Effects of Alpinia galanga oil on anesthesia and stress reduction in Oreochromis niloticus.
Oreochromis niloticus (Nile tilapia) is one widely cultured fish in Thailand. Handling processes and transportation causes high stress in Nile tilapia. This study explores anesthetic effect and stress reduction of Alpinia galanga oil (AGO) on Nile tilapia. The anesthetic activity was evaluated by the time for fish induction to anesthesia and full recovery. It was found that the suitable dose of AGO that caused desirable anesthesia of Nile tilapia was 700 mg/L. This dose gave induction and recovery times of approximately 257 and 438 sec, respectively. Blood glucose and plasma cortisol of the fish anesthetized with AGO showed nearly normal levels indicating that the fish stress during handling was not increased. Study on loading densities of fish mimicked general fish transportation and showed that loading density of fish was a crucial factor on fish stress. The highest water quality was found in the lowest loading density of fish. Water containing AGO at a concentration of 150 mg/L showed significantly higher potential for reducing fish activity and water improvement than without AGO. Therefore, AGO is a promising natural edible plant oil for anesthesia in Nile tilapia.


Metal non-oxide nanostructures developed from organic-inorganic hybrids and their catalytic application.
The rational design of metal non-oxides is important for their catalytic application, which is however limited by the fact that the current synthetic strategies are short of effective control over formation reactions. Recently, the hybrids evenly integrating organic with inorganic molecules on a nanoscale significantly provided quasi-homogeneous reactions towards well-defined nanocatalysts of metal non-oxides, in which their structures and properties can be modulated in a wide range. Focusing on the nanostructures and the related catalytic behaviors, this feature article seeks to provide some control on the key structures and properties of metal non-oxides (e.g. carbides, nitrides, sulfides and selenides). It is thus anticipated to shed some light on the development of emerging materials for efficient catalysis, especially those used in energy utilization.


Exercise blood pressure and baroreflex function in borderline hypertensive and normotensive young men.
1. Resting carotid baroreflex sensitivity and blood pressure responses to standardized conditions of rest and exercise were measured in 17 borderline hypertensive males and 12 normotensive males. 2. The borderline hypertensive group had significantly higher systolic and diastolic blood pressures during orthostatic rest and isometric handgrip exercise and higher systolic blood pressure during supine rest and submaximum and maximum treadmill exercise. 3. The borderline hypertensive group had an attenuation of baroreflex sensitivity compared with the normotensive group. Resting baroreflex sensitivity was significantly correlated with absolute systolic blood pressure during supine rest, orthostatic rest, isometric handgrip exercise and submaximum treadmill exercise. 4. The results indicate that blood pressure is regulated at a significantly higher level during rest and exercise in borderline hypertension and is associated with reduced baroreflex sensitivity measured at supine rest.


The Effects of Epigallocatechin Gallate (EGCG) on Pulmonary Fibroblasts of Idiopathic Pulmonary Fibrosis (IPF)-A Next-Generation Sequencing and Bioinformatic Approach.
Idiopathic pulmonary fibrosis (IPF) is a disabling and lethal chronic progressive pulmonary disease. Epigallocatechin gallate (EGCG) is a polyphenol, which is the major biological component of green tea. The anti-oxidative, anti-inflammatory, and anti-fibrotic effects of EGCG have been shown in some studies, whereas its effects in altering gene expression in pulmonary fibroblasts have not been systematically investigated. This study aimed to explore the effect of EGCG on gene expression profiles in fibroblasts of IPF. The pulmonary fibroblasts from an IPF patient were treated with either EGCG or water, and the expression profiles of mRNAs and microRNAs were determined by next-generation sequencing (NGS) and analyzed with the bioinformatics approach. A total of 61 differentially expressed genes and 56 differentially expressed microRNAs were found in EGCG-treated IPF fibroblasts. Gene ontology analyses revealed that the differentially expressed genes were mainly involved in the biosynthetic and metabolic processes of cholesterol. In addition, five potential altered microRNA-mRNA interactions were found, including hsa-miR-939-5p-PLXNA4, hsa-miR-3918-CTIF, hsa-miR-4768-5p-PDE5A, hsa-miR-1273g-3p-VPS53, and hsa-miR-1972-PCSK9. In summary, differentially expressed genes and microRNAs in response to EGCG treatment in IPF fibroblasts were identified in the current study. Our findings provide a scientific basis to evaluate the potential benefits of EGCG in IPF treatment, and warrant future studies to understand the role of molecular pathways underlying cholesterol homeostasis in the pathogenesis of IPF.


