogenic Gram-negative bacteria and the small molecules that have been discovered, which target their specific biogenesis pathways and/or actively block their virulence. The future perspective for the use of antivirulence compounds is also assessed.


Transparent ferroelectric crystals with ultrahigh piezoelectricity.
Transparent piezoelectrics are highly desirable for numerous hybrid ultrasound-optical devices ranging from photoacoustic imaging transducers to transparent actuators for haptic applications1-7. However, it is challenging to achieve high piezoelectricity and perfect transparency simultaneously because most high-performance piezoelectrics are ferroelectrics that contain high-density light-scattering domain walls. Here, through a combination of phase-field simulations and experiments, we demonstrate a relatively simple method of using an alternating-current electric field to engineer the domain structures of originally opaque rhombohedral Pb(Mg1/3Nb2/3)O3-PbTiO3 (PMN-PT) crystals to simultaneously generate near-perfect transparency, an ultrahigh piezoelectric coefficient d33 (greater than 2,100 picocoulombs per newton), an excellent electromechanical coupling factor k33 (about 94 per cent) and a large electro-optical coefficient γ33 (approximately 220 picometres per volt), which is far beyond the performance of the commonly used transparent ferroelectric crystal LiNbO3. We find that increasing the domain size leads to a higher d33 value for the [001]-oriented rhombohedral PMN-PT crystals, challenging the conventional wisdom that decreasing the domain size always results in higher piezoelectricity8-10. This work presents a paradigm for achieving high transparency and piezoelectricity by ferroelectric domain engineering, and we expect the transparent ferroelectric crystals reported here to provide a route to a wide range of hybrid device applications, such as medical imaging, self-energy-harvesting touch screens and invisible robotic devices.


Lack of association between CD226 genetic variants and inflammatory demyelinating diseases in Korean population.
This study was conducted to find the possible association between CD226 polymorphisms and inflammatory demyelinating diseases in Korean population. A total of 14 CD226 SNPs were selected based on their linkage disequilibrium, minor allele frequency, and location. Then, the SNPs were genotyped in 178 IDD patients and 237 healthy controls. Subsequently, we conducted logistic analysis to find possible associations Statistical analyses revealed only a marginal signal for a common SNP rs1788229 with inflammatory demyelinating disease (p=0.05), while other SNPs failed to show associations with any diseases. However, the significance of rs1788229 disappeared after a multiple testing correction of the data (p>0.05). Interestingly, rs763361, which showed significant associations with multiple sclerosis in several previous studies, did not show any association at all. While prior studies have found CD226 polymorphisms to be significantly associated with inflammatory demyelinating diseases, our results indicate the CD226 polymorphisms to be not associated with the diseases in Korean population. However, our results suggest that the causal genes for inflammatory demyelinating diseases may vary depending on the population.


Bisphosphonate induced osteonecrosis of the jaw masquerading as tumor: a word of caution for oral surgeons and oncologists.
To highlight the misdiagnosis or delay in the detection of Bisphosphonate induced necrosis of Jaw (BINJ). It is associated with prolonged administration of intravenous bisphosphonates that are routinely used in the management of osteoporosis, Paget's disease, Multiple Myeloma, bone metastases. It improves quality of life, delays the skeletal complication, decreases the pain and hypercalcemia. We prospectively collected data of those patients who were receiving bisphosphonates for management of their primary illness and developed BINJ. This pathology being a new entity most oncologists are still ignorant about its existence. Use of intravenous bisphosphanates can lead to BINJ which may mimic malignancy or metastasis. None of our patients were counseled, oncologists did not perform routine oral examinations, dentists went ahead with unwarranted interventions, radiologist raised false alarm and oral surgeons undertook unnecessary biopsies. Misled by clinical presentation and radiological appearance, all patients were initially misdiagnosed and underwent unwarranted interventions. A careful dental clinical examination and appropriate imaging study is recommended before starting bisphosphonate therapy. The doctors prescribing Bisphosphonates especially intravenous preparations should not only counsel the patients but also routinely examine patient's oral cavity.


Reducibility of ZrO2/Pt3Zr and ZrO2/Pt 2D films compared to bulk zirconia: a DFT+U study of oxygen removal and H2 adsorption.
Oxide reducibility is an important property that determines the chemical and physical behavior of the materials under working conditions. Zirconia is a non-reducible oxide that exhibits high resistance to the loss of oxygen and low reactivity towards hydrogen, two typical processes involved in oxide reduction. Oxide reducibility can change substantially by nanostructuring (e.g. formation of nanoparticles). In this study, we investigate theoretically by means of DFT+U calculations including dispersion interactions the properties of 2D zirconia films supported on a Pt3Zr alloy and Pt metal surfaces, two systems recently prepared experimentally. The results show that the supported ZrO2 ultrathin films behave very differently from the corresponding bulk oxide, with a low formation energy of oxygen vacancies, and a clear tendency to split the H2 molecule homolytically with direct reduction of the oxide. The comparison of free-standing and supported ZrO2 films shows that these peculiar properties are not due to the formation of a 2D nanostructure, but rather to the presence of the metal support and of a metal/oxide interface. The results provide evidence for the uncommon properties of supported 2D oxides.


Mapping of a blood pressure QTL on chromosome 17 in American Indians of the strong heart family study.
Blood pressure (BP) is a complex trait, with a heritability of 30 to 40%. Several genome wide associated BP loci explain only a small fraction of the phenotypic variation. Family studies can provide an important tool for gene discovery by utilizing trait and genetic transmission information among relative-pairs. We have previously described a quantitative trait locus at chromosome 17q25.3 influencing systolic BP in American Indians of the Strong Heart Family Study (SHFS). This locus has been reported to associate with variation in BP traits in family studies of Europeans, African Americans and Hispanics. To follow-up persuasive linkage findings at this locus, we performed comprehensive genotyping in the 1-LOD unit support interval region surrounding this QTL using a multi-step strategy. We first genotyped 1,334 single nucleotide polymorphisms (SNPs) in 928 individuals from families that showed evidence of linkage for BP. We then genotyped a second panel of 306 SNPs in all SHFS participants (N = 3,807) for genes that displayed the strongest evidence of association in the region, and, in a third step, included additional genotyping to better cover the genes of interest and to interrogate plausible candidate genes in the region. Three genes had multiple SNPs marginally associated with systolic BP (TBC1D16, HRNBP3 and AZI1). In BQTN analysis, used to estimate the posterior probability that any variant in each gene had an effect on the phenotype, AZI1 showed the most prominent findings (posterior probability of 0.66). Importantly, upon correction for multiple testing, none of our study findings could be distinguished from chance. Our findings demonstrate the difficulty of follow-up studies of linkage studies for complex traits, particularly in the context of low powered studies and rare variants underlying linkage peaks.


Molecular epidemiology of A/H3N2 and A/H1N1 influenza virus during a single epidemic season in the United States.
To determine the spatial and temporal dynamics of influenza A virus during a single epidemic, we examined whole-genome sequences of 284 A/H1N1 and 69 A/H3N2 viruses collected across the continental United States during the 2006-2007 influenza season, representing the largest study of its kind undertaken to date. A phylogenetic analysis revealed that multiple clades of both A/H1N1 and A/H3N2 entered and co-circulated in the United States during this season, even in localities that are distant from major metropolitan areas, and with no clear pattern of spatial spread. In addition, co-circulating clades of the same subtype exchanged genome segments through reassortment, producing both a minor clade of A/H3N2 viruses that appears to have re-acquired sensitivity to the adamantane class of antiviral drugs, as well as a likely antigenically distinct A/H1N1 clade that became globally dominant following this season. Overall, the co-circulation of multiple viral clades during the 2006-2007 epidemic season revealed patterns of spatial spread that are far more complex than observed previously, and suggests a major role for both migration and reassortment in shaping the epidemiological dynamics of human influenza A virus.


Repair of post-infarction left ventricular free wall rupture using an extracellular matrix patch.
Several techniques for surgical treatment of acute or subacute left ventricular free wall rupture (LVFWR) have been described using a sutured or sutureless patch with different currently available materials. We present a case report of a 50-year-old male with acute LVFWR, who was treated with a simple surgical technique using an 'off-pump' epicardially sutured LV patch consisting of an acellular xenogeneic extracellular matrix (ECM). ECM patches are structurally more surgeon-friendly and have shown to be bioactive, and capable of activating remodelling and even tissue regeneration. Compared with conventional pericardial patches, the advantage of this material is excellent pliability and very easy stitching owing to the thin composition of the material. In addition, and most importantly, in case of complex structural reconstructions, the patch is highly tear-proof.


Mental Health Issues and Psychological Factors in Athletes: Detection, Management, Effect on Performance, and Prevention: American Medical Society for Sports Medicine Position Statement.
The American Medical Society for Sports Medicine convened a panel of experts to provide an evidence-based, best practices document to assist sports medicine physicians and other members of the athletic care network with the detection, treatment, and prevention of mental health issues in competitive athletes. This statement discusses how members of the sports medicine team, including team physicians, athletic trainers, and mental health providers, work together in providing comprehensive psychological care to athletes. It specifically addresses psychological factors in athletes including personality issues and the psychological response to injury and illness. The statement also examines the athletic culture and environmental factors that commonly impact mental health, including sexuality and gender issues, hazing, bullying, sexual misconduct, and transition from sport. Specific mental health disorders in athletes, such as eating disorders/disordered eating, depression and suicide, anxiety and stress, overtraining, sleep disorders, and attention-deficit/hyperactivity disorder, are reviewed with a focus on detection, management, the effect on performance, and prevention. This document uses the Strength of Recommendation Taxonomy (SORT) to grade level of evidence.


