Chronotype differences in suicidal behavior and impulsivity among suicide attempters.
Morning- and evening-type individuals differ on a number of psychological and biological variables. There has been increasing interest in the relationship between chronotype and personality traits. The aim of this study was to investigate the relationship between impulsivity and chronotype in suicide attempters. Eighty-nine suicide attempters were included in the study, and systematic information on suicide attempts was recorded. The Morningness-Eveningness Questionnaire was applied to determine chronotype, and attempter impulsivity was measured by the total score of the Barratt Impulsiveness Scale. Significant differences between chronotype and impulsivity scores were found. Evening-type subjects reported significantly higher impulsivity scores than both neither- and morning-types. A significant association between chronotype and type of suicide attempt was detected. The largest proportion of violent suicide attempters were evening-type subjects. Violent suicide attempters also reported significantly higher impulsivity scores than nonviolent attempters. Previous studies have pointed out possible relations between eveningness and impulsivity. Current findings suggest that eveningness may be a risk factor for violent suicide attempts by increasing impulsivity.


Cortactin localization to sites of actin assembly in lamellipodia requires interactions with F-actin and the Arp2/3 complex.
Cortactin is an actin-binding protein that is enriched within the lamellipodia of motile cells and in neuronal growth cones. Here, we report that cortactin is localized with the actin-related protein (Arp) 2/3 complex at sites of actin polymerization within the lamellipodia. Two distinct sequence motifs of cortactin contribute to its interaction with the cortical actin network: the fourth of six tandem repeats and the amino-terminal acidic region (NTA). Cortactin variants lacking either the fourth tandem repeat or the NTA failed to localize at the cell periphery. Tandem repeat four was necessary for cortactin to stably bind F-actin in vitro. The NTA region interacts directly with the Arp2/3 complex based on affinity chromatography, immunoprecipitation assays, and binding assays using purified components. Cortactin variants containing the NTA region were inefficient at promoting Arp2/3 actin nucleation activity. These data provide strong evidence that cortactin is specifically localized to sites of dynamic cortical actin assembly via simultaneous interaction with F-actin and the Arp2/3 complex. Cortactin interacts via its Src homology 3 (SH3) domain with ZO-1 and the SHANK family of postsynaptic density 95/dlg/ZO-1 homology (PDZ) domain-containing proteins, suggesting that cortactin contributes to the spatial organization of sites of actin polymerization coupled to selected cell surface transmembrane receptor complexes.


L-glutamine supplementation reduces gastrointestinal permeability and biomarkers of physiological stress in preweaning Holstein heifer calves.
L-glutamine supplementation improves gastrointestinal and immune function in dairy calves during controlled immune and stress challenges. However, it is unknown whether supplementing milk replacer (MR) with L-glutamine improves preweaning dairy calf health and welfare under production conditions. Therefore, the study objective was to evaluate the effects of supplementing MR with L-glutamine on gastrointestinal permeability, immune function, growth performance, postabsorptive metabolic biomarkers, and physiological stress response in preweaning dairy calves. In 3 repetitions, Holstein heifer calves (n = 30; 1.5 ± 0.5 d old; 37.1 ± 0.86 kg body weight) were blocked by serum total protein, body weight, and age, and provided MR (3.8 L/calf per d; 24% CP, 17% fat, 12.5% solids) supplemented with L-glutamine (GLN; 10g/kg MR powder; n = 5 calves/repetition) or nonsupplemented (NSMR; n = 5 calves/repetition). Calves were individually housed with ad libitum starter grain and water access until weaning (56.4 ± 0.5 d old). At 1 and 6 wk of age, urinary catheters were placed, and calves were orally dosed with 1 L chromium (Cr)-EDTA. Urine samples were collected over a 24-h period for Cr output analysis as an in vivo biomarker of gastrointestinal permeability. Blood was collected on study d 1, 5, 7, 14, 21, 42, and 56 to measure white blood cell counts, cortisol, insulin, glucose, nonesterified fatty acids, serum amyloid A, haptoglobin, and neutrophil: lymphocyte. Two study intervals were used in the statistical analyzes representing greater (P1; wk 1-3) and reduced (P2; wk 4-8) enteric disease susceptibility. Data were analyzed using PROC GLIMMIX in SAS 9.4 with calf as the experimental unit. Overall, total urinary Cr output was reduced in GLN versus NSMR calves. Total Cr output was reduced at 1 wk of age in GLN versus NSMR calves, but no differences were detected at 6 wk of age. Neutrophil: lymphocyte was decreased both overall and during P2 in GLN versus NSMR calves, and neutrophil counts tended to be reduced in GLN versus NSMR calves during P2. No MR treatment differences were detected for average daily feed intake, average daily gain, body measurements, postabsorptive metabolic biomarkers, disease scores, and therapeutic treatments between GLN and NSMR calves. In summary, L-glutamine supplementation reduced gastrointestinal permeability and biomarkers of physiological stress in preweaning Holstein heifer calves.


Chemotherapy and metformin in pancreatic adenocarcinoma and neuroendocrine tumors.
Pancreatic cancer, despite being a relatively less commonly occurring cancer is among the deadliest ones, leading to a grave prognosis. Surgery stands as the mainstay of treatment of pancreatic cancer but is an option in less than 15% patients owing to the late presentation of the tumor. Chemotherapy offers an important part of treatment but can adversely affect the quality of life because of devastating side effects and has limited survival benefit. Unavailability of effective and less toxic treatment options for pancreatic cancer has prompted the search for new treatment strategies. One such drug being considered for its potential anti-neoplastic role is the time-tested and widely used oral hypoglycemic drug, metformin. Metformin is proposed to target metabolic pathways involved in tumorigenesis, specifically the AMPK-mTOR complex. Epidemiological evidence is mounting in favor of its role in various cancers both for treatment and prophylaxis. Herein, we aim to summarize the epidemiological data on metformin as a potential anti-cancer drug in various cancers followed by a look at some of the abstracts relating to this topic that were presented at the American Society of Clinical Oncology (ASCO) Annual Meeting 2014.


Identification of Arabidopsis mutants with altered freezing tolerance.
Low temperature is an important determinant in the configuration of natural plant communities and defines the range of distribution and growth of important crops. Some plants, including Arabidopsis, have evolved sophisticated adaptive mechanisms to tolerate low and freezing temperatures. Central to this adaptation is the process of cold acclimation. By means of this process, many plants from temperate regions are able to develop or increase their freezing tolerance in response to low, nonfreezing temperatures. The identification and characterization of factors involved in freezing tolerance are crucial to understand the molecular mechanisms underlying the cold acclimation response and have a potential interest to improve crop tolerance to freezing temperatures. Many genes implicated in cold acclimation have been identified in numerous plant species by using molecular approaches followed by reverse genetic analysis. Remarkably, however, direct genetic analyses have not been conveniently exploited in their capacity for identifying genes with pivotal roles in that adaptive response. In this chapter, we describe a protocol for evaluating the freezing tolerance of both non-acclimated and cold-acclimated Arabidopsis plants. This protocol allows the accurate and simple screening of mutant collections for the identification of novel factors involved in freezing tolerance and cold acclimation.


In vivo glucocorticoid effects on porcine natural killer cell activity and circulating leukocytes.
Porcine natural killer (NK) cell cytotoxicity, plasma cortisol, total white blood cells (WBC), neutrophil:lymphocyte ratio (N:L), and circulating blood leukocytes were examined from pigs injected i.v. with either saline, ACTH, cortisol, or treated with metyrapone. Plasma cortisol increased (P < .05) after ACTH and cortisol treatments and decreased (P < .05) after metyrapone treatment; thus, treatments had the intended effects on in vivo cortisol concentrations. In Exp. 1, pigs were injected with either saline or ACTH at 0600 after the initial blood samples were taken (time 0). The ACTH had no effect (P > .10) on NK cytotoxicity. Pigs injected i.v. with ACTH had fewer lymphocytes and more neutrophils (P < .05) than control pigs. The N:L ratio was greater (P < .05) among ACTH-injected than among control pigs. In Exp. 2, pigs were injected i.v. with either saline or 40 or 400 micrograms of cortisol at 0600 after the initial blood samples were obtained (time 0). Cortisol at 40 micrograms had no effect (P > .10) on NK cytotoxicity. However, a 400-micrograms bolus of cortisol reduced (P < .05) NK cytotoxicity (control = 39.5, cortisol = 28.3% cytotoxicity, SEM = 3.7). Each dose of cortisol reduced (P < .05) circulating blood lymphocyte numbers. In Exp. 3, pigs were fed 1 g of metyrapone or no metyrapone the night before sampling. Blood samples were obtained at 0600, 0700, and 0800. Metyrapone reduced (P < .05) NK cytotoxicity (control = 28.6, metyrapone = 11.8%, SEM = 1.9). Pigs treated with metyrapone had greater (P < .05) numbers of neutrophils than control pigs. Numbers of lymphocytes were greater (P < .05) among control than among treated pigs. Pigs treated with metyrapone had a greater (P < .05) N:L ratio than control pigs. In conclusion, normal physiological concentrations or moderately increased blood cortisol concentrations did not influence NK activity, although leukocyte distributions were changed. We conclude that greatly increased or greatly decreased circulating concentrations of cortisol reduced NK cytotoxicity.


[Factors influencing depression in elderly people living at home].
This study was done to identify the factors which influence depression for elderly people who live at home. The participants were 134 elderly people living at home in M city. Data were collected from April 2 to 30, 2009 and analyzed using SPSS/WIN 12.0 and AMOS 5.0 program. I assumed path coefficients by doing path analysis to understand synthetically causal relationship which influences on depression. Social support, sleep pattern and self esteem had significant direct effects on life satisfaction and accounted for 50% of the total variance in life satisfaction. Physical symptoms, sleep pattern and life satisfaction also had significant direct effects on depression and accounted for 59% of the variance in depression. But social support, self assertiveness and self esteem were not significant for depression. These results provide guidance for designing useful strategies to reduce depression in elderly people living at home.