Disaster nursing: Self-reported competence of nursing students and registered nurses, with focus on their readiness to manage violence, serious events and disasters.
The World Health Organization and the International Council of Nurses recognises the importance of nurses' involvement in disaster preparedness and response. The aim of this study was to describe and compare self-reported disaster nursing competence (DNC) among nursing students (NSs) and among registered nurses (RNs) with professional experience. Further to investigate possible associations between self-reported DNC and background factors. A cross-sectional study was conducted of 569 NSs and 227 RNs. All respondents completed the 88-item Nurse Professional Competence Scale, including three items assessing DNC. Significant differences were found among the NSs depending on which University/University College they had attended. RNs reported significantly higher overall DNC and better ability to handle situations involving violence, and to apply principles of disaster medicine during serious events. RNs working in emergency care reported significantly better DNC ability, compared with RNs working in other areas of healthcare. Multiple linear regression analysis showed that working night shift and working in emergency care were positively associated with high self-reported overall DNC. The results indicate that workplace experience of serious events increase the readiness of registered nurses to handle violence, to act in accordance with safety regulations, and to apply principles of disaster medicine during serious events.


MR cholangiography in children and young adults with biliary disease.
Our objective was to describe the MR cholangiography findings for young patients with suspected biliary disease who underwent half-Fourier acquisition fast spin-echo technique with respiratory triggering. Twenty-eight MR cholangiography studies were performed in 22 patients on a 1.5-T MR unit. Ten of these 22 patients had undergone liver transplantation. MR cholangiography revealed abnormalities of both the extrahepatic and the intrahepatic major and minor bile duct systems, despite the small diameter of the duct system in this group of patients. Four patterns of biliary disease were shown: global dilatation of extrahepatic or intrahepatic ducts (n = 7); segmental, uniform dilatation of central or peripheral intrahepatic ducts (n = 9); segmental, nonuniform dilatation of central or peripheral intrahepatic ducts (n = 2); and fusiform ectasia with segmental, irregular intrahepatic dilatation and bile lakes (n = 2). The findings of eight studies were interpreted as normal. The four patterns of abnormalities were correlated with the results from percutaneous transhepatic cholangiography, T-tube cholangiography, and liver biopsy and with clinical and surgical information, as available. MR cholangiography is a noninvasive technique for evaluation of biliary disease. The improved resolution afforded by respiratory triggering permits evaluation of both major and minor bile ducts, even in young, uncooperative subjects. Four patterns of abnormalities were prospectively identified, correlated with other information, and used to direct clinical treatment.


The involvement of TRPC3 channels in sinoatrial arrhythmias.
Atrial fibrillation (AF) is a significant contributor to cardiovascular morbidity and mortality. The currently available treatments are limited and AF continues to be a major clinical challenge. Clinical studies have shown that AF is frequently associated with dysfunction in the sino-atrial node (SAN). The association between AF and SAN dysfunction is probably related to the communication between the SAN and the surrounding atrial cells that form the SAN-atrial pacemaker complex and/or pathological processes that affect both the SAN and atrial simultaneously. Recent evidence suggests that Ca(2+) entry through TRPC3 (Transient Receptor Potential Canonical-3) channels may underlie several pathophysiological conditions -including cardiac arrhythmias. However, it is still not known if atrial and sinoatrial node cells are also involved. In this article we will first briefly review TRPC3 and IP3R signaling that relate to store/receptor-operated Ca(2+) entry (SOCE/ROCE) mechanisms and cardiac arrhythmias. We will then present some of our recent research progress in this field. Our experiments results suggest that pacing-induced AF in angiotensin II (Ang II) treated mice are significantly reduced in mice lacking the TRPC3 gene (TRPC3(-/-) mice) compared to wild type controls. We also show that pacemaker cells express TRPC3 and several other molecular components related to SOCE/ROCE signaling, including STIM1 and IP3R. Activation of G-protein coupled receptors (GPCRs) signaling that is able to modulate SOCE/ROCE and Ang II induced Ca(2+) homeostasis changes in sinoatrial complex being linked to TRPC3. The results provide new evidence that TRPC3 may play a role in sinoatrial and atrial arrhythmias that are caused by GPCRs activation.


The role of the physician in modern military operations: 12 months experience in Southern Iraq.
To examine the profile of medical morbidity and the role of the physician in modern conflict. Retrospective survey of admission records at a British Military Field Hospital on operational duty in Southern Iraq. 62.5% of 4870 admissions to the Field Hospital in Shaibah during the first 12 months of military operations in Iraq were under the care of physicians. Of these 1531 (31.4%) were due to diarrhoea and vomiting (D&V) and 764 (15.7%) due to heat illness. The incidence of heat illness rose with ambient temperature, but soldiers were more likely to be admitted with heat illness shortly after arrival in theatre than when fully acclimatised. There was also a steady flow of admissions with a broad spectrum of medical pathology requiring the clinical skills of a general physician. A general physician is a necessary part of the clinical team in modern conflict. The incidence of D&V and of heat illness on military operations remains high. Planners for any operation in tropical climates should take this into consideration and put preventative measures into place early.