[Usefulness of comorbidity indices in operative gastric cancer cases].
The purpose of the current study was to evaluate the usefulness of the following four comorbidity indices in gastric cancer patients who underwent surgery: Charlson Comorbidity Index (CCI), Cumulative Illness rating scale (CIRS), Index of Co-existent Disease (ICED), and Kaplan-Feinstein Scale (KFS). The study subjects were 614 adults who underwent surgery for gastric cancer at K hospital between 2005 and 2007. We examined the test-retest and inter-rater reliability of 4 comorbidity indices for 50 patients. Reliability was evaluated with Spearman rho coefficients for CCI and CIRS, while Kappa values were used for the ICED and KFS indices. Logistic regression was used to determine how these comorbidity indices affected unplanned readmission and death. Multiple regression was used for determining if the comorbidity indices affected length of stay and hospital costs. The test-retest reliability of CCI and CIRS was substantial (Spearman rho=0.746 and 0.775, respectively), while for ICED and KFS was moderate (Kappa=0.476 and 0.504, respectively). The inter-rater reliability of the CCI, CIRS, and ICED was moderate (Spearman rho=0.580 and 0.668, and Kappa=0.433, respectively), but for KFS was fair (Kappa=0.383). According to the results from logistic regression, unplanned readmissions and deaths were not significantly different between the comorbidity index scores. But, according to the results from multiple linear regression, the CIRS group showed a significantly increased length of hospital stay (p<0.01). Additionally, CCI showed a significant association with increased hospital costs (p<0.01). This study suggests that the CCI index may be useful in the estimation of comorbidities associated with hospital costs, while the CIRS index may be useful where estimatation of comorbiditie associated with the length of hospital stay are concerned.


Effect of body mass index on mortality and clinical status in rheumatoid arthritis.
To study the relative risk (RR) of all-cause and cause-specific mortality in rheumatoid arthritis (RA) associated with body mass index (BMI), and to quantify the clinical and outcome consequences of abnormal BMI. We studied mortality in 24,535 patients over 12.3 years, dividing patients into 3 age groups, <50, 50-70, and >70 years and fit Cox regression models separately within each age stratum. We used BMI categories of <18.5 kg/m(2) (underweight), 18.5 to <25 kg/m(2) (normal weight, reference category), 25 to <30 kg/m(2) (overweight), and ≥30 kg/m(2) (obesity). BMI ≥30 kg/m(2) was seen in 63-68% and underweight in ~2%. Reduction in the RR (95% confidence interval [95% CI]) for all-cause (AC) and cardiovascular mortality was seen for overweight (AC 0.8 [95% CI 0.8, 0.9]) and obese groups (AC 0.8 [95% CI 0.7, 0.8]), with and without comorbidity adjustment. Underweight was associated with increased mortality risk (AC 1.9 [95% CI 1.7, 2.3]). By contrast, obesity produced profound changes in clinical variables. Compared with normal weight, the odds ratio in the obese group was 4.8 for diabetes mellitus, 3.4 for hypertension, 1.3 for myocardial infarction, 1.4 for joint replacement, and 1.9 for work disability. Total semiannual direct medical costs were $1,683 greater, annual household income $6,481 less, pain scores 1.1 units higher, Health Assessment Questionnaire 0.28 higher, and EuroQol utility 0.7 units lower in the obese. Overweight and obesity reduce the RR of all-cause and cardiovascular mortality across different age groups and durations of RA. By contrast, overweight and obesity are associated with substantial increased risks of comorbidity, total joint replacement, greater pain, medical costs, and decreased quality of life.


Interaction of the Doa4 deubiquitinating enzyme with the yeast 26S proteasome.
e Saccharomyces cerevisiae Doa4 deubiquitinating enzyme is required for the rapid degradation of protein substrates of the ubiquitin-proteasome pathway. Previous work suggested that Doa4 functions late in the pathway, possibly by deubiquitinating (poly)-ubiquitin-substrate intermediates associated with the 26S proteasome. We now provide evidence for physical and functional interaction between Doa4 and the proteasome. Genetic interaction is indicated by the mutual enhancement of defects associated with a deletion of DOA4 or a proteasome mutation when the two mutations are combined. Physical association of Doa4 and the proteasome was investigated with a new yeast 26S proteasome purification procedure, by which we find that a sizeable fraction of Doa4 copurifies with the protease. Another yeast deubiquitinating enzyme, Ubp5, which is related in sequence to Doa4 but cannot substitute for it even when overproduced, does not associate with the proteasome. DOA4-UBP5 chimeras were made by a novel PCR/yeast recombination method and used to identify an N-terminal 310-residue domain of Doa4 that, when appended to the catalytic domain of Ubp5, conferred Doa4 function, consistent with Ubp enzymes having a modular architecture. Unlike Ubp5, a functional Doa4-Ubp5 chimera associates with the proteasome, suggesting that proteasome binding is important for Doa4 function. Together, these data support a model in which Doa4 promotes proteolysis through removal of ubiquitin from proteolytic intermediates on the proteasome before or after initiation of substrate breakdown.


[Clinical characteristics of patients with renovascular hypertension].
The aim of our study was to show the value of comparing clinical parameters in patients with renovascular hypertension (RVH) and essential hypertension (EH). We examined the differences between renovascular hypertension patients with atherosclerosis (ATH) and those with fibromuscular dysplasia (FMD). The diagnosis of renovascular hypertension was established on the basis of renal angiography finding, which also defined the type of stenosis (ATH or FMD). Our patient group included 108 patients with atherosclerotic RVH (46 male / 62 female, median age 53 yrs), 16 patients with FMD (3 male / 13 female, median age 49 yrs), and 106 patients with EH (61 male / 45 female, median age 38 yrs). In comparison with patients with EH, patients with atherosclerotic RVH were found to be more frequently of female gender with lower body weight and height, older, and more frequently on therapy with antihypertensives. Their hypertension was of later onset and more severe stage. All those differences were statistically significant (P < 0.05). When analysis by genders was performed, women were more frequently smokers and had higher serum cholesterol levels, which is an explanation for higher proportion of female gender in atherosclerotic RVH patients. In patients with fibromuscular dysplasia a higher proportion of female gender was also present, but in comparison with ATH patients their hypertension was more often of a less than 5 years duration and they had lower serum creatinine and triglyceride levels. Our results are in agreement with the results of other authors who showed clinical parameters to be useful in screening of patients for further diagnostic procedure. This stresses the importance of good history, physical examination and well-chosen laboratory tests. They can't clearly establish or exclude the diagnosis of renovascular hypertension, but this approach could more easily point out those hypertensive patients who require a thorough work-up. Clinical parameters could furthermore help in determining the type of treatment of RVH.


Smoking cessation is associated with lower disease activity and predicts cardiovascular risk reduction in rheumatoid arthritis patients.
Smoking is a major risk factor for the development of both cardiovascular disease (CVD) and RA and may cause attenuated responses to anti-rheumatic treatments. Our aim was to compare disease activity, CVD risk factors and CVD event rates across smoking status in RA patients. Disease characteristics, CVD risk factors and relevant medications were recorded in RA patients without prior CVD from 10 countries (Norway, UK, Netherlands, USA, Sweden, Greece, South Africa, Spain, Canada and Mexico). Information on CVD events was collected. Adjusted analysis of variance, logistic regression and Cox models were applied to compare RA disease activity (DAS28), CVD risk factors and event rates across categories of smoking status. Of the 3311 RA patients (1012 former, 887 current and 1412 never smokers), 235 experienced CVD events during a median follow-up of 3.5 years (interquartile range 2.5-6.1). At enrolment, current smokers were more likely to have moderate or high disease activity compared with former and never smokers (P < 0.001 for both). There was a gradient of worsening CVD risk factor profiles (lipoproteins and blood pressure) from never to former to current smokers. Furthermore, former and never smokers had significantly lower CVD event rates compared with current smokers [hazard ratio 0.70 (95% CI 0.51, 0.95), P = 0.02 and 0.48 (0.34, 0.69), P < 0.001, respectively]. The CVD event rates for former and never smokers were comparable. Smoking cessation in patients with RA was associated with lower disease activity and improved lipid profiles and was a predictor of reduced rates of CVD events.


