Nicotinic partial agonists varenicline and sazetidine-A have differential effects on affective behavior.
Clinical and preclinical studies suggest that nicotinic acetylcholine receptors are involved in affective disorders; therefore, the potential therapeutic value of nicotinic partial agonists as treatments of these disorders is of growing interest. This study evaluated the effects of acute and chronic administration of nicotine and the alpha4beta2 nicotinic partial agonists varenicline and sazetidine-A in mouse models of anxiety and depression. Acutely, only nicotine and varenicline had anxiolytic effects in the marble-burying test and in the novelty-induced hypophagia (NIH) test. In contrast, in animal models of antidepressant efficacy, such as the forced swim and the tail suspension test, only acute sazetidine-A had significant antidepressant-like effects. The NIH test provides an anxiety-related measure that is sensitive to the effects of chronic but not acute antidepressant treatment. Chronic nicotine and chronic sazetidine-A treatment were effective in this paradigm, but varenicline was ineffective. These results suggest that the partial agonists varenicline and sazetidine-A may have diverse therapeutic benefits in affective disorders.


[Ketamine racemate or S-(+)-ketamine and midazolam. The effect on vigilance, efficacy and subjective findings].
Ketamine is a racemic mixture containing equal amounts of optical isomers that have almost identical pharmacokinetic properties but different pharmacodynamic effects. The S-(+)-isomer of ketamine has about twice the anaesthetic and analgesic potency of the racemic ketamine preparation and is judged to induce less psychic emergence reactions and to be followed by a more rapid recovery of vigilance. The present study was designed to assess whether the S-(+)-isomer of ketamine is superior to the racemic mixture in cardiovascular characteristics, emergence reactions and cognitive functions, and whether side effects may be reduced or prevented by administration of midazolam prior to injection of S-(+)-ketamine. METHODS. Following ethics committee approval and informed consent, 30 volunteers were randomly allocated in this double-blind study to three groups of 10 each. Group 1 received 2 mg/kg bw racemic ketamine, group 2, 1 mg/kg bw S-(+)-ketamine and group 3, 1 mg/kg bw S-(+)-ketamine after premedication with 0.1 mg/kg midazolam i.v. Cardiovascular changes, state of vigilance, cognitive performance, subjective mood and acceptance of anaesthesia were assessed by means of haemodynamic routine monitoring, electroencephalography (EEG), psychometric tests and interview. RESULTS. The increases in mean arterial pressure and heart rate following the injection of racemic ketamine and S-(+)-ketamine were identical and the differences from baseline values significant after both. Premedication with midazolam ensured stable haemodynamics after injection of S-(+)-ketamine. EEG analysis displayed the characteristic changes well known from ketamine anaesthesia for both racemic and S-(+)-ketamine. The vigilosomnoscript showed an identical profile of vigilance up to 30 min after injection of both drugs. The vigilance status after 125 min was less impaired by S-(+)-ketamine than by racemic ketamine. Psychological assessment showed a prompter recovery of visual attentiveness and sensorimotor performance in the S-(+)-ketamine group. Subjective mood was judged by the volunteers to be significantly better after S-(+)-ketamine, and volunteers found S-(+)-ketamine to be more acceptable than racemic ketamine. The frequency of dreams was the same after both drugs. No unpleasant dreams were reported after S-(+)-ketamine, but one of the volunteers who received racemic ketamine had uncomfortable dreams. Midazolam prevented any unpleasant emergence sequelae. On the other hand, the cognitive performance could not be restored to the baseline values until at least 240 min after injection of S-(+)-ketamine, because of the sedative effects of midazolam. DISCUSSION. These results suggest that S-(+)-ketamine offers the advantages of faster recovery of cognitive performance, greater acceptance by the volunteers and identical depth of anaesthesia after injection of half the dose compared with racemic ketamine. The clinical use of S-(+)-ketamine therefore seems to be justified. Premedication with benzodiazepines, e.g. midazolam, is essential. The dose to be administered, however, should be carefully selected in order not to abolish the positive effect of S-(+)-ketamine on vigilance by the sedative effects of the benzodiazepine.


Large-area tungsten disulfide for ultrafast photonics.
Two-dimensional (2D) layered transition metal dichalcogenides (TMDs) have attracted significant interest in various optoelectronic applications due to their excellent nonlinear optical properties. One of the most important applications of TMDs is to be employed as an extraordinary optical modulation material (e.g., the saturable absorber (SA)) in ultrafast photonics. The main challenge arises while embedding TMDs into fiber laser systems to generate ultrafast pulse trains and thus constraints their practical applications. Herein, few-layered WS2 with a large-area was directly transferred on the facet of the pigtail and acted as a SA for erbium-doped fiber laser (EDFL) systems. In our study, WS2 SA exhibited remarkable nonlinear optical properties (e.g., modulation depth of 15.1% and saturable intensity of 157.6 MW cm-2) and was used for ultrafast pulse generation. The soliton pulses with remarkable performances (e.g., ultrashort pulse duration of 1.49 ps, high stability of 71.8 dB, and large pulse average output power of 62.5 mW) could be obtained in a telecommunication band. To the best of our knowledge, the average output power of the mode-locked pulse trains is the highest by employing TMD materials in fiber laser systems. These results indicate that atomically large-area WS2 could be used as excellent optical modulation materials in ultrafast photonics.


Clinical and genetic characteristics of late-onset Huntington's disease.
The frequency of late-onset Huntington's disease (>59 years) is assumed to be low and the clinical course milder. However, previous literature on late-onset disease is scarce and inconclusive. Our aim is to study clinical characteristics of late-onset compared to common-onset HD patients in a large cohort of HD patients from the Registry database. Participants with late- and common-onset (30-50 years)were compared for first clinical symptoms, disease progression, CAG repeat size and family history. Participants with a missing CAG repeat size, a repeat size of ≤35 or a UHDRS motor score of ≤5 were excluded. Of 6007 eligible participants, 687 had late-onset (11.4%) and 3216 (53.5%) common-onset HD. Late-onset (n = 577) had significantly more gait and balance problems as first symptom compared to common-onset (n = 2408) (P < .001). Overall motor and cognitive performance (P < .001) were worse, however only disease motor progression was slower (coefficient, -0.58; SE 0.16; P < .001) compared to the common-onset group. Repeat size was significantly lower in the late-onset (n = 40.8; SD 1.6) compared to common-onset (n = 44.4; SD 2.8) (P < .001). Fewer late-onset patients (n = 451) had a positive family history compared to common-onset (n = 2940) (P < .001). Late-onset patients present more frequently with gait and balance problems as first symptom, and disease progression is not milder compared to common-onset HD patients apart from motor progression. The family history is likely to be negative, which might make diagnosing HD more difficult in this population. However, the balance and gait problems might be helpful in diagnosing HD in elderly patients.


Radiotherapy for Adrenal Metastasis from Hepatocellular Carcinoma: A Multi-Institutional Retrospective Study (KROG 13-05).
Although the adrenal glands are not common sites of metastasis from hepatocellular carcinoma (HCC), this metastasis can be met in patients with advanced HCC in some clinical settings. However, the effectiveness of radiotherapy against such metastases is unclear. Therefore, we performed the present multi-institutional study to investigate tumor response, overall survival (OS), treatment-related toxicity, and prognostic factors after radiotherapy. We retrospectively reviewed 134 patients who completed a planned radiotherapy for their adrenal metastases. Complete response was noted in 6 (4.3%), partial response in 48 (34.0%), and stable disease in 78 patients (55.3%). The median OS was 12.8 months, and the 1-, 2-, and 5-year OS rates were 53.1%, 23.9%, and 9.3%, respectively. Grade 3 anorexia occurred in 2 patients, grade 3 diarrhea in 1, and grade 3 fatigue in 1. Multivariate analyses revealed that the following factors had significant effects on OS: controlled intrahepatic tumor; controlled extrahepatic metastasis; and Child-Pugh class A. Although patients with adrenal metastasis from HCC had poor OS, radiotherapy provided an objective response rate of 38.3% and disease stability of 93.6%, with minimal adverse events. Therefore, radiotherapy for these patients could represent a good treatment modality, especially for patients with controlled intrahepatic tumors, controlled extrahepatic metastasis, and good hepatic function.


How to increase safety in complex systems--an ongoing project.
The aim of this paper is to describe an ongoing project with the aim of improving safety in an organization working with maintenance and development of the railway infrastructure in Sweden. The first sub goal was to investigate the General Failure Types in the organization. Seminars and interviews, based on the Tripod Delta method, with 62 employees resulted in a description of these latent errors in the organization. Recommendations for an improvement toward a safety culture was suggested, action plans were formulated and, in some cases, implemented. A follow up study is planned in a two year perspective.


Social Welfare Control in Mobile Crowdsensing Using Zero-Determinant Strategy.
As a promising paradigm, mobile crowdsensing exerts the potential of widespread sensors embedded in mobile devices. The greedy nature of workers brings the problem of low-quality sensing data, which poses threats to the overall performance of a crowdsensing system. Existing works often tackle this problem with additional function components. In this paper, we systematically formulate the problem into a crowdsensing interaction process between a requestor and a worker, which can be modeled by two types of iterated games with different strategy spaces. Considering that the low-quality data submitted by the workers can reduce the requestor's payoff and further decrease the global income, we turn to controlling the social welfare in the games. To that aim, we take advantage of zero-determinant strategy, based on which we propose two social welfare control mechanisms under both game models. Specifically, we consider the requestor as the controller of the games and, with proper parameter settings for the to-be-adopted zero-determinant strategy, social welfare can be optimized to the desired level no matter what strategy the worker adopts. Simulation results demonstrate that the requestor can achieve the maximized social welfare and keep it stable by using our proposed mechanisms.