Scoring Divergent Thinking Tests by Computer With a Semantics-Based Algorithm.
Divergent thinking (DT) tests are useful for the assessment of creative potentials. This article reports the semantics-based algorithmic (SBA) method for assessing DT. This algorithm is fully automated: Examinees receive DT questions on a computer or mobile device and their ideas are immediately compared with norms and semantic networks. This investigation compared the scores generated by the SBA method with the traditional methods of scoring DT (i.e., fluency, originality, and flexibility). Data were collected from 250 examinees using the "Many Uses Test" of DT. The most important finding involved the flexibility scores from both scoring methods. This was critical because semantic networks are based on conceptual structures, and thus a high SBA score should be highly correlated with the traditional flexibility score from DT tests. Results confirmed this correlation (r = .74). This supports the use of algorithmic scoring of DT. The nearly-immediate computation time required by SBA method may make it the method of choice, especially when it comes to moderate- and large-scale DT assessment investigations. Correlations between SBA scores and GPA were insignificant, providing evidence of the discriminant and construct validity of SBA scores. Limitations of the present study and directions for future research are offered.


Participants' and caregivers' experiences of a multidisciplinary programme for healthy lifestyle change in Aotearoa/New Zealand: a qualitative, focus group study.
Child and adolescent obesity continues to be a major health issue internationally. This study aims to understand the views and experiences of caregivers and participants in a child and adolescent multidisciplinary programme for healthy lifestyle change. Qualitative focus group study. Community-based healthy lifestyle intervention programme in a mixed urban-rural region of Aotearoa/New Zealand. Parents/caregivers (n=6) and children/adolescents (n=8) who participated in at least 6 months of an assessment and weekly session, family-based community intervention programme for children and adolescents affected by obesity. Findings covered participant experiences, healthy lifestyle changes due to participating in the programme, the delivery team, barriers to engagement and improvements. Across these domains, four key themes emerged from the focus groups for participants and their caregivers relating to their experience: knowledge-sharing, enabling a family to become self-determining in their process to achieve healthy lifestyle change; the importance of connectedness and a family-based programme; the sense of a collective journey and the importance of a nonjudgemental, respectful welcoming environment. Logistical challenges and recommendations for improvement were also identified. Policymakers need to consider the experiences of participants alongside quantitative outcomes when informing multidisciplinary intervention programmes for children and adolescents affected by obesity.Trial registration number Australian New Zealand Clinical Trials Registry (ANZCTR):12611000862943; Post-results.


Antigenic distribution of west nile virus in various organs of wildly infected american crows (corvus brachyrhynchos).
Since its discovery in the western hemisphere in 1999, West Nile virus (WNv) has caused extensive bird mortality across North America, especially in American crows (Corvus brachyrhynchos) which are highly susceptible to WNv. In this study, antigenic distribution of WNv among different organs of American crows was studied, using the immunohistochemistry technique (IHC). Dead crows reported by residents were collected, transported on ice, and were necropsied for heart, lung, brain, intestine, kidney, liver, spleen, pancreas, and gonad tissues. Gross examination was performed on brain, heart, lung, liver, kidney, spleen, bursa of fabricius, gastrointestinal tract, skeletal muscle, pancreas, reproductive tract, and skin. Gross hemorrhage of brain, splenomegaly, meningoencephalitis, myocarditis, and trauma were sporadically observed in some of the infected carcasses. Formalin-fixed paraffin-embedded tissue sections were stained with IHC technique followed by counter staining with hematoxylin and eosin. WNv antigen was detected in brain, spleen, heart, kidney, liver, gonads, intestine, lung, and pancreas. The spleen was found to be positive in all infected crows, followed by kidney, liver, and duodenum (95% each). Heart and pancreas were positive in 63% while brain was positive in 36.5% of the infected crows. More than one tissue sample is suggested to screen WNv infection using IHC technique. IHC has the advantage of correlating the visual destruction of tissue architecture with the presence of stained WNv antigen but as compared to PCR, IHC has the disadvantage of longer turnaround time, which is critical when used as a surveillance tool.


Murine cystathionine gamma-lyase: complete cDNA and genomic sequences, promoter activity, tissue distribution and developmental expression.
Cystathionine gamma-lyase (CSE) is the last key enzyme in the trans-sulphuration pathway for biosynthesis of cysteine from methionine. Cysteine could be provided through diet; however, CSE has been shown to be important for the adequate supply of cysteine to synthesize glutathione, a major intracellular antioxidant. With a view to determining physiological roles of CSE in mice, we report the sequence of a complete mouse CSE cDNA along with its associated genomic structure, generation of specific polyclonal antibodies, and the tissue distribution and developmental expression patterns of CSE in mice. A 1.8 kb full-length cDNA containing an open reading frame of 1197 bp, which encodes a 43.6 kDa protein, was isolated from adult mouse kidney. A 35 kb mouse genomic fragment was obtained by lambda genomic library screening. It contained promoter regions, 12 exons, ranging in size from 53 to 579 bp, spanning over 30 kb, and exon/intron boundaries that were conserved with rat and human CSE. The GC-rich core promoter contained canonical TATA and CAAT motifs, and several transcription factor-binding consensus sequences. The CSE transcript, protein and enzymic activity were detected in liver, kidney, and, at much lower levels, in small intestine and stomach of both rats and mice. In developing mouse liver and kidney, the expression levels of CSE protein and activity gradually increased with age until reaching their peak value at 3 weeks of age, following which the expression levels in liver remained constant, whereas those in kidney decreased significantly. Immunohistochemical analyses revealed predominant CSE expression in hepatocytes and kidney cortical tubuli. These results suggest important physiological roles for CSE in mice.