Peripheral Solitary Osteoma of the Zygomatic Arch: A Case Report and Literature Review.
Osteoma is a benign slow-growing osteogenic neoplasm commonly occurring in the craniofacial skeleton, characterized by the proliferation of compact and/or cancellous bone. Osteomas may be peripheral, central, or extraskeletal. Peripheral osteomas arise from the periosteum and are quite uncommon in the jaw bones. The exact aetiology and pathogenesis of peripheral osteoma are unknown. Clinically, peripheral osteomas are usually asymptomatic, but depending on the location and size of the lesion, it may cause swelling, pain, esthetic disfigurement and functional impairment. On radiological imaging, a peripheral osteoma appears often as well-circumscribed, round to oval, pedunculated radiopaque mass attached to the cortex by a broad base or a pedicle. Asymptomatic osteomas are treated conservatively, while surgical excision is indicated when the lesion is symptomatic, actively growing, or for cosmetic reasons. Histologically, osteomas are composed of a normal-appearing, dense mass of lamellar bone. Recurrence of peripheral osteoma after surgical removal is extremely rare and there are no reports of malignant transformation. A review of the literature disclosed only 7 well-documented cases of peripheral osteoma located at the zygomatic bone. The purpose of this article is to present the clinical, radiographic, surgical and histological features of a solitary peripheral osteoma of the left zygomatic arch in a 55-year-old woman and to review the literature about this uncommon pathologic entity.


Effects of Streptococcus mutans on dendritic cell activation and function.
Despite existing preventive and therapeutic measures, caries remains a ubiquitous infectious disease. Vaccine studies suggest that an adaptive immune response, culminating in effective antibody production, may reduce an individual's susceptibility to caries. However, the efficacy of the immune response elicited by mutans streptococci in the oral cavity remains controversial. A greater understanding of the early stages of the adaptive immune response to cariogenic bacteria may potentially assist therapeutic targeting and design. We therefore sought to characterize dendritic cell (DC) activation and antigen presentation following Streptococcus mutans exposure. We found that S. mutans up-regulated DC expression of co-stimulatory molecules and MHCII in vitro and that DCs effectively processed and presented exogenously administered antigen. These DCs effectively initiated T-cell proliferation, but this was abrogated by live bacteria. The in vitro DC activation effects were not mirrored in vivo, where DCs in draining lymph nodes did not mature following oral exposure to S. mutans. Analysis of these data provides a model for studying antigen uptake from the oral cavity and evidence that, in vitro, S. mutans activates dendritic cells, a critical event for initiating adaptive immunity.


Inhibition of Hypoxylon pruinatum by pyrocatechol isolated from bark of aspen.
Pyrocatechol has been identified as one of two main substances isolated from bark of aspen (Populus tremuloides Michx.) which inhibited Hypoxylon pruinatum (Klot.) Cke. Total inhibition of this fungus was obtained at a dosage of 640 parts per million. Tests with bark extract from two localities showed that inhibition was maximal in samples obtained in the dormant season and from the base of the trees.


Impact of General Practitioner Education on Acceptance of an Adjuvanted Seasonal Influenza Vaccine among Older Adults in England.
Seasonal vaccination against influenza and in-pandemic COVID-19 vaccination are top public health priorities; vaccines are the primary means of reducing infections and also controlling pressures on health systems. During the 2018-2019 influenza season, we conducted a study of the knowledge, attitudes, and behaviours of 159 general practitioners (GPs) and 189 patients aged ≥65 years in England using a combination of qualitative and quantitative approaches to document beliefs about seasonal influenza and seasonal influenza vaccine. GPs were surveyed before and after a continuing medical education (CME) module on influenza disease and vaccination with an adjuvanted trivalent influenza vaccine (aTIV) designed for patients aged ≥65 years, and patients were surveyed before and after a routine visit with a GP who participated in the CME portion of the study. The CME course was associated with significantly increased GP confidence in their ability to address patients' questions and concerns about influenza disease and vaccination (p < 0.001). Patients reported significantly increased confidence in the effectiveness and safety of aTIV after meeting their GP. Overall, 82.2% of the study population were vaccinated against influenza (including 137 patients vaccinated during the GP visit and 15 patients who had been previously vaccinated), a rate higher than the English national average vaccine uptake of 72.0% that season. These findings support the value of GP-patient interactions to foster vaccine acceptance.


High basal cell surface levels of fish GLUT4 are related to reduced sensitivity of insulin-induced translocation toward GGA and AS160 inhibition in adipocytes.
Glucose entry into cells is mediated by a family of facilitative transporter proteins (GLUTs). In mammals, GLUT4 is expressed in insulin-sensitive tissues and is responsible for the postprandial uptake of glucose. In fish, GLUT4 also mediates insulin-regulated glucose entry into cells but differs from mammalian GLUT4 in its affinity for glucose and in protein motifs known to be important for the traffic of GLUT4. In this study, we have characterized the intracellular and plasma membrane (PM) traffic of two orthologs of GLUT4 in fish, trout (btGLUT4) and salmon (okGLUT4), that do not share the amino terminal FQQI targeting motif of mammalian GLUT4. btGLUT4 (FQHL) and, to a lesser extent, okGLUT4 (FQQL) showed higher basal PM levels, faster traffic to the PM after biosynthesis, and earlier acquisition of insulin responsiveness than rat GLUT4. Furthermore, btGLUT4 showed a similar profile of internalization than rat GLUT4. Expression of the dominant-interfering AS160-4P mutant caused a significant decrease in the insulin-induced PM levels of okGLUT4 and rat GLUT4 and, to a lesser extent, of btGLUT4, suggesting that btGLUT4 has reduced retention into the IRC. Contrary to rat GLUT4 and okGLUT4, the presence of btGLUT4 at the PM under insulin-stimulated conditions was not affected by coexpression of a dominant-interfering GGA mutant. These data suggest that fish GLUT4 follow a different trafficking pathway to the PM compared with rat GLUT4 that seems to be relatively independent of GGA. These results indicate that the regulated trafficking characteristics of GLUT4 have been modified during evolution from fish to mammals.


The value of musculoskeletal ultrasound in geriatric care and rehabilitation.
The WHO reports that one of the major chronic conditions affecting the elderly worldwide is musculoskeletal disorders that are associated with long-term pain and disability. Considering the healthcare needs of the elderly (i.e. comprehensive, accessible, efficient) and the advantages of ultrasound (US) use (patient-friendly, convenient, cost-effective, and does not require exposure to radiation or magnetic fields), there seems to be a 'gap' in the actual clinical practice. In this paper, we aimed to highlight the potential value of US imaging in the management of the elderly with a wide spectrum of musculoskeletal conditions (degenerative/rheumatic joint diseases, falls/trauma, nursing care, peripheral nerve problems, sarcopenia, and interventions). In this respect, electronic databases (ISI Web of Science, PubMed, Elsevier Science Direct) and reference lists of relevant articles/reviews were screened by two blinded investigators for each topic. The main medical subject heading terms selected to capture the most relevant papers on the topics in accordance with the literature were knee/hip/hand osteoarthritis, prevalence, rotator cuff injury, lateral epicondylitis, tendinopathy, rheumatoid arthritis, Sjogren's syndrome, polymyalgia rheumatica, crystal arthropathies, gout, pseudogout, carpal tunnel syndrome, fall, fractures, hematoma, pressure ulcer, ultrasonography, interventional, sarcopenia, body composition, rehabilitation, frail elderly, and aged. The search was limited to peer-reviewed full-text English journals starting from the earliest papers to May 2017. A study population (or part of the study population) of adults older than 65 years (if possible) was included. We especially underscore the use of US by clinicians as an extension of their physical examination or as a practical guide for an immediate intervention.


Perioperative neurologic complications during spinal fusion surgery: incidence and trends.
Perioperative neurologic complications after spine surgery may increase morbidity and health-care costs related to the procedure. We estimate the national incidence of perioperative neurologic complications following anterior cervical discectomy and fusion (ACDF), posterior cervical fusion, and thoracolumbar fusion procedures using the Nationwide Inpatient Sample (NIS) data from 1999 to 2011. Additionally, we identify risk factors for developing perioperative neurologic complications and the effects of these injuries on quantifiable patient outcomes. A cross-sectional study was carried out. All patients included in the NIS databases from 1999 to 2011 comprised the sample. The primary outcome evaluated was the incidence of new neurologic deficits following elective spine surgery. Secondary outcomes evaluated include length of hospital stay, total hospital charges, hospital mortality rate, and discharge disposition. A retrospective analysis of the NIS databases from the years 1999 to 2011 was conducted to identify the proportion of patients who underwent ACDFs, posterior cervical fusions, and thoracolumbar fusions who also developed perioperative neurologic complications. Statistical analyses were also conducted to identify statistically significant differences in demographics and outcomes between patients who did and did not develop perioperative neurologic complications. From 1999 to 2011, the total national incidence of perioperative neurologic deficits following elective ACDFs, posterior cervical fusions, and thoracolumbar fusions was 0.82%, which equates to a total of 15,066 patients who experienced these complications. The annual incidence rate of perioperative neurologic deficits has increased 54.41%, from 0.68% in the year 1999 to 1.05% in the year 2011. Additionally, the total number of procedures performed increased from 82,167 in 1999 to 186,353 in the year 2011. Perioperative neurologic deficits were associated with longer lengths of stay (9.68 days vs. 2.59 days; p<.001), higher total charges ($110,326.23 vs. $48,695.93; p<.001), and higher in-hospital mortality (2.84% vs. 0.13%; p<.001). The incidence rate of perioperative neurologic deficits associated with elective spine surgery documented in the NIS has increased over the time period from 1999 to 2011. The number of elective spine procedures performed has also increased over the same time period. Finally, outcomes data indicate that occurrence of perioperative neurologic complications is associated with increased rates of morbidity and mortality, as well as increased health-care use and cost. These trends indicate that the perioperative neurologic complications following spine surgery represent a growing problem in today's health-care system; further study is warranted to prevent and treat these complications to improve patient care and reduce health-care use and cost.