Cannabinoids for behavioral symptoms in severe dementia: Safety and feasibility in a long-term pilot observational study in nineteen patients.
The management of behavioral symptoms and rigidity in patients with dementia constitutes a significant challenge. Short-term studies suggest an interest in the use of medical cannabis, but long-term data are lacking. The objective of this study was to investigate the feasibility and long-term safety of administering tetrahydrocannabinol/cannabidiol (THC/CBD) treatment as an additional drug to a poly medicated population with severe dementia, evaluate clinical improvements, and collect information on the pharmacokinetics of cannabinoids and possible drug-drug interactions. A prospective observational study of patients with severe dementia living in a long-term care home to whom the physicians had prescribed a medical cannabis treatment. Data were collected over 2 years. We assessed the changes in medical cannabis dosages, safety parameters, variations in neuropsychiatric problems, agitation, rigidity, the most invalidating daily activity, and disabling behavior trouble scores. We evaluated the pharmacokinetics of cannabinoids by measuring plasma levels and analyzing the enzymatic activity. We assessed 19 patients (81.4 years-17 women and two men) receiving an average of 12.4 mg THC/24.8 mg CBD per day for up to 13 months, with no reported problems related to the treatment and limited adverse drug reactions. Clinical scores showed a marked improvement that was stable over time, deprescription of other medications, and care facilitated. The pharmacokinetic evaluation showed an expected slight reduction in the enzymatic activity of CYP1A2 and CYP2C19. A long-term THC/CBD (1:2) medication can be administered safely and with overall positive clinical improvement to poly medicated older adults with severe dementia and associated problems. The results must be confirmed in a randomized trial.


The role of microRNAs in the biology of rare diseases.
Rare diseases (RD) are characterized by low prevalence and affect not more than five individuals per 10,000 in the European population; they are a large and heterogeneous group of disorders including more than 7,000 conditions and often involve all organs and tissues, with several clinical subtypes within the same disease. Very often information concerning either diagnosis and/or prognosis on many RD is insufficient. microRNAs are a class of small non-coding RNAs that regulate gene expression at the posttranscriptional level by either degrading or blocking translation of messenger RNA targets. Recently, microRNA expression patterns of body fluids underscored their potential as noninvasive biomarkers for various diseases. The role of microRNAs as potential biomarkers has become particularly attractive. The identification of disease-related microRNAs is essential for understanding the pathogenesis of diseases at the molecular level, and is critical for designing specific molecular tools for diagnosis, treatment and prevention. Computational analysis of microRNA-disease associations is an important complementary means for prioritizing microRNAs for further experimental examination. In this article, we explored the added value of miRs as biomarkers in a selected panel of RD hitting different tissues/systems at different life stages, but sharing the need of better biomarkers for diagnostic and prognostic purposes.


Novel In Situ Synthesis of Freestanding Carbonized ZIF67/Polymer Nanofiber Electrodes for Supercapacitors via Electrospinning and Pyrolysis Techniques.
Zeolitic imidazolate framework-67 (ZIF67) has been regarded as an effective energy storage material due to its high surface area and electroactive cobalt center. Carbonizing ZIF67 can enhance electrical conductivity by converting 2-methylimidazole (2-melm) to carbon with cobalt doping. In this work, a novel in situ electrospinning is proposed to fabricate carbonized ZIF67 on carbon fiber (C67@PAN-OC) as a freestanding supercapacitor electrode. Polyacrylonitrile solution containing a cobalt precursor is used for electrospinning, and produced fibers are immersed in 2-melm to form ZIF67. Individually grown carbonized ZIF67 on carbon fiber is obtained using the in situ electrospinning method, while the one-body mixed carbon electrode is formed using the ex situ electrospinning method. A highest specific capacitance (CF) of 386.3 F/g at 20 mV/s is obtained for the in situ synthesized C67@PAN-OC electrode due to the largest electrochemical surface area and the smallest resistance, while the ex situ synthesized electrode only shows a CF value of 27.7 F/g. A symmetric supercapacitor (SSC) assembled using the optimized C67@PAN-OC electrodes and gel electrolytes shows a maximum energy density of 9.64 kWh/kg at 0.55 kW/kg and a CF retention of 59.5% after 1000 times charge/discharge process. A CF retention of 75.6% after bending 100 times is also obtained for SSC.


Value of screening for markers of hepatitis in dialysis units.
The value of monitoring the serum activity of SGOT, as well as markers of hepatitis B virus and hepatitis A virus infections, in the patients and staff of two dialysis units has been assessed retrospectively. Sera were checked each month for SGOT and HBsAg on 406 patients and 170 staff members over a 4-year period. Anti-HBc, anti-HBs, and anti-hepatitis A antibodies were assayed on the stored sera. Only 30% of the patients had normal SGOT values (less than 65 units per ml) on all occasions. Most of the abnormal values were less than 100 units per ml and could not be explained. Viral hepatitis was a reasonable explanation for only half of those instances where the SGOT value was greater than 100 units per ml. Hepatitis A virus contributed nothing to the problem of dialysis-associated liver disease. Testing for HBsAg alone missed approximately 40% of the hepatitis B events acquired in the unit. Only two of these episodes were of epidemiologic importance, however, because the rest were recognized only after there was serologic resolution of the infection. There was a high frequency of potentially "false positive" reactions with all the antibodies tested. It is not cost-effective to monitor dialysis patients and staff regularly with anti-HBc, anti-HBs, or antibodies against hepatitis A. Initial screening with anti-HBc and anti-HBs on entry to the unit is of value but weak positive results must be interpreted with caution since approximately half of such results will prove to be nonspecific.


Optimizing the management of HER2-positive early breast cancer: the clinical reality.
Breast cancer positive for HER2 (human epidermal growth factor receptor 2) is associated with a poor prognosis for patients with both early-stage and metastatic breast cancer. Trastuzumab has been shown to be effective and is now considered the standard of care for early-stage patients with HER2-positive breast cancer. In that population, trastuzumab has been studied in six randomized clinical trials. Overall, use of this agent leads to a significant reduction in risk of disease recurrence and improvement in overall survival. Despite the strong evidence for the use of trastuzumab in managing HER2-positive early breast cancer (EBC), a number of clinical controversies remain. The authors of this paper undertook a review of the available scientific literature on adjuvant trastuzumab to produce practical considerations from Canadian oncologists. The panel focused their discussion on five key areas: Management of node-negative disease with tumours 1 cm or smaller in size. Management of HER2-positive EBC across the spectrum of the disease (that is, nodal and steroid hormone receptor status, tumour size) Timing of trastuzumab therapy with chemotherapy for early-stage disease: concurrent or sequential. Treatment duration of trastuzumab for EBC. The role of non-anthracycline trastuzumab-based regimens.


Auditory effects of developmental exposure to purity-controlled polychlorinated biphenyls (PCB52 and PCB180) in rats.
Polychlorinated biphenyls (PCBs) are still present in the environment, with ongoing exposure in humans, including babies nursed by their mothers. Whereas toxicity of dioxin-like PCBs is well described, less systematic knowledge is available for non-dioxin like PCBs (NDL-PCBs) that do not act via the Ah receptor. This study compared effects of developmental exposure to two ultrapure NDL-PCB congeners (PCB52 and PCB180) on auditory function in rats, using the brainstem auditory evoked potential (BAEP). Pregnant rats received repeated oral doses of PCB52 (total dose-0, 30, 100, 300, 1000, or 3000 mg/kg body weight) or of PCB180 (total dose-0, 10, 30, 100, 300, or 1000 mg/kg). BAEPs were recorded in adult male and female offspring after stimulation with clicks or pure tones in the frequency range from 0.5 to 16 kHz. Significant elevation of BAEP thresholds was detected in the low-frequency range after developmental exposure to PCB52. Calculation of benchmark doses revealed lowest values in the frequency range of 0.5-2 kHz. Effects were more pronounced in male compared with female offspring. Latencies of waves II and IV were prolonged in exposed males, whereas only wave IV was affected in females. PCB180 increased thresholds only at few conditions and only in female offspring. These results confirm that developmental exposure to ultrapure NDL-PCBs affects auditory function, but different congeners exhibit differences in potencies.


The role of tissue adhesives and sealants in colorectal anastomotic healing-a scoping review.
Anastomotic leakage (AL) after colorectal resection is a serious postoperative complication with grave consequences for patients. Despite several efforts to reduce its incidence, AL is still seen among 2-20% of colorectal cancer patients receiving an anastomosis. The use of tissue adhesives and sealants as an extra layer of protection around the anastomosis has shown promising results. We conducted a scoping review to provide an overview of the current knowledge on the effect of tissue adhesives and sealants on colorectal anastomosis healing, as well as their effect on the postoperative outcome. The databases of PubMed, Embase, and Cochrane Library were systematically searched on 14/10/2022. Studies addressing the use of a tissue adhesive or tissue sealant applied around a colorectal anastomosis, with the goal to prevent AL or to decrease AL-related complications, were included. We presented an overview of the available studies and summarized their results narratively. Seven studies were included out of the 846 screened. All authors reported the rate of AL in their interventions group. Five of the studies found a decreased rate of AL compared to the control group. One study had no incidences of AL, while the last study had a seemingly low rate of AL but no comparison group. Information on secondary outcomes was sparingly reported, but the results hinted at a positive effect. Tissue adhesives and sealants might have a beneficial effect on colorectal anastomosis healing. The literature is sparse, and this review has shown the need for further clinical studies.