Identification of the tliDEF ABC transporter specific for lipase in Pseudomonas fluorescens SIK W1.
Pseudomonas fluorescens, a gram-negative psychrotrophic bacterium, secretes a thermostable lipase into the extracellular medium. In our previous study, the lipase of P. fluorescens SIK W1 was cloned and expressed in Escherichia coli, but it accumulated as inactive inclusion bodies. Amino acid sequence analysis of the lipase revealed a potential C-terminal targeting sequence recognized by the ATP-binding cassette (ABC) transporter. The genetic loci around the lipase gene were searched, and a secretory gene was identified. Nucleotide sequencing of an 8.5-kb DNA fragment revealed three components of the ABC transporter, tliD, tliE, and tliF, upstream of the lipase gene, tliA. In addition, genes encoding a protease and a protease inhibitor were located upstream of tliDEF. tliDEF showed high similarity to ABC transporters of Pseudomonas aeruginosa alkaline protease, Erwinia chrysanthemi protease, Serratia marcescens lipase, and Pseudomonas fluorescens CY091 protease. tliDEF and the lipase structural gene in a single operon were sufficient for E. coli cells to secrete the lipase. In addition, E. coli harboring the lipase gene secreted the lipase by complementation of tliDEF in a different plasmid. The ABC transporter of P. fluorescens was optimally functional at 20 and 25 degrees C, while the ABC transporter, aprD, aprE, and aprF, of P. aeruginosa secreted the lipase irrespective of temperature between 20 and 37 degrees C. These results demonstrated that the lipase is secreted by the P. fluorescens SIK W1 ABC transporter, which is organized as an operon with tliA, and that its secretory function is temperature dependent.


Tobacco cessation and brief advice.
Patients who are enrolled on tuberculosis (TB) treatment are often ill and are seeking ways to get better. They are more likely at that time to adopt risk-reducing health behaviours. Interventions that are neither complicated nor time-consuming are available to health service personnel to help patients undertake smoking cessation. Brief advice to patients repeated at various times throughout their TB care can increase cessation rates. All tobacco use needs to be identified and reasons for quitting enunciated. Patients are thus given a framework for considering smoking cessation. If patients then choose not to stop currently, they can be asked to reconsider at a later visit, and also be cautioned to avoid smoking in the presence of others. Smokers who want to stop can discuss strategies for avoiding craving and withdrawal, and pharmacological agents can be recommended if they are available. Because the brief advice is repeated, patients are reinforced either for having stopped or for their progress towards stopping.


Preparation of magnetic molecularly imprinted polymers for selective isolation and determination of kaempferol and protoapigenone in Macrothelypteris torresiana.
Novel uniform-sized magnetic molecularly imprinted polymers (MMIPs) were synthesized for selective recognition of active antitumor ingredients of kaempferol (KMF) and protoapigenone (PA) in Macrothelypteris torresiana (M. torresiana) by surface molecular imprinting technique in this study. Super paramagnetic core-shell nanoparticles (γ-MPS-SiO2@Fe3O4) were used as seeds, KMF as template molecule, acrylamide (AM) as functional monomer, and N, N'-methylene bisacrylamide (BisAM) as cross-linker. The prepared MMIPs were characterized by X-ray diffraction (XRD), Fourier transform infrared spectrum (FTIR), transmission electron microscopy (TEM) and thermo-gravimetric analysis (TGA), respectively. The recognition capacity of MMIPs was 2.436 times of non-imprinted polymers. The adsorption results based on kinetics and isotherm analysis were in accordance with the pseudo-second-order model (R (2)=0.9980) and the Langmuir adsorption model (R (2)=0.9944). The value of E (6.742 kJ/mol) calculated from the Dubinin-Radushkevich isotherm model suggested that the physical adsorption via hydrogen-bonding might be predominant. The Scatchard plot showed a single line (R (2)=0.9172) and demonstrated the homogeneous recognition sites on MMIPs for KMF. The magnetic solid phase extraction (MSPE) based on MMIPs as sorbent was established for fast and selective enrichment of KMF and its structural analogue PA from the crude extract of M. torresiana and then KMF and PA were detected by HPLC-UV. The established method showed good performance and satisfactory results for real sample analysis. It also showed the feasibility of MMIPs for selective recognition of active structural analogues from complex herbal extracts.