Human insulin B24 (Phe----Ser). Secretion and metabolic clearance of the abnormal insulin in man and in a dog model.
We have already demonstrated that a hyperinsulinemic, diabetic subject secreted an abnormal insulin in which serine replaced phenylalanine B24 (Shoelson S., M. Fickova, M. Haneda, A. Nahum, G. Musso, E. T. Kaiser, A. H. Rubenstein, and H. Tager. 1983. Proc. Natl. Acad. Sci. USA. 80:7390-7394). High performance liquid chromatography analysis now shows that the circulating insulin in several other family members also consists of a mixture of the abnormal human insulin B24 (Phe----Ser) and normal human insulin in a ratio of approximately 9.5:1 during fasting. Although all affected subjects show fasting hyperinsulinemia, only the propositus and her father are overtly diabetic. Analysis of the serum insulin from two nondiabetic siblings revealed that normal insulin increased from approximately 2 to 15% of total serum insulin after the ingestion of glucose and that the proportion of the normal hormone plateaued or fell while the level of total insulin continued to rise. Animal studies involving the graded intraportal infusion of equimolar amounts of semisynthetic human [SerB24]-insulin and normal human insulin in pancreatectomized dogs (to simulate the secretion of insulin due to oral glucose in man) also showed both a rise in the fraction of normal insulin that reached the periphery and the attainment of a brief steady state in this fraction while total insulin levels continued to rise. Separate experiments documented a decreased hepatic extraction, a decreased metabolic clearance rate, and an increased plasma half-life of human [SerB24]-insulin within the same parameters as those determined for normal human insulin. These results form a basis for considering (a) the differential clearance of low activity abnormal insulins and normal insulin from the circulation in vivo, and (b) the causes of hyperinsulinemia in both diabetic and nondiabetic individuals who secrete abnormal human insulins.


Fixation of deleterious mutations in clonal lineages: evidence from hybridogenetic frogs.
The hemiclonal waterfrog Rana esculenta (RL genotype), a bisexual hybrid between R. ridibunda (RR) and R. lessonae (LL), eliminates the L genome from its germline and clonally transmits the R genome (hybridogenesis). Matings between hybrids produce R. ridibunda offspring, but they generally die at an early larval stage. Mortality may be due to fixed recessive deleterious mutations in the clonally inherited R genomes that were either acquired through the advance of Muller's ratchet or else frozen in these genomes at hemiclone formation. From this hypothesis results a straightforward prediction: Matings between different hemiclones, that is, between R. esculenta possessing different R genomes of independent origin, should produce viable R. ridibunda offspring because it is unlikely that different clonal lineages have become fixed for the same mutations. I tested this prediction by comparing survival and larval performance of tadpoles from within- and between-population crossings using R. esculenta from Seseglio (Se) in southern, Alpnach (Al) in central, and Elliker Auen (El) in northern Switzerland, respectively. Se is isolated from the other populations by the Alps. Enzyme electrophoresis revealed that parents from Se belonged to a single hemiclone that was different from all hemiclones found north of the Alps. Parents from Al also belonged to one hemiclone, but parents from El belonged to three hemiclones, one of which was indistinguishable from the one in Al. Rana esculenta from Se produced inviable tadpoles when crossed with other hybrids of their own population, but when crossed with R. esculenta from Al and El, tadpoles successfully completed metamorphosis, supporting the hypothesis I tested. Within-population crosses from Al were also inviable, but some within-population crosses from El, where three hemiclones were present, produced viable offspring. Only part of the crosses between Al and El were viable, but there was no consistent relationship between hemiclone combination and tadpole survival. When backcrossed with the parental species R. ridibunda, hybrids from all source populations produced viable offspring. Performance of these tadpoles with a sexual and a clonal genome was comparable to that of normal, sexually produced R. ridibunda tadpoles. Thus, in the heterozygous state, the deleterious mutations on the clonal R genomes did not appear to reduce tadpole fitness.


Ethnic Identity as a Moderator against Discrimination for Transracially and Transnationally Adopted Korean American Adolescents.
Despite the growing practice of international adoption over the past 60 years, the racial and ethnic experiences of adopted youth are not well known. This study examined the moderating role of ethnic identity in the association between racial/ethnic discrimination and adjustment among transracially, transnationally adopted Korean American adolescents (N = 136). Building on self-categorization theory and past empirical research on Asian Americans, it was hypothesized that ethnic identity would exacerbate negative outcomes associated with discrimination. The moderating role of ethnic identity was found to vary by specific ethnic identity dimensions. For individuals with more pride in their ethnic group (affective dimension of ethnic identity), discrimination was positively associated with externalizing problems. For individuals with greater engagement with their ethnic group (behavioral dimension of ethnic identity), discrimination was positively associated with substance use. By contrast, clarity regarding the meaning and importance of one's ethnic group (cognitive dimension of ethnic identity) did not moderate the relationship between discrimination and negative outcomes.


Large-scale symmetry-adapted perturbation theory computations via density fitting and Laplace transformation techniques: investigating the fundamental forces of DNA-intercalator interactions.
Symmetry-adapted perturbation theory (SAPT) provides a means of probing the fundamental nature of intermolecular interactions. Low-orders of SAPT (here, SAPT0) are especially attractive since they provide qualitative (sometimes quantitative) results while remaining tractable for large systems. The application of density fitting and Laplace transformation techniques to SAPT0 can significantly reduce the expense associated with these computations and make even larger systems accessible. We present new factorizations of the SAPT0 equations with density-fitted two-electron integrals and the first application of Laplace transformations of energy denominators to SAPT. The improved scalability of the DF-SAPT0 implementation allows it to be applied to systems with more than 200 atoms and 2800 basis functions. The Laplace-transformed energy denominators are compared to analogous partial Cholesky decompositions of the energy denominator tensor. Application of our new DF-SAPT0 program to the intercalation of DNA by proflavine has allowed us to determine the nature of the proflavine-DNA interaction. Overall, the proflavine-DNA interaction contains important contributions from both electrostatics and dispersion. The energetics of the intercalator interaction are are dominated by the stacking interactions (two-thirds of the total), but contain important contributions from the intercalator-backbone interactions. It is hypothesized that the geometry of the complex will be determined by the interactions of the intercalator with the backbone, because by shifting toward one side of the backbone, the intercalator can form two long hydrogen-bonding type interactions. The long-range interactions between the intercalator and the next-nearest base pairs appear to be negligible, justifying the use of truncated DNA models in computational studies of intercalation interaction energies.


Continuous Blood Glucose Monitoring Reveals Enormous Circadian Variations in Pregnant Diabetic Rats.
Diabetes in pregnancy is a major burden with acute and long-term consequences. Its treatment requires adequate diagnosis and monitoring of therapy. Many experimental research on diabetes during pregnancy has been performed in rats. Recently, continuous blood glucose monitoring of non-pregnant diabetic rats revealed an increased circadian variability of blood glucose that made a single blood glucose measurement per day inappropriate to reflect glycemic status. Continuous blood glucose measurement has never been performed in pregnant rats. We wanted to perform continuous blood glucose monitoring in pregnant rats to decipher the influence of pregnancy on blood glucose in diabetic and normoglycemic status. We used the transgenic Tet29 diabetes rat model with an inducible knock down of the insulin receptor via RNA interference upon application of doxycycline (DOX) leading to insulin resistant type II diabetes. All Tet29 rats received a HD-XG telemetry implant (Data Sciences International, USA) that measured blood glucose and activity continuously. Rats were divided into four groups and blood glucose was monitored until end of pregnancy or the corresponding period: Tet29 + DOX (diabetic) non-pregnant, Tet29 + DOX (diabetic) pregnant, Tet29 (normoglycemic) non-pregnant, Tet29 (normoglycemic) pregnant. All analyzed rats displayed a circadian variation in blood glucose concentration. Circadian variability was much more pronounced in pregnant diabetic rats than in normoglycemic pregnant rats. Pregnancy ameliorated variation in blood glucose in diabetic situation. Pregnancy continuously decreased blood glucose during normoglycemic pregnancy. Diabetic rats were less active than normoglycemic rats. We performed a calculation showing that application of continuous blood glucose measurement reduces animal numbers needed to detect a given effect in experimental setting by decreasing variability and SD. Continuous blood glucose monitoring via a telemetry device in pregnant rats provides a more informative picture of the glycemic situation in comparison to single measurements. This could improve diagnosis and therapy of diabetes, decrease animal numbers within experimental settings, and add another physiological parameter (activity) to the analysis that could be helpful in testing therapeutic concepts targeting blood glucose levels and peripheral muscle function. We propose continuous glucose monitoring as a new tool for the evaluation of pregnant diabetic rats.