Influence of weight status in the response to Step-2 maintenance therapies in children with asthma.
Overweight children with asthma may display impaired response to inhaled corticosteroids (ICS), possibly due to non-eosinophilic inflammation or weight-related lung compression; these mechanisms may differentially affect response to ICS and leukotriene receptor antagonists (LTRAs). We assessed whether weight status modified the response to low-dose ICS and LTRA Step-2 monotherapy. A historical cohort study from clinical data linked to administrative databases was conducted among children aged 2-18 years with specialist-diagnosed asthma who were initiating or continuing a Step-2 monotherapy from 2000 to 2007 at the Montreal Children's Hospital Asthma Centre. The outcome was time-to-management failure defined as any step-up in therapy, acute care visit, hospitalisation or oral corticosteroids for asthma, whichever occurred first. The independent and joint effects of weight status (body mass index [BMI] percentile) and time-varying treatment on time-to-management failure were estimated with marginal structural Cox models. The likelihood ratio test (LRT) and relative excess risk due to interaction (RERI) were computed to assess treatment effect modification by weight status on the multiplicative and additive scales. Of the 433 and 85 visits with a low-dose ICS and LTRA prescription, respectively, 388 management failures occurred over 14 529 visit-weeks of follow-up. Children using LTRA compared with low-dose ICS tended to have an overall higher risk of early management failure (HR 1.52; 95% CI 0.72 to 3.22). Irrespective of treatment, the hazard of management failure increased by 5% (HR 1.05; 95% CI 1.01 to 1.10) for every 10-unit increase in BMI percentile. An additional hazard reduction of 17% (HR 0.83; 95% CI 0.70 to 0.99) was observed for every 10-unit increase in BMI percentile among LTRA users, but not for ICS (HR 0.95; 95% CI 0.86 to 1.04). The LRT indicated a departure from exact multiplicativity (p<0.0001), and the RERIs for ICS and LTRA were -0.05 (95% CI -0.14 to 0.05) and -0.52 (95% CI -1.76 to 0.71). Weight status was associated with earlier time-to-management failure in children prescribed Step-2 therapy. This hypothesis-generating study suggests that LTRA response increases in children with higher BMI percentiles, although further research is warranted to confirm findings.


Epidemiologic, clinical and socioeconomic factors of atopic dermatitis in Spain: Alergológica-2005.
To analyze the clinical and epidemiologic characteristics of the population with atopic dermatitis (AD) consulting in Allergology services in Spain. The study was a multi-center, observational, descriptive, cross-sectional epidemiologic study with prospective collection of data on patients consulting for the first time in Allergology services in Spain. By means of a data collection record, personal and specific variables were collected during the calendar year 2005 from a total of 4991 patients with AD. AD was diagnosed in 171 patients (3.4% of patients seen in Allergology services), which represented no significant change with regard to the Alergológica-1992 study. In 72% of cases, AD was associated with other allergic disorders. The mean age of the onset of clinical manifestations of AD was 1 year and 4 months. During the first consultations, the suspected diagnosis of AD was established in 83% of cases. In 58% of cases the cause was considered idiopathic and 42% were associated with sensitization to allergens. In 10% of patients with AD the triggering allergens were foods and in 26% aeroallergens. Most patients (94%) received hydrating skin and drug treatment (anti-histamines 73%, topical corticoids 49%, calcineurin inhibitors 31%). Only 10% of patients followed an exclusion diet. No significant increase in the demand for AD consultations was observed in comparison with Alergológica-1992. AD was frequently associated with other allergic disorders. In few cases was food involved in the etiology of the disease. In most cases nothing more than topical drug treatment was indicated.


Women's policy networks and the Infanticide Act 1922.
This article examines the reason for the passage of the 1922 Infanticide Act, arguing that it owes much to the influence and work of women's policy networks. Historians have disagreed as to why the Act was passed with relative suddenness in the early 1920s, at a time when infanticide was generally considered a much less pressing social issue than it had been in Victorian England. Moreover, several Bills brought between 1908 and 1913 proposing that the law on this subject be amended so that women who killed their newborns no longer faced the death penalty had all failed. Importantly, the roles of juror and lay magistrate had become open to women in 1920, following the passage of the Sex Disqualification (Removal) Act 1919. The public interest generated by a case of newborn murder tried at the Leicester Assizes in 1921 (particularly amongst women's organizations, including the suffragette group the Women's Freedom League) led several leading women with political connections to push for a change in the law. Without the pressure these women could bring to bear on civil servants and politicians, attempts to bring in new legislation on infanticide would have been postponed well into the twentieth century.


A systems approach to clinical oncology uses deep phenotyping to deliver personalized care.
Cancer encompasses a complex, heterogeneous and dynamic group of diseases that arise from perturbations to multiple biological networks within the body. A systems biology-based approach would help to decipher this complexity, to deeply characterize the pathophysiology of the disease and to stratify cancers into appropriate molecular subtypes to facilitate the development of personalized therapies. Technological advances made over the past decade have enabled multiscale, longitudinal measurements ('snapshots') of human biology, from single-cell analyses to whole-body monitoring. In this Perspective, we discuss some of these technologies and how they have (and will) contributed to our understanding of cancer biology as well as to the development of early diagnostics and personalized therapies. We argue that the integration of molecular profiling of cancerous tissues with deep, longitudinal profiling of the physiological state of an individual ('deep phenotyping') is key to understanding the prevention, initiation, progression and response to treatment of cancers. Systems biology-based approaches can provide an unprecedented trove of data for early detection of disease transitions, prediction of therapeutic responses and clinical outcomes, and for the design of personalized treatments.


Ongoing activity of Toscana virus genotype A and West Nile virus lineage 1 strains in Turkey: a clinical and field survey.
Toscana virus (TOSV), West Nile virus (WNV) and tickborne encephalitis virus (TBEV) are among major viral pathogens causing febrile disease and meningitis/encephalitis. The impact of these viruses was investigated at a referral centre in Ankara Province, Central Anatolia in 2012, where previous reports suggested virus circulation but with scarce information on clinical cases and vector activity. Serum and/or cerebrospinal fluid samples from 94 individuals were evaluated, in addition to field-collected arthropod specimens that included 767 sandflies and 239 mosquitoes. Viral nucleic acids in clinical samples and arthropods were sought via specific and generic nested/real-time PCRs, and antibody responses in clinical samples were investigated via commercial indirect immunofluorescence tests (IIFTs) and virus neutralization. A WNV antigen assay was also employed for mosquitoes. WNV neuroinvasive disease has been identified in a 63-year-old male via RNA detection, and the WNV strain was characterized as lineage 1. TOSV infections were diagnosed in six individuals (6.3%) via RNA or IgM detection. Partial sequences in a 23-year-old female, presented with fever and transient pancytopenia, were characterized as TOSV genotype A. Febrile disease with arthralgia and/or peripheral cranial nerve involvement was noted in cases with TOSV infections. Previous WNV and TOSV exposures have been observed in 5.3% and 2.1% of the subjects, respectively. No confirmed TBEV exposure could be identified. Morphological identification of the field-collected mosquitoes revealed Culex pipiens sensu lato (74.4%), Anopheles maculipennis (20.9%), An. claviger (2.1%) and others. Sandfly species were determined as Phlebotomus papatasi (36.2%), P. halepensis (27.3%), P. major s. l. (19.3%), P. sergenti (8.9%), P. perfiliewi (4.4%), P. simici (2.6%) and others. Viral infections in arthropods could not be demonstrated. TOSV genotype A and WNV lineage 1 activity have been demonstrated as well as serologically proven exposure in patients. Presence of sandfly and mosquito species capable of virus transmission has also been revealed.


Supercoiled induced transition to the Z-DNA conformation affects the ability of a d(CG/GC)12 sequence to be organized into nucleosome-cores.
Nucleosome-cores were reconstituted by the salt-dialysis method onto closed circular pDHg16 DNA which contains a d(CG/GC)12 sequence. Alternating d(CG/GC)n sequences form left-handed Z-DNA readily when contained in negatively supercoiled DNA. We have investigated the ability of the d(CG/GC)12 sequence to be organized into nucleosome-cores when stabilized as Z-DNA through negative supercoiling. We have found that nucleosome assembly at the d(CG/GC)12 insert is prevented when the sequence is stable in the Z-conformation but it is not affected at all when the sequence adopts the right-handed B-form.


Home and community care services: a major opportunity for preventive health care.
In Australia, the Home and Community Care (HACC) program provides services in the community to frail elderly living at home and their carers. Surprisingly little is known about the health of people who use these services. In this study we sought to describe health-related factors associated with use of HACC services, and to identify potential opportunities for targeting preventive services to those at high risk. We obtained questionnaire data from the 45 and Up Study for 103,041 men and women aged 45 years and over, sampled from the general population of New South Wales, Australia in 2006-2007, and linked this with administrative data about HACC service use. We compared the characteristics of HACC clients and non-clients according to a range of variables from the 45 and Up Study questionnaire, and estimated crude and adjusted relative risks for HACC use with generalized linear models. 4,978 (4.8%) participants used HACC services in the year prior to completing the questionnaire. Increasing age, female sex, lower pre-tax household income, not having a partner, not being in paid work, Indigenous background and living in a regional or remote location were strongly associated with HACC use. Overseas-born people and those speaking languages other than English at home were significantly less likely to use HACC services. People who were underweight, obese, sedentary, who reported falling in the past year, who were current smokers, or who ate little fruit or vegetables were significantly more likely to use HACC services. HACC service use increased with decreasing levels of physical functioning, higher levels of psychological distress, and poorer self-ratings of health, eyesight and memory. HACC clients were more likely to report chronic health conditions, in particular diabetes, stroke, Parkinson's disease, anxiety and depression, cancer, heart attack or angina, blood clotting problems, asthma and osteoarthritis. HACC clients have high rates of modifiable lifestyle risk factors and health conditions that are amenable to primary and secondary prevention, presenting the potential for implementing preventive health care programs in the HACC service setting.


Human scavenger receptor class B type II (SR-BII) and cellular cholesterol efflux.
Although studies in recombinant cells indicate that scavenger receptor class B, type I (SR-BI) can promote cholesterol efflux, investigations in transgenic mice overexpressing or deficient in SR-BI endorse its physiological function as selectively sequestering cholesteryl esters from high-density lipoproteins (HDLs). Less clear is the role of SR-BII, a splice variant of the SR-B gene that differs only in the C-terminal cytoplasmic domain. Here, we identify several putative signalling motifs in the C-terminus of human SR-BII, which are absent from SR-BI, and hypothesize that these motifs interact with signalling molecules to mobilize stored cholesteryl esters and/or promote the efflux of intracellular free cholesterol. 'Pull-down' assays using a panel of tagged SH3 (Src homology 3) domains showed that cytoplasmic SR-BII, but not cytoplasmic SR-BI, bound the SH3 domain of phospholipase C-gamma1; this interaction was not, however, detected under more physiological conditions. Specific anti-peptide antisera identified SR-BII in human monocyte/macrophage THP-1 cells and, in recombinant cells, revealed receptor localization to caveolae, a plasma membrane microdomain that concentrates signal-transducer molecules and acts as a conduit for cholesterol flux between cells and lipoproteins. Consistent with its caveolar localization, expression of human SR-BII in recombinant Chinese hamster ovary cells (CHO-SR-BII) was associated with increased HDL-mediated cholesterol efflux. Nevertheless, when CHO-SR-BII cells were pre-loaded with cholesteryl [(3)H]oleate and incubated with HDL, cholesteryl ester stores were not reduced compared with control cells. We conclude that although human SR-BII is expressed by macrophages, contains cytoplasmic signalling motifs and localizes to caveolae, its ability to stimulate cholesterol efflux does not reflect enhanced hydrolysis of stored cholesteryl esters.