The herbal medicine Sho-saiko-to inhibits growth and metastasis of malignant melanoma primarily developed in ret-transgenic mice.
Sho-saiko-to is the most popular herbal medicine in Japan. We investigated the anti-tumor and anti-metastatic effects of Sho-saiko-to and its chemically defined ingredients on the primary skin melanoma that developed in a metallothionein-I (MT)/ret transgenic mouse line and on a melanoma cell line (Mel-ret), which was derived from a primary tumor developed in a MT/ret transgenic mouse. In vitro, Sho-saiko-to suppressed the growth of Mel-ret cells more strongly than any single ingredient of Sho-saiko-to, although baicalin as one of several ingredients tested also suppressed it significantly. In vivo, Sho-saiko-to (i) significantly (p < 0.02) prolonged the onset of tumor development (1.5 mo), (ii) definitely retarded the transition to malignancy, (iii) significantly decreased the incidence of distant metastasis to brain (p < 0.002), kidney (p < 0.05), and liver (p < 0.05) at the malignant stage, and (iv) significantly (p < 0.02) prolonged life span (2.6 mo). Moreover, Sho-saiko-to and baicalin down-regulated the matrix metalloproteinase-2 and -9 expression levels, and upregulated their inhibitor expression level in both the primary tumors and Mel-ret cells. In conclusion, Sho-saiko-to displayed anti-tumor and anti-metastatic effects on melanoma with regulation of the balance of matrix metalloproteinase and tissue inhibitor of the matrix metalloproteinase levels.


How the brain translates money into force: a neuroimaging study of subliminal motivation.
Unconscious motivation in humans is often inferred but rarely demonstrated empirically. We imaged motivational processes, implemented in a paradigm that varied the amount and reportability of monetary rewards for which subjects exerted physical effort. We show that, even when subjects cannot report how much money is at stake, they nevertheless deploy more force for higher amounts. Such a motivational effect is underpinned by engagement of a specific basal forebrain region. Our findings thus reveal this region as a key node in brain circuitry that enables expected rewards to energize behavior, without the need for the subjects;awareness.


Genetic structure and evolution of the Leishmania genus in Africa and Eurasia: what does MLSA tell us.
Leishmaniasis is a complex parasitic disease from a taxonomic, clinical and epidemiological point of view. The role of genetic exchanges has been questioned for over twenty years and their recent experimental demonstration along with the identification of interspecific hybrids in natura has revived this debate. After arguing that genetic exchanges were exceptional and did not contribute to Leishmania evolution, it is currently proposed that interspecific exchanges could be a major driving force for rapid adaptation to new reservoirs and vectors, expansion into new parasitic cycles and adaptation to new life conditions. To assess the existence of gene flows between species during evolution we used MLSA-based (MultiLocus Sequence Analysis) approach to analyze 222 Leishmania strains from Africa and Eurasia to accurately represent the genetic diversity of this genus. We observed a remarkable congruence of the phylogenetic signal and identified seven genetic clusters that include mainly independent lineages which are accumulating divergences without any sign of recent interspecific recombination. From a taxonomic point of view, the strong genetic structuration of the different species does not question the current classification, except for species that cause visceral forms of leishmaniasis (L. donovani, L. infantum and L. archibaldi). Although these taxa cause specific clinical forms of the disease and are maintained through different parasitic cycles, they are not clearly distinct and form a continuum, in line with the concept of species complex already suggested for this group thirty years ago. These results should have practical consequences concerning the molecular identification of parasites and the subsequent therapeutic management of the disease.


Physiologic Specialization of Puccinia triticina on Wheat in the United States in 2002.
Collections of Puccinia triticina were obtained from rust-infected wheat leaves by cooperators throughout the United States and from surveys of wheat fields and nurseries in the Great Plains, Ohio Valley, Southeast, California, and the Pacific Northwest, in order to determine the virulence of the wheat leaf rust fungus in 2002. Single uredinial isolates (785 in total) were derived from the wheat leaf rust collections and tested for virulence phenotype on lines of Thatcher wheat that are near-isogenic for leaf rust resistance genes Lr1, Lr2a, Lr2c, Lr3, Lr9, Lr16, Lr24, Lr26, Lr3ka, Lr11, Lr17, Lr30, LrB, Lr10, Lr14a, and Lr18. In the United States in 2002, 52 virulence phenotypes of P. triticina were found. Virulence phenotype MBDS, which is virulent to resistance gene Lr17, was the most common phenotype in the United States. MBDS was found in the Southeast, Great Plains, and the Ohio Valley regions, and also in California. Phenotype MCDS, virulent to Lr17 and Lr26, was the second most common phenotype and occurred in the same regions as MBDS. Virulence phenotype THBJ, which is virulent to Lr16 and Lr26, was the third most common phenotype, and was found in the southern and northern central Great Plains region. Phenotype TLGJ, with virulence to Lr2a, Lr9, and Lr11, was the fourth most common phenotype and was found primarily in the Southeast and Ohio Valley regions. The Southeast and Ohio Valley regions differed from the Great Plains regions for predominant virulence phenotypes, which indicate that populations of P. triticina in those areas are not closely connected. The northern and southern areas of the Great Plains were similar for frequencies of predominant phenotypes, indicating a strong south to north migration of urediniospores.


Identification and molecular epidemiology of dermatophyte isolates by repetitive-sequence-PCR-based DNA fingerprinting using the DiversiLab system in Turkey.
Dermatophyte species, isolation and identification in clinical samples are still difficult and take a long time. The identification and molecular epidemiology of dermatophytes commonly isolated in a clinical laboratory in Turkey by repetitive sequence-based PCR (rep-PCR) were assessed by comparing the results with those of reference identification. A total of 44 dermatophytes isolated from various clinical specimens of 20 patients with superficial mycoses in Kayseri and 24 patients in Hatay were studied. The identification of dermatophyte isolates was based on the reference identification and rep-PCR using the DiversiLab System (BioMerieux). The genotyping of dermatophyte isolates from different patients was determined by rep-PCR. In the identification of dermatophyte isolates, agreement between rep-PCR and conventional methods was 87.8 % ( 36 of 41). The dermatophyte strains belonged to four clones (A -D) which were determined by the use of rep-PCR. The dermatophyte strains in Clone B, D showed identical patterns with respect to the region. In conclusion, rep-PCR appears to be useful for evaluation of the identification and clonal relationships between Trichophyton rubrum species complex and Trichophyton mentagrophytes species complex isolates. The similarity and diversity of these isolates may be assessed according to different regions by rep-PCR.


Sexuality and the limits of agency among South African teenage women: theorising femininities and their connections to HIV risk practices.
In South Africa, both HIV and gender-based violence are highly prevalent. Gender inequalities give men considerable relational power over young women, particularly in circumstances of poverty and where sex is materially rewarded. Young women are often described as victims of men, but this inadequately explains women's observed sexual agency. This paper takes a different approach. We use qualitative interviews and ethnographic observation among 16 young women from the rural Eastern Cape to explore ways young women construct their femininities and exercise agency. The data were collected as part of an evaluation of Stepping Stones, which is a participatory behavioural intervention for HIV prevention that seeks to be gender transformative. Agency was most notable in particular stages of the dating 'game', especially relationship initiation. Constructions of desirable men differed but generally reflected a wish to avoid violence, and a search for mutual respect, sexual pleasure, romance, modernity, status and money. Agency was constrained once relationships were consented to, as men expected to control their partners, using violent and non-violent methods. Women knew this and many accepted this treatment, although often expressing ambivalence. Many of the women expressed highly acquiescent femininities, with power surrendered to men, as a 'choice' that made their lives in cultural terms more meaningful. In marked contrast to this was a 'modern' femininity, centred around a desire to be 'free'. A visible third position, notably emerging after the Stepping Stones intervention, rested not on a feminist challenge to patriarchy, but on an accommodation with men's power whilst seeking to negotiate greater respect and non-violence within relations with men. These multiple and dynamic femininities open up possibilities for change. They demonstrate the need to engage with women, both as victims of patriarchy and active supporters of the gender order. The multiplicity of women's hopes and desires and circumstances of emotional and relational fulfillment provides potential for interventions with women that acknowledge existing gender inequalities, validate women's agency, reduce violence and prevent HIV.


Protective effect of green tea against prostate cancer: a case-control study in southeast China.
To investigate whether green tea consumption has an etiological association with prostate cancer, a case-control study was conducted in Hangzhou, southeast China during 2001-2002. The cases were 130 incident patients with histologically confirmed adenocarcinoma of the prostate. The controls were 274 hospital inpatients without prostate cancer or any other malignant diseases, and matched to the age of cases. Information on duration, quantity and frequency of usual tea consumption, as well as the number of new batches brewed per day, were collected by face-to-face interview using a structured questionnaire. The risk of prostate cancer for tea consumption was assessed using multivariate logistic regression adjusting for age, locality, education, income, body mass index, physical activity, alcohol consumption, tobacco smoking, total fat intake, marital status, age at marriage, number of children, history of vasectomy and family history of prostate cancer. Among the cases, 55.4% were tea drinkers compared to 79.9% for the controls. Almost all the tea consumed was green tea. The prostate cancer risk declined with increasing frequency, duration and quantity of green tea consumption. The adjusted odds ratio (OR), relative to non-tea drinkers, were 0.28 (95% CI = 0.17-0.47) for tea drinking, 0.12 (95% CI = 0.06-0.26) for drinking tea over 40 years, 0.09 (95% CI = 0.04-0.21) for those consuming more than 1.5 kg of tea leaves yearly, and 0.27 (95% CI = 0.15-0.48) for those drinking more than 3 cups (1 litre) daily. The dose response relationships were also significant, suggesting that green tea is protective against prostate cancer.


Looking at long molecules in solution: what happens when they are subjected to Couette flow?
Knowing the structure of a molecule is one of the keys to deducing its function in a biological system. However, many biomacromolecules are not amenable to structural characterisation by the powerful techniques often used namely NMR and X-ray diffraction because they are too large, or too flexible or simply refuse to crystallize. Long molecules such as DNA and fibrous proteins are two such classes of molecule. In this article the extent to which flow linear dichroism (LD) can be used to characterise the structure and function of such molecules is reviewed. Consideration is given to the issues of fluid dynamics and light scattering by such large molecules. A range of applications of LD are reviewed including (i) fibrous proteins with particular attention being given to actin; (ii) a far from comprehensive discussion of the use of LD for DNA and DNA-ligand systems; (iii) LD for the kinetics of restriction digestion of circular supercoiled DNA; and (iv) carbon nanotubes to illustrate that LD can be used on any long molecules with accessible absorption transitions.