The epidemiology of newly diagnosed chronic liver disease in gastroenterology practices in the United States: results from population-based surveillance.
Chronic liver disease (CLD) is an important cause of morbidity and mortality, but the epidemiology is not well described. We conducted prospective population-based surveillance to estimate newly diagnosed CLD incidence, characterize etiology distribution, and determine disease stage. We identified cases of CLD newly diagnosed during 1999-2001 among adult county residents seen in any gastroenterology practice in New Haven County, Connecticut; Multnomah County, Oregon; and Northern California Kaiser Permanente Medical Care Program (KPMCP, Oakland, California [total population 1.48 million]). We defined CLD as abnormal liver tests of at least 6 months' duration or pathologic, clinical, or radiologic evidence of CLD. Consenting patients were interviewed, a blood specimen obtained, and the medical record reviewed. We identified 2,353 patients with newly diagnosed CLD (63.9 cases/100,000 population), including 1,225 hepatitis C patients (33.2 cases/100,000). Men aged 45-54 yr had the highest hepatitis C incidence rate (111.3/100,000). Among 1,040 enrolled patients, the median age was 48 yr (range 19-86 yr). Hepatitis C, either alone (442 [42%]) or in combination with alcohol-related liver disease (ALD) (228 [22%]), accounted for two-thirds of the cases. Other etiologies included nonalcoholic fatty liver disease (NAFLD, 95 [9%]), ALD (82 [8%]), and hepatitis B (36 [3%]). Other identified etiologies each accounted for <3% of the cases. A total of 184 patients (18%) presented with cirrhosis, including 44% of patients with ALD. Extrapolating from this population-based surveillance network to the adult U.S. population, approximately 150,000 patients with CLD were diagnosed in gastroenterology practices each year during 1999-2001. Most patients had hepatitis C; heavy alcohol consumption among these patients was common. Almost 20% of patients, an estimated 30,000 per year, had cirrhosis at presentation. These results provide population-level baseline data to evaluate trends in identification of patients with CLD in gastroenterology practices.


Efficacy of endoport-guided endoscopic resection for deep-seated brain lesions.
Surgery for deep-seated brain lesions without causing significant trauma to the overlying cortex is difficult because brain retraction is required to approach these lesions. The aim of this study was to determine the efficacy of endoport-guided endoscopic or microscopic removal for deep-seated lesions using the neuronavigation system. Between October 2008 and December 2009, 21 patients (17 men and 4 women; average age, 40.8 years) underwent endoport-guided endoscopic tumor removal. We adapted the transparent tubular conduit, so-called "endoport," to target the lesions under the guidance of neuronavigation. We then determined the efficacy and limitations of this technique with fully endoscopic removal, compared with standard approaches using a spatula retractor. Gross total resection of the lesions was achieved in 14 of 21 patients (66%), and partial removal occurred in four (19%) patients. However, there was failure to remove the lesion through the endoport in three patients (14.3%), requiring the use of blade spatula retractors. In reviewing the seven cases with either failure or partial removal, it was found that a large tumor size (≥ 3 cm) and calcified lesions were the major factors limiting the application of this technique. Endoport-guided endoscopic surgery facilitated an accurate and minimally invasive technique for removal of these deep-seated brain lesions. This procedure required a protracted learning curve although, when successful, this approach can minimize brain retraction and provide satisfactory visualization.


Germline variation in inflammation-related pathways and risk of Barrett's oesophagus and oesophageal adenocarcinoma.
Oesophageal adenocarcinoma (OA) incidence has risen sharply in Western countries over recent decades. Local and systemic inflammation is considered an important contributor to OA pathogenesis. Established risk factors for OA and its precursor, Barrett's oesophagus (BE), include symptomatic reflux, obesity and smoking. The role of inherited genetic susceptibility remains an area of active investigation. Here, we explore whether germline variation related to inflammatory processes influences susceptibility to BE/OA. We used data from a genomewide association study of 2515 OA cases, 3295 BE cases and 3207 controls. Our analysis included 7863 single-nucleotide polymorphisms (SNPs) in 449 genes assigned to five pathways: cyclooxygenase (COX), cytokine signalling, oxidative stress, human leucocyte antigen and nuclear factor-κB. A principal components-based analytic framework was employed to evaluate pathway-level and gene-level associations with disease risk. We identified a significant signal for the COX pathway in relation to BE risk (p=0.0059, false discovery rate q=0.03), and in gene-level analyses found an association with microsomal glutathione-S-transferase 1 (MGST1); (p=0.0005, q=0.005). Assessment of 36 MGST1 SNPs identified 14 variants associated with elevated BE risk (q<0.05). Four of these were subsequently confirmed (p<5.5×10-5) in a meta-analysis encompassing an independent set of 1851 BE cases and 3496 controls, and are known strong expression quantitative trait loci for MGST1. Three such variants were associated with similar elevations in OA risk. This study provides the most comprehensive evaluation of inflammation-related germline variation in relation to risk of BE/OA and suggests that variants in MGST1 influence disease susceptibility.