Patient-related diet and exercise counseling: do providers' own lifestyle habits matter?
The goal of this research was to evaluate the personal health behaviors of physicians in training and attending physicians in association with patient-related lifestyle counseling. Physicians at a major teaching hospital were surveyed regarding their personal lifestyle behavior, perceived confidence, and frequency of counseling patients regarding lifestyle behaviors. One hundred eighty-three total responses were received. Trainees were more likely to consume fast food and less likely to consume fruits and vegetables than attendings. Attending physicians were more likely to exercise 4 or more days per week and more than 150 minutes per week. Attending physicians were more likely to counsel their patients regarding a healthy diet (70.7% vs 36.3%, P<.0001) and regular exercise (69.1% vs 38.2%, P<.0001) compared with trainees. Few trainees or attendings were confident in their ability to change patients' behaviors. Predictors of confidence in counseling for exercise included the provider's own exercise time of > 150 minutes per week, being overweight, and reported adequate training in counseling. Only adequate training in counseling was a predictor of strong self-efficacy for counseling in diet. Many physicians lack confidence in their ability to counsel patients regarding lifestyle. Personal behaviors including regular exercise and better training in counseling techniques may improve patient counseling.


Long-term light history modulates the light response kinetics of luminosity (L)-type horizontal cells in the roach retina.
We have examined the effects of prolonged periods of darkness on the responses of luminosity-type horizontal cells (L-HCs) in the freshwater cyprinid, Rutilus rutilus. Two groups of retinae were compared, those recorded after 10 min dark adaptation (SA) and those recorded after 3 h dark adaptation (LA). The results suggest that long-term light history does not modify the general responsiveness of the L-HCs in this species. However, there are apparent changes in the receptive field of the cells and modifications to the kinetics of the light-evoked response. The kinetics changes involve both a delay in the onset of light response and a selective effect on the hyperpolarizing light-ON response. Thus the mean time constant (tau) for the SA cells was 32.4+/-2.39 ms (n=62), whilst that for the LA cells was 53.4+/-3.03 ms (n=61). These effects occur in the absence of changes in the relative spectral sensitivity or threshold sensitivity of the HCs. The results suggest that in some vertebrate retinae, prolonged darkness (light-history) may regulate long-term plasticity in the kinetics of the cone-HC pathway.


Assessment of Hair Zinc in the School Children in Kayseri, Turkey.
Zinc is an essential micronutrient for the organism and is critical for the functional and structural integrity of cells. Determination of the amount of trace element concentrations in tissues such as hair samples have been used for the evaluation of the metabolic status especially in children. Unlike serum zinc, concentrations of zinc in hair are more stable and indicative of variations over time. The purpose of this study is to assess the zinc status of healthy school-age children in Kayseri (Turkey) by measuring the zinc level in hair samples and its association with BMI and the frequency of intake of zinc-rich foods. A total of 527 healthy children, including preadolescent (n = 360) aged 6-10 years and adolescent (n = 167) aged 11-15 years were included in this study. Hair samples were analyzed for zinc content by the inductively coupled plasma-mass spectrophotometry. Analysis of 527 healthy children showed that the mean hair zinc level was 186 ± 77 μg/g. Mean hair zinc level was lower in preadolescent age group than adolescents. There was no significant relationship between the monthly income of the family and the zinc-rich food intake and the zinc level of the hair. Our study shows that samples for analysis of zinc can be obtained with a noninvasive method for determining cases of deficiency during periods of rapid growth. However, further studies are needed to determine the normal tissue zinc level in healthy children, especially in our country and including different geographical regions.


Theory of own mind in autism: Evidence of a specific deficit in self-awareness?
Assuming that self-awareness is not a unitary phenomenon, and that one can be aware of different aspects of self at any one time, it follows that selective impairments in self-awareness can occur. This article explores the idea that autism involves a particular deficit in awareness of the 'psychological self', or 'theory of own mind'. This hypothesised deficit renders individuals with autism spectrum disorder (ASD) at least as impaired at recognising their own mental states as at recognising mental states in other people. This deficit, it is argued, stands in contrast to an apparently typical awareness of the 'physical self' amongst people with autism. Theoretical implications of the empirical evidence are discussed.


Multigenerational Disruption of the Thyroid Endocrine System in Marine Medaka after a Life-Cycle Exposure to Perfluorobutanesulfonate.
Accumulation of perfluorobutanesulfonate (PFBS) is frequently detected in biota, raising concerns about its ecological safety. However, hazardous effects of PFBS remain largely unexplored, especially for endocrine disrupting potency. In the present study, the multigenerational endocrine disrupting potential of PFBS was investigated by exposing F0 marine medaka eggs to PFBS at different concentrations (0, 1.0, 2.9, and 9.5 μg/L) until sexual maturity. The F1 and F2 generations were reared without continued exposure. Thyroidal disturbances were examined in all three generations. PFBS exposure decreased the levels of 3,5,3'-triiodothyronine (T3) in F0 female blood; however, it increased T3 or thyroxine (T4) levels in F0 brains, in which hyperthyroidism suppressed the local transcription of 5'-deiodinase 2 ( Dio2). Obviously decreased T3 was transferred to F1 eggs, although the parental influences were reversed in F1 larvae. Delayed hatching was coupled with elevated T3 levels in F1 larvae. F1 adults showed comparable symptoms of thyroidal disruption with F0 adults. A slight recovery was noted in the F2 generation, although F2 larvae still exhibited thyroid disruption and synthesized excessive T4. Our results suggested that the offspring suffered more severe dysfunction of the thyroidal axis albeit without direct exposure. This study provided the first molecular insight about PFBS toxicology on the thyroid, beneficial to both human and environmental risk assessment.


Improving medication adherence in stroke survivors: mediators and moderators of treatment effects.
The purpose of the current study was to test theory-based predictions of mediators and moderators of treatment effects of a pilot randomized controlled trial, which aimed to increase adherence to preventive medication in stroke survivors via addressing both automatic (i.e., habitual responses) and reflective (i.e., beliefs and value systems) aspects of medication-taking behavior. Sixty-two stroke survivors were randomly allocated to either an intervention or control group. Intervention participants received a brief 2-session intervention aimed at increasing adherence via (a) helping patients establish better medication-taking routines using implementation intentions plans (automatic), and (b) eliciting and modifying any mistaken patient beliefs regarding medication and/or stroke (reflective). The control group received similar levels of non-medication-related contact. Primary outcome was adherence to antihypertensive medicine measured objectively over 3 months using an electronic pill bottle. Secondary outcome measures included self-reported adherence (including forgetting) and beliefs about medication. Intervention participants had 10% greater adherence on doses taken on schedule (intervention, 97%; control, 87%; 95% CI [0.2, 16.2], p = .048), as well as significantly greater increases in self-reported adherence and reductions in concerns about medication. Treatment effects were mediated by reductions in both forgetting and concerns about medication, and moderated by the presence of preexisting medication-taking routines. Addressing both automatic and reflective aspects of behavior via helping stroke survivors develop planned regular routines for medication-taking, and addressing any concerns or misconceptions about their medication, can improve adherence and thus potentially patient outcomes.


Correlates of fatigue in older adults with rheumatoid arthritis.
The purposes of this study were to describe the prevalence of fatigue, examine the association between fatigue and doctor visits, and identify correlates of fatigue in rheumatoid arthritis (RA). On average, a high degree of fatigue was reported to occur every day, to remain constant during the course of a week, and to most often affect walking and household chores. When controlling for disease severity and insurance coverage, respondents who reported more fatigue made more visits to the rheumatologist than those reporting less fatigue. A regression model with fatigue as the dependent variable revealed that the following variables explained a significant amount of variance: pain rating, functional status, sleep quality, female gender, comorbid conditions, and duration of disease.


Extracellular matrix composition influences insulinlike growth factor I receptor expression in rat IEC-18 cells.
The composition of the extracellular matrix (ECM) as well as insulinlike growth factor I (IGF-I) receptor density vary along the crypt-villus axis. We determined whether components of the ECM influence IGF-I receptor expression in IEC-18 rat small intestine crypt cells. IEC-18 cells were cultured on plastic, collagen type IV, Matrigel, and laminin at the plateau and proliferative growth phases. Receptor affinity (Kd) and number (Bmax) were determined by competitive binding of 125I-IGF-I in the presence of increasing concentrations of unlabeled IGF-I. Receptor isolation was performed by affinity cross linking. Messenger RNA (mRNA) for IGF-I receptor was quantified by Northern analysis. Specific binding of IGF-I > IGF-II > insulin was observed. A 130,000-molecular weight protein was identified by cross-linking, consistent with the alpha subunit of the IGF-I receptor. Scatchard analysis revealed no effect of ECM on IGF-I binding affinity. In contrast, the Bmax was 18% lower for plateau-phase cells cultured on Matrigel vs. plastic and was 42% lower for cells cultured on laminin vs. collagen type IV. The Bmax for proliferative growth phase cells was decreased when cultured on Matrigel vs. plastic and was 10-fold less than for cells cultured at the plateau growth phase. Northern analysis revealed that IEC-18 cells cultured on Matrigel had less mRNA for IGF-I receptor than cells cultured on plastic. The rate of cell proliferation and the composition of the ECM influence IGF-I receptor expression in IEC-18 cells.