IBD Around the world: comparing the epidemiology, diagnosis, and treatment: proceedings of the World Digestive Health Day 2010--Inflammatory Bowel Disease Task Force meeting.
Every May 29th the World Gastroenterology Organization (WGO) celebrates World Digestive Health Day (WDHD) and initiates a worldwide public health campaign through its 110 national societies and 50,000 members. Each year focuses on a particular digestive disorder in order to increase general public awareness of prevention and therapy. 2010 is dedicated to inflammatory bowel disease (IBD). Upon this occasion a WGO IBD task force was compiled from leading international specialists and researchers. The task force also included members of the American Gastroenterological Association (AGA), International Organization for the Study of Inflammatory Diseases (IOIBD) and the European Crohn's and Colitis Organization (ECCO) of the United European Gastroenterology Federation (UEGF). The goal of the task force was to bring together IBD specialists from around the world to discuss the epidemiology, diagnosis, and management of IBD within different regions. This is a summary of the WGO task force meeting at the American Gastroenterological Association's (AGA) Digestive Disease Week, held in New Orleans, Louisiana, USA, May, 2010. The expert panel identified the most pressing issues in IBD worldwide: reliable epidemiological data, global collaboration in clinical and basic research, the approach to distinguishing intestinal tuberculosis from Crohn's disease, access to specialist care and access to the latest diagnostic and therapeutic strategies.


Direct-Acting Antivirals in Hepatitis C Virus-Associated Diffuse Large B-cell Lymphomas.
International guidelines suggest hepatitis C virus (HCV) eradication by direct-acting antivirals (DAAs) after first-line immunochemotherapy (I-CT) in patients with HCV-positive diffuse large B-cell lymphoma (DLBCL), although limited experiences substantiate this recommendation. Moreover, only a few data concerning concurrent administration of DAAs with I-CT have been reported. We analyzed hematological and virological outcome and survival of 47 consecutive patients with HCV-positive DLBCL treated at 23 Italian and French centers with DAAs either concurrently (concurrent cohort [ConC]: n = 9) or subsequently (sequential cohort [SeqC]: n = 38) to first-line I-CT (mainly rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone [R-CHOP]-like). Median age was 61 years, 89% of patients had stage III/IV, and 25% presented evidence of cirrhosis. Genotype was 1 in 56% and 2 in 34% of cases. Overall, 46 of 47 patients obtained complete response to I-CT. All patients received appropriate DAAs according to genotype, mainly sofosbuvir-based regimens (n = 45). Overall, 45 patients (96%) achieved sustained virological response, 8 of 9 in ConC and 37 of 38 in SeqC. DAAs were well tolerated, with only 11 patients experiencing grade 1-2 adverse events. Twenty-three patients experienced hepatic toxicity (grade 3-4 in seven) following I-CT in SeqC, compared to only one patient in ConC. At a median follow-up of 2.8 years, two patients died (2-year overall survival, 97.4%) and three progressed (2-year progression-free survival, 93.1%). Excellent outcome of this cohort of HCV-positive DLBCL suggests benefit of HCV eradication by DAAs either after or during I-CT. Moreover, concurrent DAAs and R-CHOP administration appeared feasible, effective, and ideally preferable to deferred administration of DAAs for the prevention of hepatic toxicity. Hepatitis C virus (HCV)-associated diffuse large B-cell lymphomas (DLBCLs) represent a great therapeutic challenge, especially in terms of hepatic toxicity during immune-chemotherapy (I-CT) and long-term hepatic complications. The advent of highly effective and toxicity-free direct-acting antivirals (DAAs) created an exciting opportunity to easily eradicate HCV shortly after or in concomitance with first-line immunochemotherapy (usually R-CHOP). This retrospective international study reports the real-life use of the combination of these two therapeutic modalities either in the concurrent or sequential approach (DAAs after I-CT) in 47 patients. The favorable reported results on long-term outcome seem to support the eradication of HCV with DAAs in all patients with HCV-positive DLBCL. Moreover, the results from the concurrent approach were effective and safe and displayed an advantage in preventing hepatic toxicity during I-CT.


Diagnosis and Management of Primary Biliary Cholangitis.
Primary biliary cholangitis (PBC) is a chronic, cholestatic, autoimmune disease with a variable progressive course. PBC can cause debilitating symptoms including fatigue and pruritus and, if left untreated, is associated with a high risk of cirrhosis and related complications, liver failure, and death. Recent changes to the PBC landscape include a name change, updated guidelines for diagnosis and treatment as well as new treatment options that have recently become available. Practicing clinicians face many unanswered questions when managing PBC. To assist these healthcare providers in managing patients with PBC, the American College of Gastroenterology (ACG) Institute for Clinical Research & Education, in collaboration with the Chronic Liver Disease Foundation (CLDF), organized a panel of experts to evaluate and summarize the most current and relevant peer-reviewed literature regarding PBC. This, combined with the extensive experience and clinical expertise of this expert panel, led to the formation of this clinical guidance on the diagnosis and management of PBC.


[Undergraduate education and health practices of speech and language pathologists working in public health services].
Comprehensive health care is still a challenge for all who participate in the transformation of undergraduate education and health care practices. Among health professionals, speech and language pathologists are also invited to reflect on these questions. The aim of this study was to investigate some aspects of the undergraduate education and health care practices of speech and language pathologists (graduates of the Federal University of Rio de Janeiro) working in public health units. A descriptive cross study was carried out with ten subjects who responded to a questionnaire and were interviewed. The transcribed data were analyzed based on their content and the frequency of the answers. The results showed that most of the interviewed professionals considered the traineeships as one of the most important experiences of the undergraduate course, had extracurricular experience in public health services, attended specialization courses, and worked in more than one public health unit. Also, the study found that individual therapy was the main activity carried out in the public health services by the professionals. The study identified relevant points to be discussed about undergraduate education and public health care practices for these health professionals.


Clinically important FEV1 declines among coal miners: an exploration of previously unrecognised determinants.
The relation between occupational exposure to dust and loss of ventilatory lung function is now well established. However, many exposures during work and other activities might also have important roles in determining clinically important losses of lung function. In this study, we attempted to explore additional plausible determinants of exposures and other potential risk factors for clinically important decline in forced expiratory volume in 1 second (FEV1) during work in dusty trades. The study was performed in 264 underground coal miners whose lung function had been followed up for an average of 11 years. With an extensive follow up questionnaire, miners were asked about their occupational and non-occupational exposures, smoking, personal and family medical history, and living conditions during childhood. Several variables of the mine environment (as well as previously recognised effects of mining work and region) were found to be associated with excess decline in FEV1, including work in roof bolting, exposure to explosive blasting, and to control dust spraying water that had been stored in holding tanks. Use of respiratory protection seemed to reduce the risk of decline in FEV1. Other factors that were found to be associated with declines in pulmonary function included smoking, body mass, weight gain, childhood pneumonia, and childhood exposure in the home to passive tobacco smoke and possibly smoke due to wood and coal fuels. Miners with excessive decline in FEV1 were less likely to be working in mining jobs at follow up. These findings suggest the existence of additional risk factors for decline in lung function in dusty trades, and may be useful in developing additional approaches to the prevention of chronic respiratory disease.


Remediation of Childhood Math Anxiety and Associated Neural Circuits through Cognitive Tutoring.
Math anxiety is a negative emotional reaction that is characterized by feelings of stress and anxiety in situations involving mathematical problem solving. High math-anxious individuals tend to avoid situations involving mathematics and are less likely to pursue science, technology, engineering, and math-related careers than those with low math anxiety. Math anxiety during childhood, in particular, has adverse long-term consequences for academic and professional success. Identifying cognitive interventions and brain mechanisms by which math anxiety can be ameliorated in children is therefore critical. Here we investigate whether an intensive 8 week one-to-one cognitive tutoring program designed to improve mathematical skills reduces childhood math anxiety, and we identify the neurobiological mechanisms by which math anxiety can be reduced in affected children. Forty-six children in grade 3, a critical early-onset period for math anxiety, participated in the cognitive tutoring program. High math-anxious children showed a significant reduction in math anxiety after tutoring. Remarkably, tutoring remediated aberrant functional responses and connectivity in emotion-related circuits anchored in the basolateral amygdala. Crucially, children with greater tutoring-induced decreases in amygdala reactivity had larger reductions in math anxiety. Our study demonstrates that sustained exposure to mathematical stimuli can reduce math anxiety and highlights the key role of the amygdala in this process. Our findings are consistent with models of exposure-based therapy for anxiety disorders and have the potential to inform the early treatment of a disability that, if left untreated in childhood, can lead to significant lifelong educational and socioeconomic consequences in affected individuals. Significance statement: Math anxiety during early childhood has adverse long-term consequences for academic and professional success. It is therefore important to identify ways to alleviate math anxiety in young children. Surprisingly, there have been no studies of cognitive interventions and the underlying neurobiological mechanisms by which math anxiety can be ameliorated in young children. Here, we demonstrate that intensive 8 week one-to-one cognitive tutoring not only reduces math anxiety but also remarkably remediates aberrant functional responses and connectivity in emotion-related circuits anchored in the amygdala. Our findings are likely to propel new ways of thinking about early treatment of a disability that has significant implications for improving each individual's academic and professional chances of success in today's technological society that increasingly demands strong quantitative skills.


Discovery and Characterization of ZUFSP/ZUP1, a Distinct Deubiquitinase Class Important for Genome Stability.
Deubiquitinating enzymes (DUBs) are important regulators of ubiquitin signaling. Here, we report the discovery of deubiquitinating activity in ZUFSP/C6orf113. High-resolution crystal structures of ZUFSP in complex with ubiquitin reveal several distinctive features of ubiquitin recognition and catalysis. Our analyses reveal that ZUFSP is a novel DUB with no homology to any known DUBs, leading us to classify ZUFSP as the seventh DUB family. Intriguingly, the minimal catalytic domain does not cleave polyubiquitin. We identify two ubiquitin binding domains in ZUFSP: a ZHA (ZUFSP helical arm) that binds to the distal ubiquitin and an atypical UBZ domain in ZUFSP that binds to polyubiquitin. Importantly, both domains are essential for ZUFSP to selectively cleave K63-linked polyubiquitin. We show that ZUFSP localizes to DNA lesions, where it plays an important role in genome stability pathways, functioning to prevent spontaneous DNA damage and also promote cellular survival in response to exogenous DNA damage.