Disrupted ADP-ribose metabolism with nuclear Poly (ADP-ribose) accumulation leads to different cell death pathways in presence of hydrogen peroxide in procyclic Trypanosoma brucei.
Poly(ADP-ribose) (PAR) metabolism participates in several biological processes such as DNA damage signaling and repair, which is a thoroughly studied function. PAR is synthesized by Poly(ADP-ribose) polymerase (PARP) and hydrolyzed by Poly(ADP-ribose) glycohydrolase (PARG). In contrast to human and other higher eukaryotes, Trypanosoma brucei contains only one PARP and PARG. Up to date, the function of these enzymes has remained elusive in this parasite. The aim of this work is to unravel the role that PAR plays in genotoxic stress response. The optimal conditions for the activity of purified recombinant TbPARP were determined by using a fluorometric activity assay followed by screening of PARP inhibitors. Sensitivity to a genotoxic agent, H2O2, was assessed by counting motile parasites over the total number in a Neubauer chamber, in presence of a potent PARP inhibitor as well as in procyclic transgenic lines which either down-regulate PARP or PARG, or over-express PARP. Triplicates were carried out for each condition tested and data significance was assessed with two-way Anova followed by Bonferroni test. Finally, PAR influence was studied in cell death pathways by flow cytometry. Abolition of a functional PARP either by using potent inhibitors present or in PARP-silenced parasites had no effect on parasite growth in culture; however, PARP-inhibited and PARP down-regulated parasites presented an increased resistance against H2O2 treatment when compared to their wild type counterparts. PARP over-expressing and PARG-silenced parasites displayed polymer accumulation in the nucleus and, as expected, showed diminished resistance when exposed to the same genotoxic stimulus. Indeed, they suffered a necrotic death pathway, while an apoptosis-like mechanism was observed in control cultures. Surprisingly, PARP migrated to the nucleus and synthesized PAR only after a genomic stress in wild type parasites while PARG occurred always in this organelle. PARP over-expressing and PARG-silenced cells presented PAR accumulation in the nucleus, even in absence of oxidative stress. Procyclic death pathway after genotoxic damage depends on basal nuclear PAR. This evidence demonstrates that the polymer may have a toxic action by itself since the consequences of an exacerbated PARP activity cannot fully explain the increment in sensitivity observed here. Moreover, the unusual localization of PARP and PARG would reveal a novel regulatory mechanism, making them invaluable model systems.


Wavelet scattering networks in deep learning for discovering protein markers in a cohort of Swedish rectal cancer patients.
Cancer biomarkers play a pivotal role in the diagnosis, prognosis, and treatment response prediction of the disease. In this study, we analyzed the expression levels of RhoB and DNp73 proteins in rectal cancer, as captured in immunohistochemical images, to predict the 5-year survival time of two patient groups: one with preoperative radiotherapy and one without. The utilization of deep convolutional neural networks in medical research, particularly in clinical cancer studies, has been gaining substantial attention. This success primarily stems from their ability to extract intricate image features that prove invaluable in machine learning. Another innovative method for extracting features at multiple levels is the wavelet-scattering network. Our study combines the strengths of these two convolution-based approaches to robustly extract image features related to protein expression. The efficacy of our approach was evaluated across various tissue types, including tumor, biopsy, metastasis, and adjacent normal tissue. Statistical assessments demonstrated exceptional performance across a range of metrics, including prediction accuracy, classification accuracy, precision, and the area under the receiver operating characteristic curve. These results underscore the potential of dual convolutional learning to assist clinical researchers in the timely validation and discovery of cancer biomarkers.


Neutrophilic eccrine hidradenitis: a case report of an unusual annular presentation.
Neutrophilic eccrine hidradenitis (NEH) is an acute, self-limited, inflammatory neutrophilic dermatosis. It is most commonly described in patients with acute myelogenous leukemia (AML) following chemotherapy. NEH generally presents as erythematous papules and plaques on the head, trunk, and extremities. Histologically, NEH is characterized by a neutrophilic infiltrate surrounding eccrine ducts and coils with occasional necrosis. We describe a case of NEH with an unusual presentation of annular plaques. A search of the literature revealed only one other case report of NEH presenting as an annular eruption.


Culturally tailored intervention for rural African Americans with type 2 diabetes.
The purpose of this pilot study was to evaluate a culturally tailored intervention for rural African Americans. Social Cognitive Theory provided the framework for the study. Twenty-two participants were recruited and randomly assigned to either Group or Individual diabetes self-management (DSME). Group DSME included story-telling, hands-on activities, and problem-solving exercises. Individual DSME sessions focused on goal-setting and problem-solving strategies. Sessions were offered in an accessible community center over a 10-week period. Outcomes included glycosylated hemoglobin (A1C), self-care actions, self-efficacy level, goal attainment, and satisfaction with DSME. Participants in both Group and Individual DSME improved slightly over the 3-month period in self-care activities, A1C level, and goal attainment. Although differences were not statistically significant, trends indicate improved scores on dietary actions, foot care, goal attainment, and empowerment for those experiencing Group DSME. The culturally tailored approach was well received by all participants. Improvements among those receiving Individual DSME may indicate that brief sessions usinga culturally tailored approach could enhance self-care and glycemic control. Additional testing among more participants over a longer time period is recommended.


[Effect of temperature for tumescence anesthesia solution on intraoperative and postoperative pain of endovenous laser ablation of lower extremity varicose vein].
To compare the effect of cold or room temperature of tumescence anesthesia solution on pain perception during and after endovenous laser ablation (EVLA) for varicose veins of lower limb. Methods: A total of 51 patients with lower extremity varicose vein were treated by EVLA with tumescence anesthesia solution. All patients were used for local anesthesia and randomly divided into 2 groups according to the temperature of tumescence anesthesia solution: Group A (n=26) with room temperature (24 ℃) of tumescence anesthesia solution and Group B (n=25) with cold (4 ℃) tumescence anesthesia solution. Number rating scale (NRS) was recorded immediately after the procedure and postoperative 1, 2, 3 day. Patients were asked to register pain scores during the week. Results: The mean linear endovenous energy density (LEED) in the 2 groups was not significantly different (P>0.05). The ratio of patients without pain during the operation in the Group A was lower than that in the Group B (30.8% vs 64%, P<0.05). On the day of operation and postoperative day 1, 2, 3, the average number rating scale (NRS) scores in the Group A were greater than those in the Group B (P<0.05). Postoperative day 1, only 30.8% of the patients in the Group A resumed daily activities, which was lower than that (68% of the patients) in the Group B. Conclusion: In the process of EVLA for varicose veins of lower limb, there is less pain during operation and post-operation using cold tumescence anesthesia solution comparing room temperature tumescence anesthesia solution.


Clinical usefulness of the Framingham cardiovascular risk profile beyond its statistical performance: the Tehran Lipid and Glucose Study.
The utility of a risk function in clinical practice is an important concept that has received insufficient attention. The authors evaluated the clinical usefulness of the Framingham risk function (FRF) for cardiovascular disease in a Middle Eastern population (2,640 men and 3,584 women aged 30-74 years) free of cardiovascular disease at baseline in 1999. They calculated the net benefit fraction for treatment of subjects with an estimated 10-year risk of ≥10% and also ≥20%, where the net benefit fraction is a weighted sum of true-positive and false-positive rates divided by incidence, as estimated by Kaplan-Meier analysis. The authors drew a decision curve by plotting the net benefit fraction against a wide range of risk thresholds for treatment. The cumulative incidence of cardiovascular disease was 7.6% and 12.3% in women and men, respectively. The FRF had a C index of 0.832 in women and 0.785 in men with a reasonable calibration. On the basis of the net benefit fraction, about 50% of the incidence in men and women could be appropriately treated by using the 10% threshold; however, the FRF was not useful at the 20% threshold, especially in women. In both genders, usefulness of the FRF was as good as the function derived directly from Tehrani data with the same variables; however, it could be useful in low thresholds for treatment.


A global test of the pollination syndrome hypothesis.
'Pollination syndromes' are suites of phenotypic traits hypothesized to reflect convergent adaptations of flowers for pollination by specific types of animals. They were first developed in the 1870s and honed during the mid 20th Century. In spite of this long history and their central role in organizing research on plant-pollinator interactions, the pollination syndromes have rarely been subjected to test. The syndromes were tested here by asking whether they successfully capture patterns of covariance of floral traits and predict the most common pollinators of flowers. Flowers in six communities from three continents were scored for expression of floral traits used in published descriptions of the pollination syndromes, and simultaneously the pollinators of as many species as possible were characterized. Ordination of flowers in a multivariate 'phenotype space' defined by the syndromes showed that almost no plant species fall within the discrete syndrome clusters. Furthermore, in approximately two-thirds of plant species, the most common pollinator could not be successfully predicted by assuming that each plant species belongs to the syndrome closest to it in phenotype space. The pollination syndrome hypothesis as usually articulated does not successfully describe the diversity of floral phenotypes or predict the pollinators of most plant species. Caution is suggested when using pollination syndromes for organizing floral diversity, or for inferring agents of floral adaptation. A fresh look at how traits of flowers and pollinators relate to visitation and pollen transfer is recommended, in order to determine whether axes can be identified that describe floral functional diversity more successfully than the traditional syndromes.