An Increase in Vigorous but Not Moderate Physical Activity Makes People Feel They Have Changed Their Behavior.
Objective: While behavioral recommendations regarding physical activity commonly focus on reaching demanding goals by proposing "thresholds," little attention has been paid to the question of how much of a behavioral change is needed to make people feel that they have changed. The present research investigated this relation between actual and felt behavior change. Design: Using data from two longitudinal community samples, Study 1 and Study 2 comprised 614 (63% women) and 398 participants (61% women) with a mean age of 40.9 years (SD = 13.6) and 42.5 years (SD = 13.4), respectively. Using a stage-approach, participants were classified into four groups by asking them at the respective second measurement to indicate whether they had become more physically active since their last participation 6 months ago ("Changers"), they had tried but did not succeed in becoming more physically active ("Attempters"), they were already physically active on a regular basis ("Regular Actives"), or they had not tried to become more physically active ("Non-Attempters"). Physical activity was measured using the International Physical Activity Questionnaire (IPAQ), and fitness level was assessed as physical working capacity (PWC) via bicycle ergometry. Mixed ANOVAs including Time and Perceived Change as within and between factors were conducted, followed up by simple effect analyses. Results: Participants stating to have become more active in the past 6 months (Changers) showed a significant increase in vigorous physical activity but not in moderate physical activity, with an average of 6.8 (Study 1) and 10.6 (Study 2) metabolic equivalent value-hours (MET-hours) per week in vigorous activity. Corroborating these findings, objective fitness also significantly increased in the group of Changers. No systematic change in moderate or vigorous physical activity was observed for the three other "non-changer" groups (Regular actives, Attempters, Non-Attempters). Conclusion: The intensity of physical activity is the crucial variable for people's perception of change in physical activity. Moderate physical activity seems not to be perceived as an effective means for behavior change. It thus might fail to unfold sufficient motivational impact, despite its known positive effects on health.


Depression, urinary free cortisol excretion and lymphocyte function.
An impairment in lymphocyte response to mitogen stimulation, a correlate of cell-mediated immunity, has been reported in patients with depressive illness. To investigate whether such impairment in lymphocyte function is related to excessive secretion of cortisol, an immunosuppressive hormone, we compared mitogen-induced lymphocyte proliferation in three groups of subjects: depressed patients with elevated 24-hour urinary free cortisol (UFC) excretion; depressed patients with normal UFC excretion; and normal controls. Depressed patients in both groups showed significant reductions in lymphocyte mitogenic activity, in comparison with the normal controls, but the two depressive groups did not significantly differ from each other in their lymphocytic responses to any of the mitogens used. Furthermore, no significant correlations were found, within depressed patients, between UFC excretion and lymphocyte mitogenic responses. Depression is therefore associated with an impairment in lymphocyte function that cannot be explained solely on the basis of increased cortisol secretion.


Resistive exercises, with or without whole body vibration, prevent vertebral marrow fat accumulation during 60 days of head-down tilt bed rest in men.
Fat accumulates in the bone marrow of lumbar vertebrae with bed rest. Exercise with or without whole body vibration may counter this effect. Our objectives were to measure 1) the vertebral fat fraction (VFF) of men subjected to bed rest who performed resistive exercises with (RVE, n = 7) or without whole body vibration(RE, n = 8) or no exercise (CTR, n = 9) using three MRI techniques; and 2) changes in peripheral blood counts. Twenty-four healthy men (age: 20-45 yr) underwent -6° head-down tilt (HDT) bed rest for 60 days. MRI was performed using three techniques (fat saturation, proton spectroscopy, and in and out of phase) to measure the fat fraction of L(3), L(4), and/or L(5) at baseline, mid-HDT, and end-HDT. Erythrocytes and leukocytes were counted at HDT days 19, 33, 47, 54, and 60. The mean absolute VFF was increased in the CTR group at mid-HDT and end-HDT (+3.9 ± 1.3 and +3.6 ± 1.2%, respectively, both P < 0.05). The RE group had a smaller VFF change than the CTR group at mid-HDT (-0.9 ± 1.2 vs. +3.9 ± 1.3%, P < 0.05). The RVE group had a smaller VFF change than the CTR group at end-HDT (-2.6 ± 1.9 vs. +3.5 ± 1.2%, P < 0.05). Erythrocyte counts were increased in all groups at HDT day 19 and HDT day 33 and in the RE group at HDT day 54 (all P < 0.05). Bed rest for 60 days at -6° HDT increased lumbar VFF in men beyond natural involution. RVE and RE regimens effectively prevented VFF accumulation. Higher erythrocyte counts were not altered by RVE or RE. Whole body vibration, along with RE administered to people with prolonged immobility, may prevent fat accumulation in their bone marrow.