Evaluating the importance of the convex hull in solving the Euclidean version of the traveling salesperson problem: reply to Lee and Vickers (2000).
Lee and Vickers (2000) suggest that the results of MacGregor and Ormerod (1996), showing that the response uncertainty to traveling salesperson problems (TSPs) increases with increasing numbers of nonboundary points, may have resulted as an artifact of constraints imposed in the construction of stimuli. The fact that similar patterns of results have been obtained for our "constrained" stimuli, for a stimulus constructed under different constraints, for 13 randomly generated stimuli, and for random and patterned 48-point problems provides empirical evidence that the results are not artifactual. Lee and Vickers further suggest that, even if not artifactual, the results are in principle limited to arrays of fewer than 50 points and that, beyond this, the total number of points and number of nonboundary points are "diagnostically equivalent." This claim seems to us incorrect, since arrays of any size can be constructed that will permit experimental tests of whether problem difficulty is influenced by the number of nonboundary points, or the total number of points, or both. We present a reanalysis of our original data using hierarchical regression analysis which indicates that both factors may influence problem complexity.


Genome sequence analyses show that Neisseria oralis is the same species as 'Neisseria mucosa var. heidelbergensis'.
Phylogenies generated from whole genome sequence (WGS) data provide definitive means of bacterial isolate characterization for typing and taxonomy. The species status of strains recently defined with conventional taxonomic approaches as representing Neisseria oralis was examined by the analysis of sequences derived from WGS data, specifically: (i) 53 Neisseria ribosomal protein subunit (rps) genes (ribosomal multi-locus sequence typing, rMLST); and (ii) 246 Neisseria core genes (core genome MLST, cgMLST). These data were compared with phylogenies derived from 16S and 23S rRNA gene sequences, demonstrating that the N. oralis strains were monophyletic with strains described previously as representing 'Neisseria mucosa var. heidelbergensis' and that this group was of equivalent taxonomic status to other well-described species of the genus Neisseria. Phylogenetic analyses also indicated that Neisseria sicca and Neisseria macacae should be considered the same species as Neisseria mucosa and that Neisseria flavescens should be considered the same species as Neisseria subflava. Analyses using rMLST showed that some strains currently defined as belonging to the genus Neisseria were more closely related to species belonging to other genera within the family; however, whole genome analysis of a more comprehensive selection of strains from within the family Neisseriaceae would be necessary to confirm this. We suggest that strains previously identified as representing 'N. mucosa var. heidelbergensis' and deposited in culture collections should be renamed N. oralis. Finally, one of the strains of N. oralis was able to ferment lactose, due to the presence of β-galactosidase and lactose permease genes, a characteristic previously thought to be unique to Neisseria lactamica, which therefore cannot be thought of as diagnostic for this species; however, the rMLST and cgMLST analyses confirm that N. oralis is most closely related to N. mucosa.


Estimating the COVID-19 Spread Through Real-time Population Mobility Patterns: Surveillance in Low- and Middle-Income Countries.
On January 21, 2020, the World Health Organization reported the first case of severe acute respiratory syndrome coronavirus 2, which rapidly evolved to the COVID-19 pandemic. Since then, the virus has also rapidly spread among Latin American, Caribbean, and African countries. The first aim of this study is to identify new emerging COVID-19 clusters over time and space (from January 21 to mid-May 2020) in Latin American, Caribbean, and African regions, using a prospective space-time scan measurement approach. The second aim is to assess the impact of real-time population mobility patterns between January 21 and May 18, 2020, under the implemented government interventions, measurements, and policy restrictions on COVID-19 spread among those regions and worldwide. We created a global COVID-19 database, of 218 countries and territories, merging the World Health Organization daily case reports with other measures such as population density and country income levels for January 21 to May 18, 2020. A score of government policy interventions was created for low, intermediate, high, and very high interventions. The population's mobility patterns at the country level were obtained from Google community mobility reports. The prospective space-time scan statistic method was applied in five time periods between January and May 2020, and a regression mixed model analysis was used. We found that COVID-19 emerging clusters within these five periods of time increased from 7 emerging clusters to 28 by mid-May 2020. We also detected various increasing and decreasing relative risk estimates of COVID-19 spread among Latin American, Caribbean, and African countries within the period of analysis. Globally, population mobility to parks and similar leisure areas during at least a minimum of implemented intermediate-level control policies (when compared to low-level control policies) was related to accelerated COVID-19 spread. Results were almost consistent when regional stratified analysis was applied. In addition, worldwide population mobility due to working during high implemented control policies and very high implemented control policies, when compared to low-level control policies, was related to positive COVID-19 spread. The prospective space-time scan is an approach that low-income and middle-income countries could use to detect emerging clusters in a timely manner and implement specific control policies and interventions to slow down COVID-19 transmission. In addition, real-time population mobility obtained from crowdsourced digital data could be useful for current and future targeted public health and mitigation policies at a global and regional level.


Middle Paleolithic shell beads in Israel and Algeria.
Perforated marine gastropod shells at the western Asian site of Skhul and the North African site of Oued Djebbana indicate the early use of beads by modern humans in these regions. The remoteness of these sites from the seashore and a comparison of the shells to natural shell assemblages indicate deliberate selection and transport by humans for symbolic use. Elemental and chemical analyses of sediment matrix adhered to one Nassarius gibbosulus from Skhul indicate that the shell bead comes from a layer containing 10 human fossils and dating to 100,000 to 135,000 years ago, about 25,000 years earlier than previous evidence for personal decoration by modern humans in South Africa.


Effects of Maternal Homelessness, Supplemental Nutrition Programs, and Prenatal PM2.5 on Birthweight.
Few studies examined the impact of maternal socioeconomic status and of its combined effects with environmental exposures on birthweight. Our goal was to examine the impact of maternal homelessness (mothers ever homeless or who lived in shelters during pregnancy) and participation in the Special Supplemental Nutrition Program for Women, Infants and Children (WIC) during pregnancy in conjunction with air pollution exposure on birthweight in the Boston-based Children's HealthWatch cohort from 2007 through 2015 (n = 3366). Birthweight was obtained from electronic health records. Information on maternal homelessness and WIC participation during pregnancy were provided via a questionnaire. Prenatal fine particulate matter (PM2.5) exposures, estimated at the subject's residential address, were calculated for each trimester. We fit linear regression models adjusting for maternal and child characteristics, seasonality, and block-group-level median household income and examined the interactions between PM2.5 and each covariate. Prenatal maternal homelessness was associated with reduced birthweight (-55.7 g, 95% CI: -97.8 g, -13.7 g), while participating in WIC was marginally associated with increased birthweight (36.1 g, 95% CI: -7.3 g, 79.4 g). Only average PM2.5 during the second trimester was marginally associated with reduced birthweight (-8.5 g, 95% CI: -19.3, 2.3) for a 1 µg/m3 increase in PM2.5. The association of PM2.5 during the second trimester with reduced birthweight was stronger among non-Hispanic Black mothers and trended toward significance among immigrants and single mothers. Our study emphasizes the independent and synergistic effects of social and environmental stressors on birthweight, particularly the potentially protective effect of participating in WIC for vulnerable populations.


Monoclonal antibody 4C5 prevents activation of MMP2 and MMP9 by disrupting their interaction with extracellular HSP90 and inhibits formation of metastatic breast cancer cell deposits.
Heat shock protein 90 (HSP90) is a molecular chaperone that is considered a new target for the treatment of cancer. Increasing data reveal an extracellular chaperoning activity for HSP90. Here we investigate the interaction of the secreted isoforms of HSP90 with matrix metalloproteinases (MMP) MMP2 and MMP9. Moreover we examine the role of a monoclonal antibody (mAb) against HSP90, mAb 4C5, regarding these interactions and its value as a potential inhibitor of human breast cancer cell invasion and metastasis. Our results showed that both HSP90alpha and HSP90beta are secreted by MDAMB453 human breast cancer cells and interact with MMP2 and MMP9. MAb 4C5, while not affecting the secretion of inactive MMPs, inhibits their activation by disrupting their interaction extracellularly with both isoforms of HSP90. The in vivo studies revealed that mAb 4C5 significantly inhibits the metastatic deposit formation of MDAMB453 cells into the lungs of SCID mice. Both isoforms of HSP90 are secreted by MDAMB453 cells and interact with MMP2 and MMP9. MAb 4C5 prevents MMP2 and MMP9 activation, by disrupting their interaction with HSP90. Finally mAb 4C5 significantly inhibits the metastatic deposit formation of MDAMB453 cells, by preventing their extravasation and infiltration in the lung tissue and therefore it could be used as a potential therapeutic agent for cancer metastasis.


Using treated wastewater to save wetlands impacted by climate change and pumping.
Wetlands occur where the watertable which underlies much of Perth intersects the land surface. Regional groundwater levels have been falling since the 1970s as a result of lower rainfall and increased extraction causing a loss of environmental and social values. This paper examines a scheme to add almost 2 GL/yr of treated wastewater to infiltration galleries immediately down-gradient of Perry Lakes so that the wetlands may be restored. Modelling suggest that groundwater levels would be raised up-gradient of the galleries, increasing both lake levels and groundwater supplies in the vicinity. It is not envisaged that wastewater will enter the lakes. Adding treated wastewater to nearby trial galleries has shown that phosphorus, pathogens and organic carbon are greatly reduced within 5 to 50 m. Nitrogen levels are less reduced but are similar to those in the lakes and nearby aquifer. It is estimated that the wetlands add about $54 m to land prices near the lakes and would add more than $24M to the sale price of proposed nearby land if they contain water. If successful, the proposal could be a test case for the use of treated wastewater to create hydraulic barriers against salt water intrusion into coastal areas.


Harnessing the power of theorising in implementation science.
Theories occupy different positions in the scientific circle of enquiry as they vary in scope, abstraction, and complexity. Mid-range theories play a crucial bridging role between raw empirical observations and all-encompassing grand-theoretical schemes. A shift of perspective from 'theories' as products to 'theorising' as a process can enable empirical researchers to capitalise on the two-way relationships between empirical data and different levels of theory and contribute to the advancement of knowledge. This can be facilitated by embracing theoretically informative (in addition to merely theoretically informed) research, developing mechanism-based explanations, and broadening the repertoire of grand-theoretical orientations.