Monocytes of patients with unstable angina express high levels of chemokine and pattern-recognition receptors.
Macrophages derived from monocytes play an important role in atherosclerosis progression. Subpopulations of circulating classical, intermediate, and non-classical monocytes possess distinct functions and phenotypes, and participate in the pathogenesis of disease. The aim of this study was to compare the quantity and phenotypes of circulating monocyte subpopulations in patients with established atherosclerosis and healthy control individuals. Additionally, the study aimed to provide insight into the functional activity of monocytes against a heat shock protein (HSP60). Chemokine and pattern recognition receptors in monocyte subsets obtained from peripheral blood of acute and chronic coronary artery disease patients and controls were quantified by flow cytometry. Furthermore, monocytes from healthy controls were stimulated in vitro with HSP60, and the cytokines produced by them were evaluated by flow cytometry. Eighteen controls (C), 34 individuals with risk factors for cardiovascular disease (RF), 32 patients with stable angina (SA), and 16 patients with unstable angina (UA) were enrolled in the study. The absolute count of intermediate monocytes was found to be increased in patients of the UA group; high frequencies of the chemokine receptors CCR2, CCR5, and CX3CR1 were also observed in this subpopulation. Moreover, the pattern recognition receptors TLR2 and TLR4 were more frequent in intermediate monocytes from the UA group. Furthermore, the intermediate monocytes from healthy individuals produced IL-12p70 after stimulation with HSP60. Our results show that intermediate monocytes of UA patients exhibited an enhanced expression of the receptors involved in the recognition of damage-associated molecular patterns (DAMPs) and enhancement of the migratory function. Hence, they might contribute to the propagation and progression of inflammation observed in atherosclerosis, especially in the acute setting.


Quorum quenching revisited--from signal decays to signalling confusion.
In a polymicrobial community, while some bacteria are communicating with neighboring cells (quorum sensing), others are interrupting the communication (quorum quenching), thus creating a constant arms race between intercellular communication. In the past decade, numerous quorum quenching enzymes have been found and initially thought to inactivate the signalling molecules. Though this is widely accepted, the actual roles of these quorum quenching enzymes are now being uncovered. Recent evidence extends the role of quorum quenching to detoxification or metabolism of signalling molecules as food and energy source; this includes "signalling confusion", a term coined in this paper to refer to the phenomenon of non-destructive modification of signalling molecules. While quorum quenching has been explored as a novel anti-infective therapy targeting, quorum sensing evidence begins to show the development of resistance against quorum quenching.


Exploring the binding mechanism between methylene blue and ovalbumin using spectroscopic analyses and computational simulations.
The detailed investigation of methylene blue (MB) dye with ovalbumin (OVA) was examined by multispectroscopic and computational techniques. The experimental results of emission spectral studies displayed that the quenching behaviour of OVA with MB dye is due to static quenching mechanism. Isothermal titration calorimetry experimental results suggested that the binding of MB dye became favoured with the aid of a favourable entropy contribution and negative enthalpy. The absorption and circular dichroism spectral experiments showed that the binding of MB dye prompted conformational modifications to the secondary structure of OVA protein. The computational studies have been used to predict the binding region and the stability of MB in OVA protein.Communicated by Ramaswamy H. Sarma.


Electronic Cigarette Use in 12 European Countries: Results From the TackSHS Survey.
Limited data on electronic cigarette prevalence, patterns, and settings of use are available from several European countries. Within the TackSHS project, a face-to-face survey was conducted in 2017-2018 in 12 European countries (Bulgaria, England, France, Germany, Greece, Ireland, Italy, Latvia, Poland, Portugal, Romania and Spain). Overall, 11,876 participants, representative of the population aged ⩾15 years in each country, provided information on electronic cigarette. 2.4% (95% confidence interval [CI], 2.2-2.7%) of the subjects (2.5% among men and 2.4% among women; 0.4% among never, 4.4% among current- and 6.5% among ex-smokers) reported current use of electronic cigarette, ranging from 0.6% in Spain to 7.2% in England. Of the 272 electronic cigarette users, 52.6% were dual users (ie, users of both electronic and conventional cigarettes) and 58.8% used liquids with nicotine. In all, 65.1% reported using electronic cigarette in at least one indoor setting where smoking is forbidden; in particular, at workplaces (34.9%) and bars and restaurants (41.5%). Multivariable logistic regression analysis showed that electronic cigarette use was lower among older individuals (P for trend <0.001) and higher among individuals with high level of education (P for trend = 0.040). Participants from countries with higher tobacco cigarette prices more frequently reported electronic cigarette use (odds ratio 3.62; 95% CI, 1.80-7.30). Considering the whole adult population of these 12 European countries, more than 8.3 million people use electronic cigarettes. The majority of users also smoked conventional cigarettes, used electronic cigarettes with nicotine, and consumed electronic cigarettes in smoke-free indoor areas.


[Painless swelling proved to be a central giant cell granuloma].
A 32-year-old female patient was referred to an oral and maxillofacial surgeon with an asymptomatic swelling in the left mandibular premolar region. After extraction of these premolars and enucleation of the lesion histopathological examination confirmed the presence of a giant cell granuloma. This is a benign lesion and enucleation generally results in a permanent cure and is only recurrent in a few cases. Approximately 1 year after treatment, the patient was still free of recurrence and together with a prosthodontist, the appropriate rehabilitation of the resulting defect will be sought.


Ceftriaxone once daily for four weeks compared with ceftriaxone plus gentamicin once daily for two weeks for treatment of endocarditis due to penicillin-susceptible streptococci. Endocarditis Treatment Consortium Group.
This randomized, multicenter, open-label study compared the efficacy and safety of monotherapy with 2 g of intravenous ceftriaxone once daily for 4 weeks with those of combination therapy with 2 g of intravenous ceftriaxone and 3 mg of intravenous gentamicin/kg once daily for 2 weeks as therapy for endocarditis due to penicillin-susceptible streptococci. Sixty-one patients were enrolled in the study. Clinical cure was observed for 51 evaluable patients both at termination of therapy and at the 3-month follow-up: 25 (96.2%) of 26 monotherapy recipients and 24 (96%) of 25 combination therapy recipients. Of the 23 patients in each treatment group who were microbiologically evaluable, 22 (95.7%) in each group were considered cured. No patient had evidence of relapse. Fourteen patients (27.5%) required cardiac surgery after initiation of treatment, including five monotherapy recipients and nine combination therapy recipients. Adverse effects were minimal in both treatment groups. We conclude that 2 g of ceftriaxone once daily for 4 weeks and 2 g of ceftriaxone in combination with 3 mg of gentamicin/kg once daily for 2 weeks are both effective and safe for the treatment of streptococcal endocarditis.


[Spin label study of the structure and conformational properties of fibers from cotton grown from gamma-irradiated seeds].
According to ESR spectra of the radical - probe I it has been shown that there are two regions in cotton cellulose: ordered and disordered ones, pointing to inhibition and free rotation of the radical. 40 spin-labeled samples of cotton filaments and their mutants by the radicals II-IX chemically bound by the cellulose hydroxyl group were obtained. From ESR spectra strong inhibition of iminoxyl radical was established which was the evidenced of high rigidity of disordered regions of cellulose. Conformational changes of cotton cellulose grown from seeds exposed to different doses of gamma-irradiation.


Biodegradation of atrazine in surface soils and subsurface sediments collected from an agricultural research farm.
The purpose of the present study was to assess atrazine (2-chloro-4-ethylamino-6-isopropylamino-s-triazine) mineralization by indigenous microbial communities and to investigate constraints associated with atrazine biodegradation in environmental samples collected from surface soil and subsurface zones at an agricultural site in Ohio. Atrazine mineralization in soil and sediment samples was monitored as 14CO2 evolution in biometers which were amended with 14C-labeled atrazine. Variables of interest were the position of the label ([U-14C-ring]-atrazine and [2-14C-ethyl]-atrazine), incubation temperature (25 degrees C and 10 degrees C), inoculation with a previously characterized atrazine-mineralizing bacterial isolate (M91-3), and the effect of sterilization prior to inoculation. In uninoculated biometers, mineralization rate constants declined with increasing sample depth. First-order mineralization rate constants were somewhat lower for [2-14C-ethyl]-atrazine when compared to those of [U-14C-ring]-atrazine. Moreover, the total amount of 14CO2 released was less with [2-14C-ethyl]-atrazine. Mineralization at 10 degrees C was slow and linear. In inoculated biometers, less 14CO2 was released in [2-14C-ethyl]-atrazine experiments as compared with [U-14C-ring]-atrazine probably as a result of assimilatory incorporation of 14C into biomass. The mineralization rate constants (k) and overall extents of mineralization (Pmax) were higher in biometers that were not sterilized prior to inoculation, suggesting that the native microbial populations in the sediments were contributing to the overall release of 14CO2 from [U-14C-ring]-atrazine and [2-14C-ethyl]-atrazine. A positive correlation between k and aqueous phase atrazine concentrations (Ceq) in the biometers was observed at 25 degrees C, suggesting that sorption of atrazine influenced mineralization rates. The sorption effect on atrazine mineralization was greatly diminished at 10 degrees C. It was concluded that sorption can limit biodegradation rates of weakly-sorbing solutes at high solid-to-solution ratios and at ambient surface temperatures if an active degrading population is present. Under vadose zone and subsurface aquifer conditions, however, low temperatures and the lack of degrading organisms are likely to be primary factors limiting the biodegradation of atrazine.


Identification of limiting amino acids in methionine- and lysine-supplemented low-protein diets for turkeys.
Large White male turkeys were fed 100, 85, 70, or 60% of NRC (1994) CP during 7 to 28 d (Experiment (EXP) 1), 8 to 12 wk (EXP 2), and 16 to 20 wk (EXP 3) of age. Diets contained corn, soybean, canola, and meat meals and were supplemented with Met and Lys to requirement. The influence of supplementary amino acids (AA) was studied at each protein level. Turkeys fed 85% CP gained BW similarly to those fed 100% of NRC CP (control) during each age range. Supplemental Thr, Val, and Ile during 7 to 28 d or 8 to 12 wk, or Thr during 16 to 20 wk, did not result in positive BW gain response. For turkeys fed 70% CP, BW gain was depressed compared with the normal-CP control in each period. During 7 to 28 d and 8 to 12 wk of age, the combination of Thr, Ile, Val, Arg, and Trp to 100% of NRC reversed the BW depression; here only Thr, Ile, and Val were essential components of the response. The BW depression during 16 to 20 wk was reversed by the combination of Thr, Ile, Val, and Trp. For turkeys fed 60% of CP, BW gain was severely depressed. The combination of Thr, Ile, Val, Trp, and Arg resulted in nearly complete BW recovery during each age.