Increased blood flow causes coordinated upregulation of arterial eNOS and biosynthesis of tetrahydrobiopterin.
Shear stress, imposed on the vascular endothelium by circulating blood, critically sustains vascular synthesis of nitric oxide (NO). Endothelial NO synthase (eNOS) activity is determined by heat shock protein 90 (HSP90), caveolin-1, and the cofactor tetrahydrobiopterin (BH4). To determine whether increased blood flow concomitantly upregulates eNOS and GTP cyclohydrolase I (GTPCH I, the rate-limiting enzyme in BH4 biosynthesis), an aortocaval fistula model in the rat was employed wherein aortic blood flow is enhanced proximal but decreased distal to the fistula. Eight weeks after the creation of the aortocaval fistula, the proximal and distal aortic segments were harvested; sham-operated rats served as controls. Vasomotor function was assessed by isometric force recording. Expression of eNOS, HSP90, caveolin-1, Akt, phosphorylated eNOS (eNOS-Ser1177), and GTPCH I were determined by Western blot analysis. Biosynthesis of BH4 and GTPCH-I activity was examined by HPLC. In the aortic segments exposed to increased flow, contractions to KCl and phenylephrine were reduced, whereas endothelium-dependent relaxations were not affected compared with sham-operated or aortic segments with reduced blood flow. Expression of eNOS, caveolin-1, phosphorylated Akt, and eNOS-Ser1177 was enhanced in aortas exposed to increased blood flow. High flow augmented levels of cGMP and BH4 and increased expression of GTPCH I. In aggregate, these findings provide the first demonstration in vivo that coordinated vascular upregulation of eNOS, and GTPCH I accompanies increased blood flow. This induction of GTPCH I increases BH4 production, thereby optimizing the generation of NO by eNOS and thus the adaptive, vasorelaxant response required in sustaining increased blood flow.


Modulation of tumor tolerance in primary central nervous system malignancies.
Central nervous system tumors take advantage of the unique immunology of the CNS and develop exquisitely complex stromal networks that promote growth despite the presence of antigen-presenting cells and tumor-infiltrating lymphocytes. It is precisely this immunological paradox that is essential to the survival of the tumor. We review the evidence for functional CNS immune privilege and the impact it has on tumor tolerance. In this paper, we place an emphasis on the role of tumor-infiltrating myeloid cells in maintaining stromal and vascular quiescence, and we underscore the importance of indoleamine 2,3-dioxygenase activity as a myeloid-driven tumor tolerance mechanism. Much remains to be discovered regarding the tolerogenic mechanisms by which CNS tumors avoid immune clearance. Thus, it is an open question whether tumor tolerance in the brain is fundamentally different from that of peripheral sites of tumorigenesis or whether it simply stands as a particularly strong example of such tolerance.


Microleakage of Class V restorations using two different compomer systems: an in vitro study.
This study compared the marginal microleakage of Class V cavities restored with Dyract-AP and F2000. Forty Class V cavity preparations were performed on extracted human teeth. As a negative control, twenty teeth were used without Class V preparations. The apical foramina of the teeth were sealed with a layer of varnish and amalgam restorations. Class V cavity preparations with occlusal margins in enamel, and gingival margins in cementum or dentin that measured approximately three millimeters in width (gingival-occlusal) and length (mesial-distal), were prepared on the buccal surface of the teeth. Samples were divided randomly into 2 groups of 15, and restored per manufacturer's instructions using experimental primer/conditioner (PCC, D/C) and Single Bond Adhesive (3M). All restorations were polished with an abrasive finishing kit. After storage in 37 degrees C water for 24 hours, all specimens were thermocycled between 5 degrees C and 55 degrees C for 500 cycles with a 30-second dwell time, followed by immersion in 0.2% basic fucsine for 24 hours. Teeth were then embedded in cold cure acrylic resin, sectioned longitudinally, and the dye penetration at the enamel and cementum margins were scored at 30x magnification. Evaluations were rated from 0 to 3 (0 = no leakage; 1 = dye penetration up to one-half of the preparation depth; 2 = dye penetration more than one-half preparation depth, but less than the axial wall; 3 = dye penetration along the axial wall). Both F-2000 and Dyract-AP indicated no leakage in the enamel margins. Dyract-AP showed no leakage at either the enamel or dentin margins. Fisher's Exact Test revealed that this difference in dentin margins was statistically significant (p < 0.05). Under the given conditions, Dyract-AP and F-2000 demonstrated resistance to microleakage in enamel, and showed Dyract-AP to be more resistant to microleakage in dentin than F-2000.