Circumferential Strain Can Be Used to Detect Lipopolysaccharide-Induced Myocardial Dysfunction and Predict the Mortality of Severe Sepsis in Mice.
Sepsis-induced myocardial dysfunction is a common and severe complication of septic shock. However, conventional echocardiography often fails to reveal myocardial depression in severe sepsis. Recently, strain measurements based on speckle tracking echocardiography (STE) have been used to evaluate cardiac function. To investigate the role of STE in detecting lipopolysaccharide (LPS)-induced cardiac dysfunction, M-mode and 2-D echocardiography were used in LPS-treated mice. The mice were treated with a 10mg/kg (n = 10), 20mg/kg (n = 10) or 25mg/kg LPS (n = 30) to induce cardiac dysfunction. Subsequently, the ejection fraction (EF) and fractional shortening (FS) were measured with standard M-mode tracings, whereas the circumferential (Scirc) and radial strain (Srad) were measured with STE. Serum biochemical and cardiac histopathological examinations were performed to assess sepsis-induced myocardial injury. 20mg/kg LPS resulted in more deterioration, myocardial damage and cardiac contractile dysfunction based on serum biochemical and histological examinations. The mice that were subjected to 20mg/kg LPS exhibited reduced Scirc but no reduction in Srad, whereas on conventional echocardiography, the ejection fraction (EF) and fractional shortening (FS) were similar in the 10mg/kg and 20mg/kg groups. Moreover, Scirc was positively correlated with body temperature in the mice at 20 h after LPS injection (r = 0.746, p = 0.001), but no significant correlation was observed between Srad and body temperature (r = 0.356, p = 0.123). Moreover, the mice with high Scirc (-5.9% to -10.4%) exhibited reduced mortality following the administration of 25mg/kg LPS (p = 0.03) compared with the low-strain group (-2% to -5.9%). Taken together, our findings indicate that circumferential strain is a specific and reliable indicator for evaluating LPS-induced cardiac dysfunction in mice.


The longevity of para-aminopropiophenone (PAPP) wild dog baits and the implications for effective and safe baiting campaigns.
Considerable effort goes into mitigating the impacts caused by invasive animals and prohibiting their establishment or expansion. In Australia, management of wild dogs (Canis lupus dingo and their hybrids) and their devastating impacts is reliant upon poison baiting. The recent release of baits containing the humane toxin para-aminopropiophenone (PAPP) offers potential improvements for control of wild dogs, but little is known about the environmental persistence of PAPP in manufactured baits that could be used to inform best practice guidelines. We investigated the degradation rate of PAPP wild dog baits (DOGABAIT™) under typical field usage and storage conditions in north-eastern Australia and calculated optimal deployment and withholding periods. The PAPP content of buried baits declines faster than surface-laid baits, but both presentations retained lethal doses to wild and domestic dogs for considerable periods (6-16 weeks). Domestic or working dogs should be suitably restrained or excluded from baited areas for extended periods, particularly under dry conditions, to minimise poisoning risk. The period of persistence of PAPP baits may provide opportunities to improve the duration or longer term efficacy of baiting campaigns, but care is needed to protect domestic and working dogs to ensure responsible and safe use.


Influence of the number of repellent-treated and untreated food or water containers on intake by the European starling.
The availability of multiple sources of food and drink has a profound influence on choice behavior in rodents. It is not known how other taxa might respond to the same kind of variation in availability. We tested European starlings (Sturnus vulgaris) with various combinations of unadulterated and repellent-treated (0.025% citronellyl acetate) resources. In Experiment 1, birds drank more plain than repellent-treated water than when given (a) 2 bottles of plain water and 2 of repellent-water, or (b) 3 bottles of plain water and 1 of repellent-water. However, they drank more repellent than water when given 3 bottles of repellent-water and 1 of plain water. Thus, the aversion to the repellent became indifference when repellent-water was abundant. In Experiment 2, birds ate more untreated than treated food when given (a) 1 cup of untreated food and 1 cup of treated food or (b) 2 cups of untreated food and 1 of treated food. They ate equal amounts of untreated and treated food when given 1 cup of untreated food and 2 cups of treated food. These results demonstrate the effect of relative availability on choice, and imply that availability should be considered when using repellents.


Endoglin promotes transforming growth factor beta-mediated Smad 1/5/8 signaling and inhibits endothelial cell migration through its association with GIPC.
Transforming growth factor beta (TGF-beta) signals through two distinct pathways to regulate endothelial cell proliferation, migration, and angiogenesis, the ALK-1/Smad 1/5/8 and ALK-5/Smad2/3 pathways. Endoglin is a co-receptor predominantly expressed in endothelial cells that participates in TGFbeta-mediated signaling with ALK-1 and ALK-5 and regulates critical aspects of cellular and biological responses. The embryonic lethal phenotype of knock-out mice because of defects in angiogenesis and disease-causing mutations resulting in human vascular diseases both support essential roles for endoglin, ALK-1, and ALK-5 in the vasculature. However, the mechanism by which endoglin mediates TGF-beta signaling through ALK-1 and ALK-5 has remained elusive. Here we describe a novel interaction between endoglin and GIPC, a scaffolding protein known to regulate cell surface receptor expression and trafficking. Co-immunoprecipitation and immunofluorescence confocal studies both demonstrate a specific interaction between endoglin and GIPC in endothelial cells, mediated by a class I PDZ binding motif in the cytoplasmic domain of endoglin. Subcellular distribution studies demonstrate that endoglin recruits GIPC to the plasma membrane and co-localizes with GIPC in a TGFbeta-independent manner, with GIPC-promoting cell surface retention of endoglin. Endoglin specifically enhanced TGF-beta1-induced phosphorylation of Smad 1/5/8, increased a Smad 1/5/8 responsive promoter, and inhibited endothelial cell migration in a manner dependent on the ability of endoglin to interact with GIPC. These studies define a novel mechanism for the regulation of endoglin signaling and function in endothelial cells and demonstrate a new role for GIPC in TGF-beta signaling.


Translational research on the way to effective therapy for Alzheimer disease.
Alzheimer disease (AD) is a major public health issue with a prediction of 12 million Americans being affected by 2025 from the present 4 million. Molecular and genetic findings have provided significant insights into the roles that amyloid, tau, and apolipoprotein E isoforms have in the causation of AD. A central issue in AD pathogenesis is the amyloid cascade hypothesis. It states that abnormal amyloid processing and accumulation is the primary causative factor of AD and other associated neuropathologic abnormalities are of secondary consequence. It is presented to provide the rationale for novel drug and vaccination therapeutic strategies. Future research directed at prediction and prevention of AD through a genomic and proteomic analysis with identification of multiple polymorphic genes that interact, resulting in increased risk for late-onset AD, are the realistic and ultimate goals. A new approach for drug development is required, one that will emphasize a genomic and proteomic analysis to identify at-risk gene sets whose genetic expression is sufficient to cause late onset, sporadic AD. Prediction and prevention of disease prior to clinical signs and symptoms are the goals. A review and analysis from electronic literature databases and subsequent reference searches of the molecular genetic data. including pertinent genetic mutations and abnormal biochemical findings causal of AD, are cited. The amyloid cascade hypothesis, the contributions of apolipoprotein E, and hyperphosphorylated tau are discussed as to their roles in pathogenesis. Molecular targets for potential drug and vaccination therapies are cited from a critical assessment of the molecular and biomedical data. These data form the basis for rational, target-specific drug and vaccination therapies currently employed and planned for the near future. Phase 2 and 3 clinical trial results of drug and vaccination therapies are cited. A new approach is needed as current pharmacologic therapy directed at symptomatic relief has proved to be marginally effective. The genomic and proteomic basis of AD will be defined in the near future, and corresponding molecular therapeutic targets will be identified. Genomic neurology has arrived and its application to resolving AD is our best hope.


Dynamic social networks promote cooperation in experiments with humans.
Human populations are both highly cooperative and highly organized. Human interactions are not random but rather are structured in social networks. Importantly, ties in these networks often are dynamic, changing in response to the behavior of one's social partners. This dynamic structure permits an important form of conditional action that has been explored theoretically but has received little empirical attention: People can respond to the cooperation and defection of those around them by making or breaking network links. Here, we present experimental evidence of the power of using strategic link formation and dissolution, and the network modification it entails, to stabilize cooperation in sizable groups. Our experiments explore large-scale cooperation, where subjects' cooperative actions are equally beneficial to all those with whom they interact. Consistent with previous research, we find that cooperation decays over time when social networks are shuffled randomly every round or are fixed across all rounds. We also find that, when networks are dynamic but are updated only infrequently, cooperation again fails. However, when subjects can update their network connections frequently, we see a qualitatively different outcome: Cooperation is maintained at a high level through network rewiring. Subjects preferentially break links with defectors and form new links with cooperators, creating an incentive to cooperate and leading to substantial changes in network structure. Our experiments confirm the predictions of a set of evolutionary game theoretic models and demonstrate the important role that dynamic social networks can play in supporting large-scale human cooperation.