Amiodarone-induced epididymitis: a pathologically confirmed case report and review of the literature.
We report a case of amiodarone-induced epididymitis and review the pertinent literature. This disease is currently a diagnosis of exclusion and is believed to be self-limiting. We found new evidence for the pathological diagnosis and identified amiodarone-like crystals in the epididymis as a pathological mechanism of this disease. This case also suggests that amiodarone-induced epididymitis is not self-limiting. Continued use of amiodarone according to the current guidelines led to a bilateral epididymectomy. We recommend withdrawal or reduction of amiodarone dosage immediately once the signs and symptoms of epididymitis present in this population of patients. When epididymitis does not seem to be caused by an infection or any other identifiable etiology, this should not be overlooked by the cardiologist, urologist or general practitioner. These findings and recommendations should help reduce the suffering of patients and improve their clinical outcomes.


Spatio-temporal model for multiple ChIP-seq experiments.
The increasing availability of ChIP-seq data demands for advanced statistical tools to analyze the results of such experiments. The inherent features of high-throughput sequencing output call for a modelling framework that can account for the spatial dependency between neighboring regions of the genome and the temporal dimension that arises from observing the protein binding process at progressing time points; also, multiple biological/technical replicates of the experiment are usually produced and methods to jointly account for them are needed. Furthermore, the antibodies used in the experiment lead to potentially different immunoprecipitation efficiencies, which can affect the capability of distinguishing between the true signal in the data and the background noise. The statistical procedure proposed consist of a discrete mixture model with an underlying latent Markov random field: the novelty of the model is to allow both spatial and temporal dependency to play a role in determining the latent state of genomic regions involved in the protein binding process, while combining all the information of the replicates available instead of treating them separately. It is also possible to take into account the different antibodies used, in order to obtain better insights of the process and exploit all the biological information available.


[Plasma renin activity, arterial blood pressure and response to beta-adrenergic blockade: a non-demostrated correlation. Practical view points (author's transl)].
Nineteen patients have been treated with timolol maleate (a non selective beta-blocking) and the decrease of their blood arterial pressure was correlated with the suppression of renine secretion. The patients which controlled their arterial pressure (63%) as well as those who did not (37%) showed a significative decrease of the plasmatic renine. The patients were diagnosed of essential hypertension, with normal renal function and formed an homogenous group. The sodium intake was similar in all of them. The results showed that although the beta-blocking can act in hypertensive patients through the suppression of the renine angiotensine system, this is not the only maintenance factor of the arterial pressure, nor its only way of action. A relevant point to be stressed in the possibility of ARP stimulation by walking, in spite of the beta-blocking, which means that this is not a total blocking or that there are other factors regulating the ARP secretion, and that act together with the autonomous nervous system.


Functional analysis of a tyrosinase gene involved in early larval shell biogenesis in Crassostrea angulata and its response to ocean acidification.
The formation of the primary shell is a vital process in marine bivalves. Ocean acidification largely influences shell formation. It has been reported that enzymes involved in phenol oxidation, such as tyrosinase and phenoloxidases, participate in the formation of the periostracum. In the present study, we cloned a tyrosinase gene from Crassostrea angulata named Ca-tyrA1, and its potential function in early larval shell biogenesis was investigated. The Ca-tyrA1 gene has a full-length cDNA of 2430bp in size, with an open reading frame of 1896bp in size, which encodes a 631-amino acid protein that includes a 24-amino acid putative signal peptide. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis revealed that Ca-tyrA1 transcription mainly occurs at the trochophore stage, and the Ca-tyrA1 mRNA levels in the 3000ppm treatment group were significantly upregulated in the early D-veliger larvae. WMISH and electron scanning microscopy analyses showed that the expression of Ca-tyrA1 occurs at the gastrula stage, thereby sustaining the early D-veliger larvae, and the shape of its signal is saddle-like, similar to that observed under an electron scanning microscope. Furthermore, the RNA interference has shown that the treatment group has a higher deformity rate than that of the control, thereby indicating that Ca-tyrA1 participates in the biogenesis of the primary shell. In conclusion, and our results indicate that Ca-tyrA1 plays a vital role in the formation of the larval shell and participates in the response to larval shell damages in Crassostrea angulata that were induced by ocean acidification.


Current chemotherapy options for thymic epithelial neoplasms.
Thymomas and thymic carcinoma are rare neoplasms. Surgical resection is the cornerstone of effective therapy. Stage I disease is effectively treated by complete surgical resection. The role of radiation therapy in completely resected stage II disease remains controversial. Adjuvant radiation therapy is useful for local control and may improve survival in patients with incompletely resected tumours. Cisplatin-based chemotherapy regimens play an important role in the treatment of advanced stage III/IV or recurrent disease thymomas, but have proven less effective for thymic carcinoma. Phase II trials of multimodality therapy incorporating neoadjuvant chemotherapy, surgery and postoperative radiation therapy show promise for unresectable disease. This review discusses recent clinical data and the potential role for agents targeting the epidermal growth factor receptor, angiogenesis and apoptotic pathways.


Mechanical impedance of the lung periphery.
The mechanics of the regional airways and tissues was studied in isolated dog lobes by means of a modified wave-tube technique. Small-amplitude pseudorandom forced oscillations between 0.1 and 48 Hz were applied through catheters wedged in 2-mm-diameter bronchi in three regions of each lobe at translobar pressures (PL) of 10, 7, 5, 3, 2, and 1 cmH2O. The measured regional input impedances were fitted by a model containing the resistance (R1) and inertance (I) of the regular (segmental) airways, the resistance of the collateral channels (R2), and the damping (G) and elastance (H) of the local tissues. This model gave far better fits to the data on impedance of the lung periphery than when G and H were replaced by a single tissue compliance, which explains why interruption of segmental flow did not lead to monoexponential pressure decay in previous studies. The interlobar and intralobar variances of the parameters were equally significant, and poor correlations were found between the airway parameters R1 and R2 and between any airway and tissue parameter (e.g., R1 and H). R2 was on average approximately 10 times higher than R1, although the R2-to-R1 ratios and their dependencies on PL were regionally highly variable. However, for the total of 33 regions studied, the PL dependence was the same for R1 and R2, which may reflect similar morphological structures for the regular and collateral airways. The dependencies of G and H on PL showed high interregional variations; generally, however, they assumed their minima at medium PL values (approximately 5 cmH2O).


Prognostic impact of monosomal karyotype in young adult and elderly acute myeloid leukemia: the Southwest Oncology Group (SWOG) experience.
Monosomal karyotype (MK), defined as 2 or more monosomies, or a single monosomy in the presence of structural abnormalities, has recently been reported as identifying a distinct subset of acute myeloid leukemia (AML) patients with an extremely poor prognosis. In an effort to confirm this observation, we analyzed the prognostic impact of MK in 1344 AML patients between the ages of 16 and 88 years treated on Southwest Oncology Group protocols. MK was found in 176 (13%) patients. The proportion of patients with MK increased with age, being present in 4% of patients age 30 or younger, but in 20% of those over age 60. Ninety-eight percent of MK cases were within the unfavorable cytogenetic risk category and comprised 40% of this group. The complete remission rate in patients with unfavorable cytogenetics without MK was 34% versus 18% with MK (P < .01). The 4-year overall survival of patients with unfavorable cytogenetics but without MK was 13% in contrast to a 4-year survival of only 3% with MK (P < .01). Thus, MK defines a sizeable subset of patients with unfavorable cytogenetics who have a particularly poor prognosis.


Decomposing gender inequalities in self-assessed health status in Liberia.
Background: Understanding the magnitude of inequalities and drivers for reducing gender-related health inequalities is crucial in developing countries. This is particularly the case for Liberia with its very high level of gender-related inequalities in health and health outcomes. Objective: This paper assesses the magnitude of gender health inequalities and the relative contribution of different factors to health inequality in Liberia. Methods: Data came from the Liberian Household Income Expenditure Survey 2014. A two stage sampling methodology was used and 4,104 households were randomly selected and interviewed. The main variable of interest is dichotomised, good versus poor self-assessed health. Gender-related health inequality is assessed using the Oaxaca-Blinder decomposition for non-linear models. The decomposition reveals the magnitude of inequality and contributions of different factors. Results: We found large gender disparities (0.054, p < 0.01) characterised by women disadvantages in health status. In addition, the gender health disparities are mostly pronounced in rural areas. About 54% of the gender inequalities in health status were explained by the differences in endowments. Equalizing access to information, wealth and utilization of mosquito nets would reduce the gender gaps by 44, 5 and 4%, respectively. Conclusions: Addressing gender health inequalities inter alia requires access to health information (i.e. electronic and print media), gender responsive interventions that improve wealth in key sectors (i.e. education, employment, social protection, housing, and other appropriate infrastructure). In addition, the government, private sector and civil society should ensure that the health sector provides access to quality mosquito nets and improved health services including preventive care in order to reduce disease burden.


Acute high-altitude illness.
Acute high-altitude illness usually occurs at elevations of 8,000 ft or more, is more common than is generally appreciated and is often confused with other disorders. The acute forms of high-altitude illness include acute mountain sickness, high-altitude pulmonary edema, high-altitude cerebral edema and high-altitude retinal hemorrhage. These illnesses often occur simultaneously and in severe forms can be fatal. Gradual ascent and acetazolamide help prevent acute mountain sickness and high-altitude pulmonary edema. The definitive treatment for all forms of high-altitude illness is descent to a lower altitude.