Discovery and engineering of enhanced SUMO protease enzymes.
Small ubiquitin-like modifier (SUMO) is commonly used as a protein fusion domain to facilitate expression and purification of recombinant proteins, and a SUMO-specific protease is then used to remove SUMO from these proteins. Although this protease is highly specific, its limited solubility and stability hamper its utility as an in vitro reagent. Here, we report improved SUMO protease enzymes obtained via two approaches. First, we developed a computational method and used it to re-engineer WT Ulp1 from Saccharomyces cerevisiae to improve protein solubility. Second, we discovered an improved SUMO protease via genomic mining of the thermophilic fungus Chaetomium thermophilum, as proteins from thermophilic organisms are commonly employed as reagent enzymes. Following expression in Escherichia coli, we found that these re-engineered enzymes can be more thermostable and up to 12 times more soluble, all while retaining WT-or-better levels of SUMO protease activity. The computational method we developed to design solubility-enhancing substitutions is based on the RosettaScripts application for the macromolecular modeling suite Rosetta, and it is broadly applicable for the improvement of solution properties of other proteins. Moreover, we determined the X-ray crystal structure of a SUMO protease from C. thermophilum to 1.44 Å resolution. This structure revealed that this enzyme exhibits structural and functional conservation with the S. cerevisiae SUMO protease, despite exhibiting only 28% sequence identity. In summary, by re-engineering the Ulp1 protease and discovering a SUMO protease from C. thermophilum, we have obtained proteases that are more soluble, more thermostable, and more efficient than the current commercially available Ulp1 enzyme.


Uterine rupture after balloon inflation of the intrauterine Foley catheter during laparoscopic chromopertubation.
Laparoscopic chromopertubation is considered "gold standard" for checking the tubal patency. Foley catheter is frequently used for blue dye during chromopertubation. Complications associated with the intra-uterine use of Foley catheter are infrequent. The mean normal capacity of the uterine cavity is about 9 ml, and an inflation of up to 30 ml (e. g. during thermal balloon ablation procedures) is considered safe. We report a uterine rupture in a 36-year-old woman undergoing laparoscopic chromopertubation due to primary infertility. Thirteen years ago, the patient had three consecutive laparotomies because of appendicitis, peritonitis and retroperitoneal abscess. For the present laparoscopy, the Foley catheter (Nelaton, charier 10, balloon 5 ml) was used. The first blocking of the balloon with 3.5 ml saline was insufficient; however after inflating with 5 ml, a rupture of the uterine fundus occurred. The balloon remained intact and both tubes appeared patent. The myometrium was sutured and the postoperative course was uneventful. We presume that-in the present case-the expansive capacity of the uterine wall may have been reduced after the series of severe pelvic inflammations. Nevertheless, if using a Foley catheter for the chromopertubation, the optimal pressure for its intrauterine fixation needs still to be determined.


Enhanced Archaerhodopsin Fluorescent Protein Voltage Indicators.
A longstanding goal in neuroscience has been to develop techniques for imaging the voltage dynamics of genetically defined subsets of neurons. Optical sensors of transmembrane voltage would enhance studies of neural activity in contexts ranging from individual neurons cultured in vitro to neuronal populations in awake-behaving animals. Recent progress has identified Archaerhodopsin (Arch) based sensors as a promising, genetically encoded class of fluorescent voltage indicators that can report single action potentials. Wild-type Arch exhibits sub-millisecond fluorescence responses to trans-membrane voltage, but its light-activated proton pump also responds to the imaging illumination. An Arch mutant (Arch-D95N) exhibits no photocurrent, but has a slower, ~40 ms response to voltage transients. Here we present Arch-derived voltage sensors with trafficking signals that enhance their localization to the neural membrane. We also describe Arch mutant sensors (Arch-EEN and -EEQ) that exhibit faster kinetics and greater fluorescence dynamic range than Arch-D95N, and no photocurrent at the illumination intensities normally used for imaging. We benchmarked these voltage sensors regarding their spike detection fidelity by using a signal detection theoretic framework that takes into account the experimentally measured photon shot noise and optical waveforms for single action potentials. This analysis revealed that by combining the sequence mutations and enhanced trafficking sequences, the new sensors improved the fidelity of spike detection by nearly three-fold in comparison to Arch-D95N.


A computer based spectroradiometer system.
A spectroradiometer system is described which is designed to make measurements of the spectral energy-distribution of light sources over the 0.25-2.5-micro wavelength range. A review is presented of some of the major experimental problems encountered in radiometry, in conjunction with the approach employed here to meet these problems. A single beam optical arrangement is used, with the photodetector signal being integrated over successive wavelength intervals and recorded in digital form. A digital computer then performs all subsequent data processing, including plotting of the final spectra. A brief functional description of the computer programs is presented, and the accuracy and reproducibility of the system are discussed.


Congenital bone marrow failure in DNA-PKcs mutant mice associated with deficiencies in DNA repair.
The nonhomologous end-joining (NHEJ) pathway is essential for radioresistance and lymphocyte-specific V(D)J (variable [diversity] joining) recombination. Defects in NHEJ also impair hematopoietic stem cell (HSC) activity with age but do not affect the initial establishment of HSC reserves. In this paper, we report that, in contrast to deoxyribonucleic acid (DNA)-dependent protein kinase catalytic subunit (DNA-PKcs)-null mice, knockin mice with the DNA-PKcs(3A/3A) allele, which codes for three alanine substitutions at the mouse Thr2605 phosphorylation cluster, die prematurely because of congenital bone marrow failure. Impaired proliferation of DNA-PKcs(3A/3A) HSCs is caused by excessive DNA damage and p53-dependent apoptosis. In addition, increased apoptosis in the intestinal crypt and epidermal hyperpigmentation indicate the presence of elevated genotoxic stress and p53 activation. Analysis of embryonic fibroblasts further reveals that DNA-PKcs(3A/3A) cells are hypersensitive to DNA cross-linking agents and are defective in both homologous recombination and the Fanconi anemia DNA damage response pathways. We conclude that phosphorylation of DNA-PKcs is essential for the normal activation of multiple DNA repair pathways, which in turn is critical for the maintenance of diverse populations of tissue stem cells in mice.


Inhibition of HDAC Enzymes Contributes to Differential Expression of Pro-Inflammatory Proteins in the TLR-4 Signaling Cascade.
Class I and II histone deacetylases (HDAC) are considered important regulators of immunity and inflammation. Modulation of HDAC expression and activity is associated with altered inflammatory responses but reports are controversial and the specific impact of single HDACs is not clear. We examined class I and II HDACs in TLR-4 signaling pathways in murine macrophages with a focus on IκB kinase epsilon (IKKε) which has not been investigated in this context before. Therefore, we applied the pan-HDAC inhibitors (HDACi) trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) as well as HDAC-specific siRNA. Administration of HDACi reduced HDAC activity and decreased expression of IKKε although its acetylation was increased. Other pro-inflammatory genes (IL-1β, iNOS, TNFα) also decreased while COX-2 expression increased. HDAC 2, 3 and 4, respectively, might be involved in IKKε and iNOS downregulation with potential participation of NF-κB transcription factor inhibition. Suppression of HDAC 1-3, activation of NF-κB and RNA stabilization mechanisms might contribute to increased COX-2 expression. In conclusion, our results indicate that TSA and SAHA exert a number of histone- and HDAC-independent functions. Furthermore, the data show that different HDAC enzymes fulfill different functions in macrophages and might lead to both pro- and anti-inflammatory effects which have to be considered in therapeutic approaches.


Super-Spreaders or Victims of Circumstance? Childhood in Canadian Media Reporting of the COVID-19 Pandemic: A Critical Content Analysis.
This qualitative research study, a critical content analysis, explores Canadian media reporting of childhood in Canada during the COVID-19 global pandemic. Popular media plays an important role in representing and perpetuating the dominant social discourse in highly literate societies. In Canadian media, the effects of the pandemic on children and adolescents' health and wellbeing are overshadowed by discussions of the potential risk they pose to adults. The results of this empirical research highlight how young people in Canada have been uniquely impacted by the COVID-19 global pandemic. Two dominant narratives emerged from the data: children were presented "as a risk" to vulnerable persons and older adults and "at risk" of adverse health outcomes from contracting COVID-19 and from pandemic lockdown restrictions. This reflects how childhood was constructed in Canadian society during the pandemic, particularly how children's experiences are described in relation to adults. Throughout the pandemic, media reports emphasized the role of young people's compliance with public health measures to prevent the spread of COVID-19 and save the lives of older persons.


Association of Injury Factors, Not Body Mass Index, With Hospital Resource Usage in Trauma Patients.
Allocating resources appropriately requires knowing whether obese patients use more resources during a hospital stay than nonobese patients. To determine if trauma patients with different body mass indexes differed in use of resources measured as a multifaceted outcome variable. A trauma registry was used for a retrospective study of adult patients admitted to a midwestern level I trauma center. Patients were stratified into 3 groups: nonobese (normal weight, overweight), obese, and morbidly obese. Three canonical correlation analyses were used to determine the relationship between patient/injury characteristics and hospital resource usage. In a sample of 9771 patients, 71.2% were non-obese, 23.8% obese, and 5.0% morbidly obese. For patient/injury characteristics, Injury Severity Score and physiological complications were significant variables for all 3 groups. Scores on the Glasgow Coma Scale were significant for nonobese patients only. For resource usage, intensive care unit length of stay and procedures were significant variables for all 3 groups. Associations between body mass index and outcomes have been noted when assessed as independent variables. However, when resource usage was assessed as a multifaceted outcome variable, injury factors (higher Injury Severity Score, lower scores on the Glasgow Coma Scale, more physiological complications) were associated with resource usage (increased length of stay in the intensive care unit and increased number of procedures). These findings provide clinicians a new perspective for evaluating the complex relationship between patient/injury characteristics and hospital resource usage.