A meta-analysis of preoperative localization techniques for patients with primary hyperparathyroidism.
Reported accuracy of preoperative localization imaging for primary hyperparathyroidism (pHPT) varies. The purpose of this study is to determine the accuracy of ultrasound, sestamibi-single photon emission computed tomography (SPECT), and four-dimensional computed tomography (4D-CT) as preoperative localization strategies. A meta-analysis was performed of studies investigating the accuracy of ultrasound, sestamibi-SPECT, and 4D-CT for preoperative localization in pHPT. Electronic databases were systematically searched, and two independent reviewers reviewed results using specific criteria. Study quality was assessed using a validated measure for diagnostic imaging studies. Study heterogeneity and pooled results were calculated. 43 studies met criteria for inclusion, and data were available for extraction in 19 ultrasound, 9 sestamibi-SPECT, and 4 4D-CT studies. Ultrasound had pooled sensitivity and positive predictive value (PPV) of 76.1% (95% CI 70.4-81.4%) and 93.2% (90.7-95.3%), respectively. Sestamibi-SPECT had pooled sensitivity and PPV of 78.9% (64-90.6%) and 90.7% (83.5-96.0%), respectively. Only two 4D-CT studies investigated patients undergoing initial parathyroidectomy. Results suggested sensitivity and PPV of 89.4% and 93.5%, respectively. Ultrasound and sestamibi-SPECT are similar in ability to preoperatively localize abnormal parathyroid glands in pHPT. Accuracy may be improved with 4D-CT; however, further investigation is required. Choice of preoperative imaging strategy depends on numerous patient, institutional, and economic factors of which the surgeon must be aware.


Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement.
Inducible laryngeal obstruction (ILO) describes an inappropriate, transient, reversible narrowing of the larynx in response to external triggers. ILO is an important cause of a variety of respiratory symptoms and can mimic asthma. Current understanding of ILO has been hampered by imprecise nomenclature and variable approaches to assessment and management. A task force of the European Respiratory Society (ERS) and European Laryngological Society (ELS) was thus set up to address this, and to identify research priorities.A literature search identified relevant articles published until June 2016, using all identifiable terms for ILO, although including only articles using laryngoscopy. In total, 172 out of 252 articles met the inclusion criteria, summarised in sections on diagnostic approach, aetiology, comorbidities, epidemiology and treatment. The consensus taxonomy published by ERS, ELS and the American College of Chest Physicians (ACCP) in 2015 is used throughout this statement.We highlight the high prevalence of ILO and the clinical impact for those affected. Despite recent advances, most aspects of this condition unfortunately remain incompletely understood, precluding firm guidance. Specifically, validated diagnostic and treatment algorithms are yet to be established, and no randomised control studies were identified in this search; hence we also make recommendations for future research.


Convergent evolution in Arabidopsis halleri and Arabidopsis arenosa on calamine metalliferous soils.
It is a plausible hypothesis that parallel adaptation events to the same environmental challenge should result in genetic changes of similar or identical effects, depending on the underlying fitness landscapes. However, systematic testing of this is scarce. Here we examine this hypothesis in two closely related plant species, Arabidopsis halleri and Arabidopsis arenosa, which co-occur at two calamine metalliferous (M) sites harbouring toxic levels of the heavy metals zinc and cadmium. We conduct individual genome resequencing alongside soil elemental analysis for 64 plants from eight populations on M and non-metalliferous (NM) soils, and identify genomic footprints of selection and local adaptation. Selective sweep and environmental association analyses indicate a modest degree of gene as well as functional network convergence, whereby the proximal molecular factors mediating this convergence mostly differ between site pairs and species. Notably, we observe repeated selection on identical single nucleotide polymorphisms in several A. halleri genes at two independently colonized M sites. Our data suggest that species-specific metal handling and other biological features could explain a low degree of convergence between species. The parallel establishment of plant populations on calamine M soils involves convergent evolution, which will probably be more pervasive across sites purposely chosen for maximal similarity in soil composition. This article is part of the theme issue 'Convergent evolution in the genomics era: new insights and directions'.


Buoyancy-driven, rapid exhumation of ultrahigh-pressure metamorphosed continental crust.
Preservation of ultrahigh-pressure (UHP) minerals formed at depths of 90-125 km require unusual conditions. Our subduction model involves underflow of a salient (250 +/- 150 km wide, 90-125 km long) of continental crust embedded in cold, largely oceanic crust-capped lithosphere; loss of leading portions of the high-density oceanic lithosphere by slab break-off, as increasing volumes of microcontinental material enter the subduction zone; buoyancy-driven return toward midcrustal levels of a thin (2-15 km thick), low-density slice; finally, uplift, backfolding, normal faulting, and exposure of the UHP terrane. Sustained over approximately 20 million years, rapid ( approximately 5 mm/year) exhumation of the thin-aspect ratio UHP sialic sheet caught between cooler hanging-wall plate and refrigerating, downgoing lithosphere allows withdrawal of heat along both its upper and lower surfaces. The intracratonal position of most UHP complexes reflects consumption of an intervening ocean basin and introduction of a sialic promontory into the subduction zone. UHP metamorphic terranes consist chiefly of transformed, yet relatively low-density continental crust compared with displaced mantle material-otherwise such complexes could not return to shallow depths. Relatively rare metabasaltic, metagabbroic, and metacherty lithologies retain traces of phases characteristic of UHP conditions because they are massive, virtually impervious to fluids, and nearly anhydrous. In contrast, H2O-rich quartzofeldspathic, gneissose/schistose, more permeable metasedimentary and metagranitic units have backreacted thoroughly, so coesite and other UHP silicates are exceedingly rare. Because of the initial presence of biogenic carbon, and its especially sluggish transformation rate, UHP paragneisses contain the most abundantly preserved crustal diamonds.


Prediction of the pathogens that are the cause of pneumonia by the battlefield hypothesis.
Commensal organisms are frequent causes of pneumonia. However, the detection of these organisms in the airway does not mean that they are the causative pathogens; they may exist merely as colonizers. In up to 50% cases of pneumonia, the causative pathogens remain unidentified, thereby hampering targeting therapies. In speculating on the role of a commensal organism in pneumonia, we devised the battlefield hypothesis. In the "pneumonia battlefield," the organism-to-human cell number ratio may be an index for the pathogenic role of the organism. Using real-time PCR reactions for sputum samples, we tested whether the hypothesis predicts the results of bacteriological clinical tests for 4 representative commensal organisms: Streptococcus pneumoniae, Haemophilus influenzae, Pseudomonas spp., and Moraxella catarrhalis. The cutoff value for the organism-to-human cell number ratio, above which the pathogenic role of the organism was suspected, was set up for each organism using 224 sputum samples. The validity of the cutoff value was then tested in a prospective study that included 153 samples; the samples were classified into 3 groups, and each group contained 93%, 7%, and 0% of the samples from pneumonia, in which the pathogenic role of Streptococcus pneumoniae was suggested by the clinical tests. The results for Haemophilus influenzae, Pseudomonas spp., and Moraxella catarrhalis were 100%, 0%, and 0%, respectively. The battlefield hypothesis enabled legitimate interpretation of the PCR results and predicted pneumonia in which the pathogenic role of the organism was suggested by the clinical test. The PCR reactions based on the battlefield hypothesis may help to promote targeted therapies for pneumonia. The prospective observatory study described in the current report had been registered to the University Hospital Medical Information Network (UMIN) registry before its initiation, where the UMIN is a registry approved by the International Committee of Medical Journal Editors (ICMJE). The UMIN registry number was UMIN000001118: A prospective study for the investigation of the validity of cutoff values established for the HIRA-TAN system (April 9, 2008).


After-school programs for low-income children: promise and challenges.
Children's out-of-school time, long a low-level source of public concern, has recently emerged as a major social issue. This, in turn, has heightened interest in the heterogeneous field of after-school programs. This article provides a profile of after-school programs for low-income children, focusing on supply and demand, program emphases, and program sponsors and support organizations. It also discusses the major challenges facing the field in the areas of facilities, staffing, and financing. Details and examples are drawn from the ongoing evaluation of a specific after-school program initiative called MOST (Making the Most of Out-of-School Time), which seeks to strengthen after-school programs in Boston, Chicago, and Seattle. Looking ahead, the article highlights the pros and cons of options for increasing coverage to reach more low-income children, strengthening programs, expanding funding, and articulating an appropriate role for after-school programs to fill in the lives of low-income children.


Two aquaporins of Jatropha are regulated differentially during drought stress and subsequent recovery.
Jatropha has potential to be an important bio-fuel crop due to such advantages as high seed oil content and the ability to grow well on marginal lands less suited for food crops. Despite its ability to grow on marginal land, Jatropha is still susceptible to high salt and drought stresses, which can significantly reduce plant growth, stomatal conductance, sap-flow rate, and plant sap volume. This study was undertaken to collect basic knowledge of the physiological and molecular aspects of Jatropha response to salt and drought stresses, and to elucidate how Jatropha recovers from stress. From these studies we identified candidate genes that may be useful for the development of Jatropha cultivars that will grow efficiently in arid and barren lands. Of particular interest, two plasma membrane intrinsic proteins were identified: Jatropha plasma membrane intrinsic protein 1 (JcPIP1) and Jatropha plasma membrane intrinsic protein 2 (JcPIP2). The expression levels of JcPIP1 were dramatically increased in roots, stems, and leaves during the recovery from stress, whereas the JcPIP2 gene transcripts levels were induced in roots and stems during the water deficit stress. The protein levels of JcPIP1 and JcPIP2 were consistent with the gene expression patterns. Based on these results, we hypothesized that JcPIP1 plays a role in the recovery events from water stresses, while JcPIP2 is important in early responses to water stress. Virus induced gene silencing technology revealed that both JcPIP1 and JcPIP2 have positive roles in response to water deficit stresses, but have antagonistic functions at the recovery stage. We suggest that both JcPIP1 and JcPIP2 may play important roles in responses to water deficit conditions and both have potential as targets for genetic engineering.


Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element.
The HIFs (hypoxia-inducible factors) are a family of heterodimeric transcription factors essential for the adaptation of cells to reduced oxygen supply. Three human PHDs (prolyl hydroxylase domain proteins, PHD1-PHD3) initiate oxygen-dependent degradation of HIF-alpha-subunits in normoxia. RNA interference directed against PHD2, but not PHD1 or PHD3, is sufficient to stabilize HIF-1alpha in normoxia. Therefore PHD2 is regarded as the main cellular oxygen sensor. PHD2 itself is up-regulated by hypoxia and may thus limit hypoxic signalling. By sequence analysis, we predicted a promoter approx. 3.5 kb 5' of the translation start codon and a second promoter located in a CpG island immediately upstream of the coding sequence. A consensus HIF-1-binding site that is conserved in the murine phd2 gene was detected in the CpG island. By electrophoretic mobility-shift assay, we demonstrated binding of HIF-1 to the putative HIF-1-binding site. In luciferase reporter vectors, the isolated upstream promoter was inactive in all cell lines tested unless 200 bp were deleted at the 3'-end. The downstream promoter was active and induced by hypoxia. In reporter vectors containing both promoter sequences, luciferase activity was equal to vectors containing only the downstream promoter. In cells transfected with a vector containing both promoters, a single luciferase transcript was detectable. This transcript had the same length as transcripts from a vector containing the downstream promoter only. We conclude that the phd2 gene is transcribed exclusively from the downstream promoter that contains a functional hypoxia-responsive, cis-regulatory element. Our results establish that PHD2 is a direct HIF target gene.


Advances in Applying Computer-Aided Drug Design for Neurodegenerative Diseases.
Neurodegenerative diseases (NDs) including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and Huntington's disease are incurable and affect millions of people worldwide. The development of treatments for this unmet clinical need is a major global research challenge. Computer-aided drug design (CADD) methods minimize the huge number of ligands that could be screened in biological assays, reducing the cost, time, and effort required to develop new drugs. In this review, we provide an introduction to CADD and examine the progress in applying CADD and other molecular docking studies to NDs. We provide an updated overview of potential therapeutic targets for various NDs and discuss some of the advantages and disadvantages of these tools.


Breast cancer risk in relation to occupations with exposure to carcinogens and endocrine disruptors: a Canadian case-control study.
Endocrine disrupting chemicals and carcinogens, some of which may not yet have been classified as such, are present in many occupational environments and could increase breast cancer risk. Prior research has identified associations with breast cancer and work in agricultural and industrial settings. The purpose of this study was to further characterize possible links between breast cancer risk and occupation, particularly in farming and manufacturing, as well as to examine the impacts of early agricultural exposures, and exposure effects that are specific to the endocrine receptor status of tumours. 1005 breast cancer cases referred by a regional cancer center and 1146 randomly-selected community controls provided detailed data including occupational and reproductive histories. All reported jobs were industry- and occupation-coded for the construction of cumulative exposure metrics representing likely exposure to carcinogens and endocrine disruptors. In a frequency-matched case-control design, exposure effects were estimated using conditional logistic regression. Across all sectors, women in jobs with potentially high exposures to carcinogens and endocrine disruptors had elevated breast cancer risk (OR = 1.42; 95% CI, 1.18-1.73, for 10 years exposure duration). Specific sectors with elevated risk included: agriculture (OR = 1.36; 95% CI, 1.01-1.82); bars-gambling (OR = 2.28; 95% CI, 0.94-5.53); automotive plastics manufacturing (OR = 2.68; 95% CI, 1.47-4.88), food canning (OR = 2.35; 95% CI, 1.00-5.53), and metalworking (OR = 1.73; 95% CI, 1.02-2.92). Estrogen receptor status of tumors with elevated risk differed by occupational grouping. Premenopausal breast cancer risk was highest for automotive plastics (OR = 4.76; 95% CI, 1.58-14.4) and food canning (OR = 5.70; 95% CI, 1.03-31.5). These observations support hypotheses linking breast cancer risk and exposures likely to include carcinogens and endocrine disruptors, and demonstrate the value of detailed work histories in environmental and occupational epidemiology.


Widespread vertical transmission and associated host sex-ratio distortion within the eukaryotic phylum Microspora.
Vertical transmission (VT) and associated manipulation of host reproduction are widely reported among prokaryotic endosymbionts. Here, we present evidence for widespread use of VT and associated sex-ratio distortion in a eukaryotic phylum. The Microspora are an unusual and diverse group of eukaryotic parasites that infect all animal phyla. Following our initial description of a microsporidian that feminizes its crustacean host, we survey the diversity and distribution of VT within the Microspora. We find that vertically transmitted microsporidia are ubiquitous in the amphipod hosts sampled and that they are also diverse, with 11 species of microsporidia detected within 16 host species. We found that infections were more common in females than males, suggesting that host sex-ratio distortion occurs in five out of eight parasite species tested. Phylogenetic reconstruction demonstrates that VT occurs in all major lineages of the phylum Microspora and that sex-ratio distorters are found on multiple branches of the phylogenetic tree. We propose that VT is either an ancestral trait or evolves with peculiar frequency in this phylum. If the association observed here between VT and host sex-ratio distortion holds true across other host taxa, these eukaryotic parasites may join the bacterial endosymbionts in their importance as sex-ratio distorters.


Fucoidan Inhibits Radiation-Induced Pneumonitis and Lung Fibrosis by Reducing Inflammatory Cytokine Expression in Lung Tissues.
Purpose: Radiotherapy is a crucial treatment approach for many types of cancer. Radiation pneumonitis (RP) is one of the major complications in chest irradiation. Fucoidan is a sulfated polysaccharide found mainly in various species of brown seaweed. Recent studies have demonstrated the anti-inflammatory effects of fucoidan. However, no study has reported a well-established prophylactic agent for RP. Therefore, we investigated the effects of fucoidan on RP and radiotherapy (RT)-induced lung fibrosis. Materials and Methods: We compared RP and RT-induced fibrosis in lung tissue specimens obtained from irradiated (10 Gy/shot) C57BL/6 mice with or without fucoidan administration (200 mg/kg/day, oral gavage for 14 days). The expression patterns of cytokines in the pleural fluid were determined using a cytokine array and confirmed through enzyme immunoassays. Results: Fucoidan administration attenuated RP and RT-induced fibrosis in lung tissues. Decreased neutrophil and macrophage accumulation was observed in irradiated lung tissues, and radiation-induced lung fibrosis, as demonstrated by Masson trichrome staining, was attenuated. We investigated the expression patterns of inflammatory cytokines in the irradiated lung pleural fluid through the protein array; results revealed that fucoidan administration changed the expression patterns of inflammatory cytokines in irradiated lung tissues. Furthermore, the expression levels of TIMP-1, CXCL1, MCP-1, MIP-2, and interleukin-1Ra were substantially enhanced in the pleural fluid, but fucoidan administration significantly reduced their expression. Conclusions: Fucoidan changes the expression patterns of inflammatory cytokines, which may consequently attenuate RP and RT-induced lung fibrosis.


Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers.
Bcl-2 family proteins play a critical role in the regulation of apoptosis in chronic lymphocytic leukemia (CLL). However, their association with established prognostic markers is unknown. In this study, we analyzed the expression of Bcl-2, Bax, and Mcl-1 in 185 CLL patients and evaluated their relationship with other prognostic markers, in vitro sensitivity to fludarabine, and clinical outcome. Mcl-1 expression was significantly correlated with stage of disease (P < .001), lymphocyte doubling time (P = .01), V(H) gene mutation status (P < .001), CD38 expression (P < .001), and ZAP-70 expression (P = .003). In addition, Mcl-1 and Mcl-1/Bax ratios showed strong correlations with in vitro resistance to fludarabine (P = .005 and P < .001, respectively). Furthermore, elevated Mcl-1 expression and Mcl-1/Bax ratios were predictive of time to first treatment in the whole cohort (P < .001 and P < .001, respectively) and in stage A patients only (P = .002 and P = .001, respectively). Taken together, our data show that Mcl-1 is a key controller of in vitro drug resistance and is an important regulator of disease progression and outcome in CLL. It therefore represents a promising therapeutic target in this incurable condition. The close correlation between Mcl-1 expression and V(H) gene mutation status, CD38 expression, and ZAP-70 expression offers a biologic explanation for their association with adverse prognosis.