Systematic investigations of peak deformations due to co-solvent adsorption in preparative supercritical fluid chromatography.
Strangely shaped overloaded bands were recently reported using a standard supercritical fluid chromatographic system comprising a diol column as the stationary phase and carbon dioxide with methanol as the mobile phase. Some of these overloaded elution profiles appeared strongly deformed and even had "anti-Langmuirian" shapes although their solute compounds had "Langmuirian" adsorption. To obtain a more complete understanding of the generality of these effects, the investigation was expanded to cover also other common co-solvents, such as ethanol, 2-propanol, and acetonitrile, as well as various stationary phase materials, such as silica, and 2-ethylpyridine. From this expanded study it could be confirmed that the effects of deformed overloaded solute band shapes, due to co-solvent adsorption, is general phenomena in supercritical fluid chromatographic. It could also be concluded that these effects as well as previously observed "solvent effects" or "plug effects" are entirely due to competition between the solute and solvent molecules for the adsorption sites on the stationary phase surface. Finally, guidelines were given for how to evaluate the risk of deformations occurring for a given solvent-column combination, based simply on testing retention times of solutes and co-solvent.


Shitsukan - the Multisensory Perception of Quality.
We often estimate, or perceive, the quality of materials, surfaces, and objects, what the Japanese refer to as 'shitsukan', by means of several of our senses. The majority of the literature on shitsukan perception has, though, tended to focus on the unimodal visual evaluation of stimulus properties. In part, this presumably reflects the widespread hegemony of the visual in the modern era and, in part, is a result of the growing interest, not to mention the impressive advances, in digital rendering amongst the computer graphics community. Nevertheless, regardless of such an oculocentric bias in so much of the empirical literature, it is important to note that several other senses often do contribute to the impression of the material quality of surfaces, materials, and objects as experienced in the real world, rather than just in virtual reality. Understanding the multisensory contributions to the perception of material quality, especially when combined with computational and neural data, is likely to have implications for a number of fields of basic research as well as being applicable to emerging domains such as, for example, multisensory augmented retail, not to mention multisensory packaging design.


Glowing gels and pipettes aplenty: how do commercial stock image banks portray genetic tests?
News stories and patient-facing material about genetic tests are often illustrated by images, but the content of such images and the messages they propagate are rarely scrutinised. Stock image banks were searched to identify a hundred images relating to genetic tests and analysed using a multimodal critical discourse approach, aiming to identify what the images featured, how they were composed, and what they communicated about genetic testing. We found that images tended to focus on technical aspects of sample processing (for example, pipetting) and drew on older technologies (for example slab gel electrophoresis) when representing data arising from genetic tests. Composition choices like focussing images around pipette tips, or emphasising colour or brightness of electrophoretic bands, represented genetic testing as precise, unambiguous and illuminating. Only 7% of images featured a person having a genetic test, and only one image alluded to communication of genetic results. Current popular visual representations of genetic testing rarely highlight the possibility of uncertain or non-diagnostic outcomes, and may contribute to high public expectations of informativeness and certainty from such tests.


Antioxidant micronutrients and the risk of renal cell carcinoma in the Women's Health Initiative cohort.
Renal cell carcinoma (RCC) is the eighth leading cancer among women in incidence and commonly is diagnosed at a more advanced stage. Oxidative stress has been considered to play an important role in the pathogenesis of RCC. Various dietary micronutrients have antioxidant properties, including carotenoids and vitamins C and E; thus, diets rich in these nutrients have been evaluated in relation to RCC prevention. The objective of this study was to explore the correlation between antioxidant micronutrients and the risk of RCC. In total, 96,196 postmenopausal women who enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and were followed through July 2013 were included in this analysis. Dietary micronutrient intake was estimated from the baseline WHI food frequency questionnaire, and data on supplement use were collected using an interview-based inventory procedure. RCC cases were ascertained from follow-up surveys and were centrally adjudicated. The risks for RCC associated with intake of α-carotene, β-carotene, β-cryptoxanthin, lutein plus zeaxanthin, lycopene, vitamin C, and vitamin E were analyzed using Cox proportional hazards regression adjusted for confounders. Two hundred forty women with RCC were identified during follow-up. Lycopene intake was inversely associated with RCC risk (P = .015); compared with the lowest quartile of lycopene intake, the highest quartile of intake was associated with a 39% lower risk of RCC (hazard ratio, 0.61; 95% confidence interval, 0.39-0.97). No other micronutrient was significantly associated with RCC risk. The current results suggest that further investigation into the correlation between lycopene intake and the risk of RCC is warranted.


Predicting laser-induced bulk damage and conditioning for deuterated potassium dihydrogen phosphate crystals using an absorption distribution model.
We present an empirical model that describes the experimentally observed laser-induced bulk damage and conditioning behavior in deuterated potassium dihydrogen phosphate (DKDP) crystals. The model expands on an existing nanoabsorber precursor model and the multistep absorption mechanism to include two populations of absorbing defects, one with linear absorption and another with nonlinear absorption. We show that this model connects previously uncorrelated small-beam damage initiation probability data to large-beam damage density measurements over a range of nanosecond pulse widths. In addition, this work predicts the damage behavior of laser-conditioned DKDP.


Cell-Free DNA-Based Multi-Cancer Early Detection Test in an Asymptomatic Screening Population (NHS-Galleri): Design of a Pragmatic, Prospective Randomised Controlled Trial.
We report the design of the NHS-Galleri trial (ISRCTN91431511), aiming to establish whether a multi-cancer early detection (MCED) test that screens asymptomatic individuals for cancer can reduce late-stage cancer incidence. This randomised controlled trial has invited approximately 1.5 million persons and enrolled over 140,000 from the general population of England (50-77 years; ≥3 years without cancer diagnosis or treatment; not undergoing investigation for suspected cancer). Blood is being collected at up to three annual visits. Following baseline blood collection, participants are randomised 1:1 to the intervention (blood tested by MCED test) or control (blood stored) arm. Only participants in the intervention arm with a cancer signal detected have results returned and are referred for urgent investigations and potential treatment. Remaining participants in both arms stay blinded and return for their next visit. Participants are encouraged to continue other NHS cancer screening programmes and seek help for new or unusual symptoms. The primary objective is to demonstrate a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention versus control arm 3-4 years after randomisation. NHS-Galleri will help determine the clinical utility of population screening with an MCED test.


Demographic factors associated with bronchiolitis readmission.
The goal of this study was to evaluate patient characteristics and medical management and their association with readmission in children with bronchiolitis. This retrospective chart review included children admitted with bronchiolitis to 2 children's hospitals. Reviewers selected charts based on International Classification of Diseases, Ninth Revision, diagnosis and collected information on demographic characteristics, treatment, diagnostic testing, length of stay, and adverse outcomes. Univariate analyses were used to identify risk factors associated with any-cause readmission in 4 weeks. A total of 1229 patients met inclusion criteria. Younger children were more likely to be readmitted within 4 weeks of discharge compared with older children (mean age: 4.5 vs 5.7 months; P = .005). Readmissions did not differ based on length of stay, and no medical intervention was associated with risk for readmission. Of patients readmitted from the large service area hospital, 57% lived ≤20 miles away, compared with 26.9% of those who were not readmitted (P = .03). Patients from the lowest income zip codes within the catchment area of the small service area hospital were more likely to be readmitted compared with patients from the highest income zip codes (7.8% vs 0%; P = .025). Overall, 6.4% of hospitalized patients with bronchiolitis were readmitted. Our data did not identify any inpatient medical management or modifiable risk factor associated with readmission.


Thermotherapy for treatment of osteoarthritis.
Osteoarthritis is a degenerative joint disease that affects mostly the weight-bearing joints in the knees and hips. As the affected joint degenerates pain and restriction of movement often occur. Inflammation can also occur sometimes resulting in edema of the joint with OA. Treatment focuses on decreasing pain and improving movement. To determine the effectiveness of thermotherapy in the treatment of OA of the knee. The outcomes of interest were relief of pain, reduction of edema, and improvement of flexion or range of motion (ROM) and function. Two independent reviewers selected randomized and controlled clinical trials with participants with clinical and/or radiological confirmation of OA of the knee; and interventions using heat or cold therapy compared with standard treatment and/or placebo. Trials comparing head to head therapies, such as two different types of diathermy, were excluded. Randomized and controlled clinical trials including participants with clinical or radiographical confirmation of OA of the knee; and interventions using heat or cold compared to standard treatment or placebo were considered for inclusion. Study results were extracted by two independent reviewers. Outcomes were continuous in nature (pain, strength, improvement) and were analyzed by weighted mean difference using a fixed effects model. Graphical data were used when table data were not available. Three randomized controlled trials, involving 179 patients, were included in this review. The included trials varied in terms of design, outcomes measured, cryotherapy or thermotherapy treatments and overall methodological quality. In one trial, administration of 20 minutes of ice massage, 5 days per week, for 3 weeks, compared to control demonstrated a clinically important benefit for knee OA on increasing quadriceps strength (29% relative difference). There was also a statistically significant improvement, but no clinical benefit in improving knee flexion ROM (8% relative difference) and functional status (11% relative difference). Another trial showed that cold packs decreased knee edema. Ice massage compared to control had a statistically beneficial effect on ROM, function and knee strength. Cold packs decreased swelling. Hot packs had no beneficial effect on edema compared with placebo or cold application. Ice packs did not effect pain significantly compared to control in patients with OA. More well designed studies with a standardized protocol and adequate number of subjects are needed to evaluate the effect of thermotherapy in the treatment of OA of the knee.