The Cross-Talk between Spirochetal Lipoproteins and Immunity.
Spirochetal diseases such as syphilis, Lyme disease, and leptospirosis are major threats to public health. However, the immunopathogenesis of these diseases has not been fully elucidated. Spirochetes interact with the host through various structural components such as lipopolysaccharides (LPS), surface lipoproteins, and glycolipids. Although spirochetal antigens such as LPS and glycolipids may contribute to the inflammatory response during spirochetal infections, spirochetes such as Treponema pallidum and Borrelia burgdorferi lack LPS. Lipoproteins are most abundant proteins that are expressed in all spirochetes and often determine how spirochetes interact with their environment. Lipoproteins are pro-inflammatory, may regulate responses from both innate and adaptive immunity and enable the spirochetes to adhere to the host or the tick midgut or to evade the immune system. However, most of the spirochetal lipoproteins have unknown function. Herein, the immunomodulatory effects of spirochetal lipoproteins are reviewed and are grouped into two main categories: effects related to immune evasion and effects related to immune activation. Understanding lipoprotein-induced immunomodulation will aid in elucidating innate immunopathogenesis processes and subsequent adaptive mechanisms potentially relevant to spirochetal disease vaccine development and to inflammatory events associated with spirochetal diseases.


Vitamin E sequestration by liver fat in humans.
BACKGROUNDWe hypothesized that obesity-associated hepatosteatosis is a pathophysiological chemical depot for fat-soluble vitamins and altered normal physiology. Using α-tocopherol (vitamin E) as a model vitamin, pharmacokinetics and kinetics principles were used to determine whether excess liver fat sequestered α-tocopherol in women with obesity-associated hepatosteatosis versus healthy controls.METHODSCustom-synthesized deuterated α-tocopherols (d3- and d6-α-tocopherols) were administered to hospitalized healthy women and women with hepatosteatosis under investigational new drug guidelines. Fluorescently labeled α-tocopherol was custom-synthesized for cell studies.RESULTSIn healthy subjects, 85% of intravenous d6-α-tocopherol disappeared from the circulation within 20 minutes but reappeared within minutes and peaked at 3-4 hours; d3- and d6-α-tocopherols localized to lipoproteins. Lipoprotein redistribution occurred only in vivo within 1 hour, indicating a key role of the liver in uptake and re-release. Compared with healthy subjects who received 2 mg, subjects with hepatosteatosis had similar d6-α-tocopherol entry rates into liver but reduced initial release rates (P < 0.001). Similarly, pharmacokinetics parameters were reduced in hepatosteatosis subjects, indicating reduced hepatic d6-α-tocopherol output. Reductions in kinetics and pharmacokinetics parameters in hepatosteatosis subjects who received 2 mg were echoed by similar reductions in healthy subjects when comparing 5- and 2-mg doses. In vitro, fluorescent-labeled α-tocopherol localized to lipid in fat-loaded hepatocytes, indicating sequestration.CONCLUSIONSThe unique role of the liver in vitamin E physiology is dysregulated by excess liver fat. Obesity-associated hepatosteatosis may produce unrecognized hepatic vitamin E sequestration, which might subsequently drive liver disease. Our findings raise the possibility that hepatosteatosis may similarly alter hepatic physiology of other fat-soluble vitamins.TRIAL REGISTRATIONClinicalTrials.gov, NCT00862433.FUNDINGNational Institute of Diabetes and Digestive and Kidney Diseases and NIH grants DK053213-13, DK067494, and DK081761.


On-the-fly machine-learning for high-throughput experiments: search for rare-earth-free permanent magnets.
Advanced materials characterization techniques with ever-growing data acquisition speed and storage capabilities represent a challenge in modern materials science, and new procedures to quickly assess and analyze the data are needed. Machine learning approaches are effective in reducing the complexity of data and rapidly homing in on the underlying trend in multi-dimensional data. Here, we show that by employing an algorithm called the mean shift theory to a large amount of diffraction data in high-throughput experimentation, one can streamline the process of delineating the structural evolution across compositional variations mapped on combinatorial libraries with minimal computational cost. Data collected at a synchrotron beamline are analyzed on the fly, and by integrating experimental data with the inorganic crystal structure database (ICSD), we can substantially enhance the accuracy in classifying the structural phases across ternary phase spaces. We have used this approach to identify a novel magnetic phase with enhanced magnetic anisotropy which is a candidate for rare-earth free permanent magnet.


Differential regulation by cyclic nucleotides of the CNGA4 and CNGB1b subunits in olfactory cyclic nucleotide-gated channels.
Olfactory cyclic nucleotide-gated (CNG) ion channels are essential contributors to signal transduction of olfactory sensory neurons. The activity of the channels is controlled by the cyclic nucleotides guanosine 3',5'-monophosphate (cGMP) and adenosine 3',5'-monophosphate (cAMP). The olfactory CNG channels are composed of two CNGA2 subunits, one CNGA4 and one CNGB1b subunit, each containing a cyclic nucleotide-binding domain. Using patch-clamp fluorometry, we measured ligand binding and channel activation simultaneously and showed that cGMP activated olfactory CNG channels not only by binding to the two CNGA2 subunits but also by binding to the CNGA4 subunit. In a channel in which the CNGA2 subunits were compromised for ligand binding, cGMP binding to CNGA4 was sufficient to partly activate the channel. In contrast, in heterotetrameric channels, the CNGB1b subunit did not bind cGMP, but channels with this subunit showed activation by cAMP. Thus, the modulatory subunits participate actively in translating ligand binding to activation of heterotetrameric olfactory CNG channels and enable the channels to differentiate between cyclic nucleotides.


Implementation of a group-based diabetes prevention program within a healthcare delivery system.
Group-based Diabetes Prevention Programs (DPP), aligned with recommendations from the Centers for Disease Control and Prevention, promote clinically significant weight loss and reduce cardio-metabolic risks. Studies have examined implementation of the DPP in community settings, but less is known about its integration in healthcare systems. In 2010, a group-based DPP known as the Group Lifestyle Balance (GLB) was implemented within a large healthcare delivery system in Northern California, across three geographically distinct regional administration divisions of the organization within 12 state counties, with varying underlying socio-demographics. The regional divisions implemented the program independently, allowing for natural variation in its real-world integration. We leveraged this natural experiment to qualitatively assess the implementation of a DPP in this healthcare system and, especially, its fidelity to the original GLB curriculum and potential heterogeneity in implementation across clinics and regional divisions. Using purposive sampling, we conducted semi-structured interviews with DPP lifestyle coaches. Data were analyzed using mixed-method techniques, guided by an implementation outcomes framework consisting of eight constructs: acceptability, adoption, appropriateness, cost, feasibility, fidelity, penetration, and sustainability. We conducted 33 interviews at 20 clinics across the three regional administrative divisions. Consistencies in implementation of the program were found across regions in terms of satisfaction with the evidence base (acceptability), referral methods (adoption), eligibility criteria (fidelity), and strategies to increase retention and effectiveness (sustainability). Heterogeneity in implementation across regions were found in all categories, including: the number and frequency of sessions (fidelity); program branding (adoption); lifestyle coach training (adoption), and patient-facing cost (cost). Lifestyle coaches expressed differing attitudes about curriculum content (acceptability) and suitability of educational level (appropriateness). While difficulties with recruitment were common across regions (feasibility), strategies used to address these challenges differed (sustainability). Variation exists in the implementation of the DPP within a large multi-site healthcare system, revealing a dynamic and important tension between retaining fidelity to the original program and tailoring the program to meet the local needs. Moreover, certain challenges across sites may represent opportunities for considering alternative implementation to anticipate these barriers. Further research is needed to explore how differences in implementation domains impact program effectiveness.


The emerging role of histone deacetylase (HDAC) inhibitors in urological cancers.
WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: A growing body of evidence supports the anti-cancer effect of histone deacetylase inhibitors (HDACi) in vitro, via multiple pathways, and many Phase I clinical trials have shown them to be well-tolerated in a range of malignancies. Combined therapies, including with radiation, present an exciting area of current and planned study. This review summarises the evidence to date, including pre-clinical data and clinical trials, of the anti-cancer effect of HDACi in urological cancers. It provides an overview of epigenetics and the mechanisms of action of HDACi. It suggests areas of future development, including the current challenges for the successful introduction of HDACi into clinical therapy. Epigenetic modifications are known to play a critical role in the development and progression of many cancers. The opposing actions of histone deacetylases (HDACs) and histone acetyltransferases (HATs) modify chromatin and lead to epigenetic gene regulation, in addition to wider effects on non-histone proteins. There is growing interest in the clinical application of HDAC inhibitors (HDACi) in cancer. HDACi have been shown to inhibit cancer cell growth both in vitro and in vivo and recent clinical trials have shown encouraging results in various urological cancers. In this review, we discuss the existing evidence and potential role for HDACi in urological malignancies, including in combined therapies.


Variation in Taxonomic Composition of the Fecal Microbiota in an Inbred Mouse Strain across Individuals and Time.
Genetics, diet, and other environmental exposures are thought to be major factors in the development and composition of the intestinal microbiota of animals. However, the relative contributions of these factors in adult animals, as well as variation with time in a variety of important settings, are still not fully understood. We studied a population of inbred, female mice fed the same diet and housed under the same conditions. We collected fecal samples from 46 individual mice over two weeks, sampling four of these mice for periods as long as 236 days for a total of 190 samples, and determined the phylogenetic composition of their microbial communities after analyzing 1,849,990 high-quality pyrosequencing reads of the 16S rRNA gene V3 region. Even under these controlled conditions, we found significant inter-individual variation in community composition, as well as variation within an individual over time, including increases in alpha diversity during the first 2 months of co-habitation. Some variation was explained by mouse membership in different cage and vendor shipment groups. The differences among individual mice from the same shipment group and cage were still significant. Overall, we found that 23% of the variation in intestinal microbiota composition was explained by changes within the fecal microbiota of a mouse over time, 12% was explained by persistent differences among individual mice, 14% by cage, and 18% by shipment group. Our findings suggest that the microbiota of controlled populations of inbred laboratory animals may not be as uniform as previously thought, that animal rearing and handling may account for some variation, and that as yet unidentified factors may explain additional components of variation in the composition of the microbiota within populations and individuals over time. These findings have implications for the design and interpretation of experiments involving laboratory animals.


Remediation of contaminated sediments containing both organic and inorganic chemicals using ultrasound and ozone nanobubbles.
Most river sediments are contaminated with organic and inorganic pollutants and cause significant environmental damage and health risks. This research is evaluated an in-situ sediment remediation method using ultrasound and ozone nanobubbles to remove organic and inorganic chemicals in contaminated sediments. Contaminated sediment is prepared by mixing synthetic fine sediment with an organic (p-terphenyl) and an inorganic chemical (chromium). The prepared contaminated sediment is treated with ultrasound and ozone nanobubbles under different operating conditions. For the samples with the maximum initial concentration of 4211 mg/kg Cr and 1875 mg/kg p-terphenyl, average removal efficiencies are 71% and 60%, respectively, with 240 min of sonication with 2-min pulses, whereas 97.5% and 91.5% removal efficiencies are obtained for the same, respectively, as a single contaminant in the sediment. For the same maximum concentrations, the highest removal of p-terphenyl is 82.7% with 127.2 J/ml high energy density, and for Cr, it is 77.1% using the highest number of the treatment cycle and ozone usage with 78.75/ml energy density. The Cr highest removal efficiency of 87.2% is recorded with the reduced initial concentration of 1227 mg/kg with the highest treatment cycles. The Cr removal efficiency depends on the availability of oxidizing agents and the number of washing cycles of sediments, whereas P-terphenyl degradation is most likely influenced by the combined effects of oxidation and ultrasound-assisted pyrolysis and combustion of organics.


Controlled folding of micrometer-size structures.
Several types of microactuators have been fabricated, from simple paddles to self-assembling and -disassembling cubes. Conducting bilayers made of a layer of polymer and a layer of gold were used as hinges to connect rigid plates to each other and to a silicon substrate. The bending of the hinges was electrically controlled and reversible, allowing precise three-dimensional positioning of the plates. The structures were released from the substrate with a technique based on differential adhesion. This method, which avoids the use of a sacrificial layer and allows the actuators to pull themselves off the surface, may have general applications in micromachining. Possibilities include the manufacture, of surfaces whose light reflection or chemical properties can be switched.


[Plasmodium falciparum malaria acquired in Sub-Saharan Africa].
The purpose of this paper is to present the cases of malaria caused by Plasmodium falciparum in travelers coming from tropical Africa, who were treated at the Hospital Alemán (Buenos Aires). African malaria was defined as an infection acquired in any country within Africa, diagnosed and treated in Argentina. Diagnostic tools included clinical features and optic microscopy with Giemsa stained peripheral blood films. We reviewed the medical records of 11 adult patients -five tourists and six sailors- with no history of malaria, immunosuppressive condition or associated morbidity, admitted from 1993 to 2007. The age ranged from 21 to 48 years old, nine of them were males and two females. The patients were retrospectively classified into severe malaria -six of them- or mild malaria -five of them- according to severity criteria established by the World Health Organization, within the first three days of the beginnings of the symptoms. All patients presented fever; severe complications included encephalitis, renal failure, bleeding, haemoglobinuria, hypoglycemia, and pulmonary edema. Three patients required admission at the intensive care unit; no patient died. Only three off them had received properly chemoprophylaxis before traveling; all received treatment with at least one of the following drugs: mefloquine, quinidine, clyndamicine and cotrimoxazol.


[AWMF-guideline: disorders related to cannabis].
Actually, guidelines for treatment of substance-related disorders were written under the overall control of the DG-Sucht e. V. and the DGPPN e. V. This appears within the framework of the Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaft (AWMF). The leading objective of these guidelines is the description of the current scientifically proven and evidence-based medicine in addiction to derive recommendations to therapy. In this context, the guideline for treatment of cannabis-related disorders is introduced.


Multiparameter Phenotyping of Human PBMCs Using Mass Cytometry.
The standard for single-cell analysis of phenotype and function in recent decades has been fluorescence flow cytometry. Mass cytometry is a newer technology that uses heavy metal ions, rather than fluorochromes, as labels for probes such as antibodies. The binding of these ion-labeled probes to cells is quantitated by mass spectrometry. This greatly increases the number of phenotypic and functional markers that can be probed simultaneously. Here, we review topics that must be considered when adapting existing flow cytometry panels to mass cytometry analysis. We present a protocol and representative panels for surface phenotyping and intracellular cytokine staining (ICS) assays.


Single Nucleotide Polymorphisms in Chemosensory Pathway Genes GNB3, TAS2R19, and TAS2R38 Are Associated with Chronic Rhinosinusitis.
Chronic rhinosinusitis (CRS) is a multifaceted disease with a significant genetic component. The importance of taste receptor signaling has recently been highlighted in CRS; single nucleotide polymorphisms (SNPs) of bitter tastant-responsive G-protein-coupled receptors have been linked with CRS and with altered innate immune responses to multiple bacterially derived signals. To determine in CRS the frequency of six SNPs in genes with known bitter tastant signaling function. Genomic DNA was isolated from 74 CRS volunteers in West Virginia, and allele frequency was determined and compared with demographically matched data from the 1,000 Genomes database. For two SNPs in a gene recently associated with bitterant signaling regulation, RGS21, there were no associations with CRS (although the frequency of the minor allele of RGS21, rs7528947, was seen to increase with increasing Lund-Mackay CT staging score). Two TAS2R bitter taste receptor gene variants (TAS2R19 rs10772420 and TAS2R38 rs713598), identified in prior CRS genetics studies, were found to have similar associations in this study. Unique to our study is the establishment of an association between CRS in this patient population and GNB3 SNP rs5443, a variation in an established G protein component downstream of bitterant receptor signal transduction.


Engineering the optical response of plasmonic nanoantennas.
The optical properties of plasmonic dipole and bowtie nanoantennas are investigated in detail using the Green's tensor technique. The influence of the geometrical parameters (antenna length, gap dimension and bow angle) on the antenna field enhancement and spectral response is discussed. Dipole and bowtie antennas confine the field in a volume well below the diffraction limit, defined by the gap dimensions. The dipole antenna produces a stronger field enhancement than the bowtie antenna for all investigated antenna geometries. This enhancement can reach three orders of magnitude for the smallest examined gap. Whereas the dipole antenna is monomode in the considered spectral range, the bowtie antenna exhibits multiple resonances. Furthermore, the sensitivity of the antennas to index changes of the environment and of the substrate is investigated in detail for biosensing applications; the bowtie antennas show slightly higher sensitivity than the dipole antenna.


Tailoring the negative-refractive-index metamaterials composed of semiconductor-metal-semiconductor gold ring/disk cavity heptamers to support strong Fano resonances in the visible spectrum.
In this study, we investigated numerically the plasmon response of a planar negative-index metamaterial composed of symmetric molecular orientations of Au ring/disk nanocavities in a heptamer cluster. Using the plasmon hybridization theory and considering the optical response of an individual nanocluster, we determined the accurate geometrical sizes for a ring/disk nanocavity heptamer. It is shown that the proposed well-organized nanocluster can be tailored to support strong and sharp Fano resonances in the visible spectrum. Surrounding and filling the heptamer clusters by various metasurfaces with different chemical characteristics, and illuminating the structure with an incident light source, we proved that this configuration reflects low losses and isotropic features, including a pronounced Fano dip in the visible spectrum. Technically, employing numerical methods and tuning the geometrical sizes of the structure, we tuned and induced the Fano dip in the visible range, while the dark and bright plasmon resonance extremes are blueshifted to shorter wavelengths dramatically. Considering the calculated transmission window, we quantified the effective refractive index for the structure, while the substance of the substrate material was varied. Using Si, GaP, and InP semiconductors as substrate materials, we calculated and compared the corresponding figure of merit (FOM) for different regimes. The highest possible FOM was obtained for the GaP-Au-GaP negative-refractive-index metamaterial composed of ring/disk nanocavity heptamers as 62.4 at λ∼690 nm (arounnd the position of the Fano dip). Despite the outstanding symmetric nature of the suggested heptamer array, we provided sharp Fano dips by the appropriate tuning of the geometrical and chemical parameters. This study yields a method to employ ring/disk nanocavity heptamers as a negative-refractive-index metamaterial in designing highly accurate localization of surface plasmon resonance sensing devices and biochemical sensors.


A personal nanoparticle respiratory deposition (NRD) sampler.
A lightweight (60 g), personal nanoparticle respiratory deposition (NRD) sampler was developed to selectively collect particles smaller than 300 nm similar to their typical deposition in the respiratory tract. The sampler operates at 2.5 Lpm and consists of a respirable cyclone fitted with an impactor and a diffusion stage containing mesh screens. The cut-point diameter of the impactor was determined to be 300 nm with a sharpness σ = 1.53. The diffusion stage screens collect particles with an efficiency that matches the deposition efficiency of particles smaller than 300 nm in the respiratory tract. Impactor separation performance was unaffected by loading at typical workplace levels (p-value = 0.26). With chemical analysis of the diffusion media, the NRD sampler can be used to directly assess exposures to nanoparticles of a specific composition apart from other airborne particles. The pressure drop of the NRD sampler is sufficiently low to permit its operation with conventional, belt-mounted sampling pumps.