Phase I assessment of new mechanism-based pharmacodynamic biomarkers for MLN8054, a small-molecule inhibitor of Aurora A kinase.
The mitotic kinase Aurora A is an important therapeutic target for cancer therapy. This study evaluated new mechanism-based pharmacodynamic biomarkers in cancer patients in two phase I studies of MLN8054, a small-molecule inhibitor of Aurora A kinase. Patients with advanced solid tumors received MLN8054 orally for 7 consecutive days in escalating dose cohorts, with skin and tumor biopsies obtained before and after dosing. Skin biopsies were evaluated for increased mitotic cells within the basal epithelium. Tumor biopsies were assessed for accumulation of mitotic cells within proliferative tumor regions. Several patients in the highest dose cohorts showed marked increases in the skin mitotic index after dosing. Although some tumors exhibited increases in mitotic cells after dosing, others displayed decreases, a variable outcome consistent with dual mechanisms of mitotic arrest and mitotic slippage induced by antimitotics in tumors. To provide a clearer picture, mitotic cell chromosome alignment and spindle bipolarity, new biomarkers of Aurora A inhibition that act independently of mitotic arrest or slippage, were assessed in the tumor biopsies. Several patients, primarily in the highest dose cohorts, had marked decreases in the percentage of mitotic cells with aligned chromosomes and bipolar spindles after dosing. Evidence existed for an exposure-effect relationship for mitotic cells with defects in chromosome alignment and spindle bipolarity that indicated a biologically active dose range. Outcomes of pharmacodynamic assays from skin and tumor biopsies were concordant in several patients. Together, these new pharmacodynamic assays provide evidence for Aurora A inhibition by MLN8054 in patient skin and tumor tissues.


Likelihood ratio tests for a large directed acyclic graph.
Inference of directional pairwise relations between interacting units in a directed acyclic graph (DAG), such as a regulatory gene network, is common in practice, imposing challenges because of lack of inferential tools. For example, inferring a specific gene pathway of a regulatory gene network is biologically important. Yet, frequentist inference of directionality of connections remains largely unexplored for regulatory models. In this article, we propose constrained likelihood ratio tests for inference of the connectivity as well as directionality subject to nonconvex acyclicity constraints in a Gaussian directed graphical model. Particularly, we derive the asymptotic distributions of the constrained likelihood ratios in a high-dimensional situation. For testing of connectivity, the asymptotic distribution is either chi-squared or normal depending on if the number of testable links in a DAG model is small. For testing of directionality, the asymptotic distribution is the minimum of d independent chi-squared variables with one-degree of freedom or a generalized Gamma distribution depending on if d is small, where d is number of breakpoints in a hypothesized pathway. Moreover, we develop a computational method to perform the proposed tests, which integrates an alternating direction method of multipliers and difference convex programming. Finally, the power analysis and simulations suggest that the tests achieve the desired objectives of inference. An analysis of an Alzheimer's disease gene expression dataset illustrates the utility of the proposed method to infer a directed pathway in a gene network.


Caspase-3 gene transfected with LIGHT gene: can it be used for therapy of human hepatocellular carcinoma?
The aim of this study was to detect the expression of apoptosis factor caspase-3 in transferred HepG2 cells and provide feasible evaluation of the treatment for primary liver cancer with gene methods. The pcDNA4C-LIGHT cDNA was extracted from Escherichia coli JM-109; then, the pcDNA4C-LIGHT cDNA was transferred into the HepG2 cells by a cationic liposome mediated method. Meanwhile, the blank group was established as the control group and the HepG2 cells were collected after transfection at 12 h, 24 h, 48 h, 3 days and 5 days. The expression of caspase-3 was identified in the supernatants by ELISA. A standard curve was generated for the set of samples assayed. Statistical significance was analyzed by SPSS. The quantity of caspase-3 protein was the greatest at 48 h and the least on day 5. The secretion of caspase-3 did not increase in the control group. The coefficient of correlation was equal to 0.9986 and had evident significance. The pcDNA4C-LIGHT was effectively transfected in human HepG2 cells mediated by liposome. The expression of caspase-3 increased in the transfected group. This study provides necessary theoretic support for the treatment of liver cancer with gene methods.


Anal HPV/HIV co-infection among Men Who Have Sex with Men: a cross-sectional survey from three cities in China.
Anal human papillomavirus (HPV) infection, which is linked to anal warts and anal cancer, is common among men who have sex with men (MSM), especially among those HIV positives. MSM aged 18 years or older were recruited from mainland China. Blood and anal cytologic samples were collected for HIV-1 serological test and HPV genotyping. A total of 889 eligible participations were included. The genotyping results of HPV were available for 822 participants (92.46%), 65.32% of which were positive for the targeted 37 HPV types. Prevalence of infection with any type of HPV was higher among HIV-infected participants (82.69%) as compared to HIV-uninfected participants (62.81%) (p < 0.01). HPV06 (15.45%), HPV18(13.50%), HPV16 (11.44%), and HPV11 (10.71%) were the most frequent types identified in the study population. Ever had paid sex with man was found to be independent predictor for HPV positivity with an adjusted odds ratios (OR) of 2.34 (1.16-4.74). Anal HPV positivity was observed to be independently associated with HIV infection with an adjusted OR of 3.03 (1.76-5.21) in the study population. In conclusion, the prevalence of anal HPV infection was observed to be common among MSM from mainland China, and it was significantly associated with the status of HIV infection.


Expectation of caffeine induces dopaminergic responses in humans.
Recent neuroimaging studies indicate that placebo treatments can induce clinically relevant neurobiological responses in patients with Parkinson's disease, depression and pain. The present study aimed to investigate neurotransmitter function in psychostimulant expectation, with the focus on dopaminergic effects of placebo caffeine in healthy human subjects. Eight habitual coffee drinkers were examined twice with [11C]raclopride positron emission tomography after no treatment and after oral placebo tablets in a counter-balanced setting. During the placebo condition the subjects were instructed that they had a 50% chance of receiving caffeine, but all received placebo. As compared with no treatment, placebo induced a significant bilateral dopamine release in the thalamus, as reflected by a 15% reduction in thalamic [11C]raclopride binding (P < 0.001). The level of arousal after placebo correlated positively with the tracer binding in the putamen (r = -0.91, P = 0.004). The results indicate that caffeine expectation induces dopaminergic placebo effects, and that these effects are similar to previous findings with oral caffeine. The results therefore suggest that caffeine and placebo caffeine may share some dopaminergic mechanisms of action.


Molecular structure of P2X receptors.
P2X receptors are ligand-gated ion channels that transduce many of the physiological effects of extracellular ATP. There has been a dramatic increase in awareness of these receptors over the past 5 or so years, in great part due to their molecular cloning and characterization. The availability of cDNA clones for the various subunits has led to rapid progress in identifying their tissue-specific expression, resulting in new ideas concerning the functional roles these receptors might play in physiological and pathophysiological processes. In addition, molecular approaches have yielded much information regarding the structure and function of the receptor proteins themselves. In this review we seek to review recent findings concerning the molecular determinants of receptor-channel function, with particular focus on ligand binding and gating, ion selectivity, and subunit assembly.


A Bayesian zero-inflated beta-binomial model for longitudinal data with group-specific changepoints.
Timeline followback (TLFB) is often used in addiction research to monitor recent substance use, such as the number of abstinent days in the past week. TLFB data usually take the form of binomial counts that exhibit overdispersion and zero inflation. Motivated by a 12-week randomized trial evaluating the efficacy of varenicline tartrate for smoking cessation among adolescents, we propose a Bayesian zero-inflated beta-binomial model for the analysis of longitudinal, bounded TLFB data. The model comprises a mixture of a point mass that accounts for zero inflation and a beta-binomial distribution for the number of days abstinent in the past week. Because treatment effects appear to level off during the study, we introduce random changepoints for each study group to reflect group-specific changes in treatment efficacy over time. The model also includes fixed and random effects that capture group- and subject-level slopes before and after the changepoints. Using the model, we can accurately estimate the mean trend for each study group, test whether the groups experience changepoints simultaneously, and identify critical windows of treatment efficacy. For posterior computation, we propose an efficient Markov chain Monte Carlo algorithm that relies on easily sampled Gibbs and Metropolis-Hastings steps. Our application shows that the varenicline group has a short-term positive effect on abstinence that tapers off after week 9.


Sorting Test, Tower Test, and BRIEF-SR do not predict school performance of healthy adolescents in preuniversity education.
Executive functions (EF) such as self-monitoring, planning, and organizing are known to develop through childhood and adolescence. They are of potential importance for learning and school performance. Earlier research into the relation between EF and school performance did not provide clear results possibly because confounding factors such as educational track, boy-girl differences, and parental education were not taken into account. The present study therefore investigated the relation between executive function tests and school performance in a highly controlled sample of 173 healthy adolescents aged 12-18. Only students in the pre-university educational track were used and the performance of boys was compared to that of girls. Results showed that there was no relation between the report marks obtained and the performance on executive function tests, notably the Sorting Test and the Tower Test of the Delis-Kaplan Executive Functions System (D-KEFS). Likewise, no relation was found between the report marks and the scores on the Behavior Rating Inventory of Executive Function-Self-Report Version (BRIEF-SR) after these were controlled for grade, sex, and level of parental education. The findings indicate that executive functioning as measured with widely used instruments such as the BRIEF-SR does not predict school performance of adolescents in preuniversity education any better than a student's grade, sex, and level of parental education.


New insights into the significance of microalbuminuria.
This review summarizes recent work that has explored the association between microalbuminuria and adverse clinical outcomes in the presence and absence of diabetes. Recent investigations have documented the prevalence of microalbuminuria in the general community and have also highlighted the continuous relationship between the level of urinary albumin excretion and clinical endpoints. Even below traditional microalbuminuria thresholds, urinary albumin levels appear to correlate with clinical outcomes. Microalbuminuria is becoming increasingly recognized as an independent risk factor for cardiovascular morbidity and mortality. At least for subjects with type 2 diabetes and microalbuminuria, intensive, multifactorial interventions can reduce the risk of cardiovascular events by about 50%. Although several studies have found an association between microalbuminuria and surrogate measurements of vascular disease, the exact molecular mechanisms linking an increase in urinary albumin excretion and vascular disease are still unknown. Microalbuminuria also has a well-documented association with progressive diabetic renal disease but recent studies have suggested that the prognostic significance of microalbuminuria in this regard may not be as powerful as originally reported. Aggressive, multifactorial interventions, including the use of drugs that interrupt the renin-angiotensin system are strongly recommended for patients with diabetes and micro-albuminuria to ameliorate the progression of renal and vascular complications. This approach should also possibly apply to microalbuminuric subjects without diabetes. The relationship between microalbuminuria and progressive diabetic renal disease requires re-evaluation given temporal trends in the prevention and treatment of diabetic complications.