Patterns of DNA damage response in intracranial germ cell tumors versus glioblastomas reflect cell of origin rather than brain environment: implications for the anti-tumor barrier concept and treatment.
The DNA damage response (DDR) machinery becomes commonly activated in response to oncogenes and during early stages of development of solid malignancies, with an exception of testicular germ cell tumors (TGCTs). The active DDR signaling evokes cell death or senescence but this anti-tumor barrier can be breached by defects in DDR factors, such as the ATM-Chk2-p53 pathway, thereby allowing tumor progression. The DDR barrier is strongly activated in brain tumors, particularly gliomas, due to oxidative damage and replication stress. Here, we took advantage of rare human primary intracranial germ cell tumors (PIGCTs), to address the roles of cell-intrinsic factors including cell of origin, versus local tissue environment, in the constitutive DDR activation in vivo. Immunohistochemical analysis of 7 biomarkers on a series of 21 PIGCTs (germinomas and other subtypes), 20 normal brain specimens and 20 glioblastomas, revealed the following: i) The overall DDR signaling (γH2AX) and activation of the ATM-Chk2-p53 pathway were very low among the PIGCTs, reminiscent of TGCTs, and contrasting sharply with strong DDR activation in glioblastomas; ii) Except for one case of embryonal carcinoma, there were no clear aberrations in the ATM-Chk2-p53 pathway components among the PIGCT cohort; iii) Subsets of PIGCTs showed unusual cytosolic localization of Chk2 and/or ATM. Collectively, these results show that PIGCTs mimic the DDR activation patterns of their gonadal germ cell tumor counterparts, rather than the brain tumors with which they share the tissue environment. Hence cell-intrinsic factors and cell of origin dictate the extent of DDR barrier activation and also the ensuing pressure to select for DDR defects. Our data provide conceptually important insights into the role of DNA damage checkpoints in intracranial tumorigenesis, with implications for the differential biological responses of diverse tumor types to endogenous stress as well as to genotoxic treatments such as ionizing radiation or chemotherapy.


The stromal chloroplast Deg7 protease participates in the repair of photosystem II after photoinhibition in Arabidopsis.
Light is the ultimate source of energy for photosynthesis; however, excessive light leads to photooxidative damage and hence reduced photosynthetic efficiency, especially when combined with other abiotic stresses. Although the photosystem II (PSII) reaction center D1 protein is the primary target of photooxidative damage, other PSII core proteins are also damaged and degraded. However, it is still largely unknown whether degradation of D1 and other PSII proteins involves previously uncharacterized proteases. Here, we show that Deg7 is peripherally associated with the stromal side of the thylakoid membranes and that Deg7 interacts directly with PSII. Our results show that Deg7 is involved in the primary cleavage of photodamaged D1, D2, CP47, and CP43 and that this activity is essential for its function in PSII repair. The double mutants deg5 deg7 and deg8 deg7 showed no obvious phenotypic differences under normal growth conditions, but additive effects were observed under high light. These results suggest that Deg proteases on both the stromal and luminal sides of the thylakoid membranes are important for the efficient PSII repair in Arabidopsis (Arabidopsis thaliana).


High Resolution Dissection of Reactive Glial Nets in Alzheimer's Disease.
Fixed human brain samples in tissue repositories hold great potential for unlocking complexities of the brain and its alteration with disease. However, current methodology for simultaneously resolving complex three-dimensional (3D) cellular anatomy and organization, as well as, intricate details of human brain cells in tissue has been limited due to weak labeling characteristics of the tissue and high background levels. To expose the potential of these samples, we developed a method to overcome these major limitations. This approach offers an unprecedented view of cytoarchitecture and subcellular detail of human brain cells, from cellular networks to individual synapses. Applying the method to AD samples, we expose complex features of microglial cells and astrocytes in the disease. Through this methodology, we show that these cells form specialized 3D structures in AD that we refer to as reactive glial nets (RGNs). RGNs are areas of concentrated neuronal injury, inflammation, and tauopathy and display unique features around β-amyloid plaque types. RGNs have conserved properties in an AD mouse model and display a developmental pattern coinciding with the progressive accumulation of neuropathology. The method provided here will help reveal novel features of the healthy and diseased human brain, and aid experimental design in translational brain research.


[Efficacy of cognitive training programs based on new software technologies in patients with Alzheimer-type dementia].
The study aims to assess the efficacy of the Big Brain Academy (BBA), a computerized cognitive training program (CT) based on video games, compared to the Integrated Psychostimulation Program (IPP), a classical CT tool for patients with Alzheimer's disease (AD). A total of 45 patients with AD at the mild stage were randomly assigned to three experimental conditions. Two treatment groups were established, in which patients received either a stimulation program with BBA (EABB) or a traditional stimulation program (EAPI), based on paper-and-pencil tasks, for twelve weeks. A third group, the control group (EANT), did not receive any treatment during this period. The differential effectiveness of the programs was evaluated through pre-post design, considering neuropsychological, behavioral, and functional standard measures as outcome variables. The EABB group showed significantly slower rates of cognitive decline compared to the EAPI and EANT groups. Furthermore, the EABB group reported significantly greater decrease in depressive symptoms in comparison with the EAPI and EANT groups. The BBA program was more effective than IPP to reduce cognitive decline and depressive symptoms in patients with AD.


Lung function and respiratory symptoms in hard metal workers exposed to cobalt.
To follow-up lung function and airway symptoms in workers exposed to cobalt dust at a hard metal plant. A total of 582 employees underwent spirometry and completed a questionnaire. A historical exposure matrix was created, assigning figures for historical and recent work-related exposure. At the time of employment, 5% reported symptoms from respiratory tract. At follow-up, 5% suffered from persistent coughing and 7% reported asthma; 20% were daily smokers. Among nonsmokers without asthma, an evident, statistically nonsignificant, dose-response effect was seen between increasing cobalt exposure and decline in FEV1 (forced expiratory volume in the first second). In all exposure categories, the FEV1 in smokers declined 10 mL more per year than for nonsmokers. Even low levels of cobalt exposure seem to hamper lung function both in smokers and nonsmokers. This impact is considered low in relation to the effect of aging.


A novel method for air drying aloe leaf slices by covering with filter papers as a shrink-proof layer.
To prevent the shrinkage of aloe vera slices during air drying, a method utilizing a shrink-proof layer was developed. The sample was configured of whole leaf aloe slices, where 1 side or both sides were covered with filter papers as shrink-proof layers. After air drying by varying the air temperature and the slice thickness, the drying characteristics, as well as several quality factors of the dried aloe vera leaf slices, were analyzed. In the simulation of the drying curves, the modified Page model showed the best fitness, representing a diffusion-controlled drying mechanism. Nonetheless, there was a trace of a constant-rate drying period in the samples dried by the method. Shrinkage was greatly reduced, and the rehydration ratios increased by approximately 50%. Scanning electron microscopic analysis revealed that the surface structure of original fibrous form was well sustained. FT-IR characteristics showed that the dried samples could sustain aloe polysaccharide acetylation. Furthermore, the functional properties of the dried slices including water holding capacity, swelling, and fat absorption capability were improved, and polysaccharide retention levels increased by 20% to 30%. Therefore, we concluded that application of shrink-proof layers on aloe slices provides a novel way to overcome the shrinkage problems commonly found in air drying, thereby improving their functional properties with less cost. Practical Application: This research article demonstrates a novel air drying method using shrink-proof layers to prevent the shrinkage of aloe slices. We analyzed extensively the characteristics of shrinkage mechanism and physical properties of aloe flesh gels in this drying system. We concluded that this method can be a beneficial means to retain the functional properties of dried aloe, and a potential alternative to freeze drying, which is still costly.


Neonatal Listeriosis Presentation and Outcome: A Prospective Study of 189 Cases.
Listeriosis is caused by the foodborne pathogen Listeria monocytogenes. It can present as a maternal-neonatal infection. We implemented a nationwide prospective cohort and analyzed the features of neonatal listeriosis. We studied all neonates born alive from mothers with microbiologically proven maternal-neonatal listeriosis enrolled from November 2009 to December 2017. We analyzed presentation, neonatal outcome at discharge, and predictors of severe presentation and outcome. We studied 189 infants; 133 of 189 (70%) had abnormal clinical status at birth, including acute respiratory distress in 106 of 189 (56%). There were 132 of 189 (70%) infants who developed early-onset listeriosis and 12 of 189 (6%) who developed late-onset listeriosis; all presented with acute meningitis. There were 17 of 189 (9%) infants who had major adverse outcomes: 3%, (5 of 189) death; 6% (12 of 189), severe brain injury; and 2% (3 of 189), severe bronchopulmonary dysplasia. Fifteen of 17 infants were born <34 weeks of gestation (P < .0001 vs infants born ≥34 weeks of gestation). Maternal antimicrobial treatment ≥1 day before delivery was associated with a significant decrease in presentation severity for the infant, resulting in significantly fewer inotropic drugs, fluid resuscitation, and mechanical ventilation requirement (odds ratio, 0.23; 95% confidence interval, 0.09-0.51; P < .0001). Antenatal maternal antimicrobial treatment is associated with reduced neonatal listeriosis severity, justifying the prescription of preemptive maternal antimicrobial therapy when maternal-fetal listeriosis is suspected. Neonatal outcome is better than reported earlier, and its major determinant is gestational age at birth. NCT01520597.


Interaction and signalling networks: a report from the fourth 'Young Microbiologists Symposium on Microbe Signalling, Organisation and Pathogenesis'.
At the end of June, over 120 microbiologists from 18 countries gathered in Dundee, Scotland for the fourth edition of the Young Microbiologists Symposium on 'Microbe Signalling, Organisation and Pathogenesis'. The aim of the symposium was to give early career microbiologists the opportunity to present their work in a convivial environment and to interact with senior world-renowned scientists in exciting fields of microbiology research. The meeting was supported by the Microbiology Society, the Society of Applied Microbiology and the American Society for Microbiology with further sponsorship from the European Molecular Biology Organisation and the Royal Society of Edinburgh. In this report, we highlight some themes that emerged from the many interesting talks and poster presentations, as well as some of the other activities that were on offer at this energetic meeting.


Synaptic calcium transients in single spines indicate that NMDA receptors are not saturated.
At excitatory synapses in the central nervous system, the number of glutamate molecules released from a vesicle is much larger than the number of postsynaptic receptors. But does release of a single vesicle normally saturate these receptors? Answering this question is critical to understanding how the amplitude and variability of synaptic transmission are set and regulated. Here we describe the use of two-photon microscopy to image transient increases in Ca2+ concentration mediated by NMDA (N-methyl-D-aspartate) receptors in single dendritic spines of CA1 pyramidal neurons in hippocampal slices. To test for NMDA-receptor saturation, we compared responses to stimulation with single and double pulses. We find that a single release event does not saturate spine NMDA receptors; a second release occurring 10 ms later produces approximately 80% more NMDA-receptor activation. The amplitude of spine NMDA-receptor-mediated [Ca2+] transients (and the synaptic plasticity which depends on this) may thus be sensitive to the number of quanta released by a burst of action potentials and to changes in the concentration profile of glutamate in the synaptic cleft.