Effects of zinc on the kinetics of branchial calcium uptake in freshwater rainbow trout during adaptation to waterborne zinc.
The effects of sublethal waterborne Zn2+ (150 micrograms l-1 = 2.3 mumol-1) on the kinetics of unidirectional Ca2+ influx were studied in juvenile freshwater rainbow trout during chronic exposure (60 days) at a water [Ca2+] of 1.0 mmol l-1. An unexposed group held under identical conditions served as control. The presence of Zn2+ in the water increased the apparent Km for Ca2+ influx by up to 300% with only a small inhibitory effect (35% at most) on the maximum rate of uptake (Jmax). These results, in combination with earlier data showing that Ca2+ competitively inhibits Zn2+ uptake, suggest that Zn2+ and Ca2+ compete for the same uptake sites. Acute withdrawal of Zn2+ after 3h of exposure resulted in a 23-fold reduction in Km for Ca2+, but a persistent small depression of Jmax. During prolonged exposure to Zn2+, the apparent Km for Ca2+ remained greatly elevated and Jmax remained slightly depressed. The actual Ca2+ influx in hard water ([Ca2+] = 1.0 mmol l-1) decreased marginally and paralleled the small changes in Jmax. The increases in apparent Km had a negligible influence on the actual Ca2+ influx because Km values (38-230 mumol l-1), even when elevated by Zn2+, remained below the water [Ca2+] (1000 mumol l-1). Rainbow trout exposed to Zn2+ exhibited a slower rate of protein synthesis in the gills (measured on day 23) and an increased tolerance to Zn2+ challenge (measured on both days 27 and 50). Unidirectional Zn2+ influx, measured at the end of the exposure period, was significantly reduced in the Zn2+-exposed fish. There were no changes in hepatic or branchial Zn2+, Cu2+ or metallothionein concentrations. We hypothesize that, during exposure to sublethal [Zn2+] in hard water, the fish may change the Km for a mutual Ca2+/Zn2+ carrier so as to reduce markedly Zn2+ influx without greatly altering Ca2+ influx. This reduced Zn2+ influx, rather than metallothionein induction, may be the basis of adaptation to elevated concentrations of waterborne Zn2+.


The association between alcohol consumption and periodontitis in southern Brazilian adults.
An association between alcohol consumption and periodontitis has been suggested in the literature, but the evidence is still unclear. The aim of the present study was to investigate the relationship between alcohol consumption and periodontitis in a probability sample of adults from south Brazil. This analysis included 1115 subjects aged 18-65 years derived from a representative sample from south Brazil. Data were collected from participants from clinical examination and structured interviews. Alcohol consumption was assessed by asking participants about the usual number of drinks consumed in a week. Four categories of alcohol consumption were defined: non-drinker, ≤ 1 glass/wk, > 1 glass/wk, ≤ 1 glass/d and > 1 glass/d. Individuals with ≥ 30% teeth with periodontal attachment loss ≥ 5 mm were classified as having periodontitis. Logistic models adjusting for age, race, socioeconomic status, dental care, body mass index, self-reported diabetes and smoking were used to estimate odds ratios (OR) and confidence intervals (95% CI). After adjusting for co-factors, females who reported drinking > 1 glass/d were more likely to have periodontitis (OR = 3.8, 95% CI = 1.4-10.1), whereas females who reported drinking up to 1 glass/d were 50% less likely to have periodontitis (OR = 0.5, 95% CI = 0.3-0.8). No significant associations between overall alcohol intake and periodontitis were observed for males. In an exploratory analysis, wine consumption was associated with a lower likelihood of periodontitis among males (OR = 0.2, 95% CI = 0.1-0.5) but not females. The periodontal health of males and females appears to be affected differently by alcohol consumption. Moderate wine consumption may have a beneficial effect in males.


Analysis of the safety evaluation for premarketing clinical trials of hemodialyzer and of postmarketing safety reports of hemodialyzer in Japan and the US: insights into the construction of a sophisticated premarketing evaluation.
Our aim was to conduct a scoping review of the regulations for hemodialyzers in the safety evaluation in Japan and the United States, and to evaluate the criteria for premarketing clinical trials and postmarketing safety reports to inform the development of a sophisticated premarketing evaluation in Japan. Regulations for approval of hemodialyzers were identified from the databases of the Ministry of Health, Labor and Welfare in Japan and the Federal Drug Agency (FDA) in the United States (US). The criteria for premarket clinical trials and postmarketing safety reports were evaluated for both countries. Standards in Japan required evaluation of blood compatibility and reporting of acute adverse effects by a premarketing clinical trial in 6 of 86 applications with semipermeable membrane materials deemed to be different to those of previously approved devices from 1983 to 31 August 2015. By comparison, the clinical trial was required in one of 545 approvals in the US from 1976 to 29 January 2016, but blood compatibility was not the point. All postmarketing adverse effects identified in Japan were included in the set of 'warnings'. The more stringent requirements for evaluation of blood compatibility and acute adverse effects in Japan seemed to be related to differences in the history of quality management systems for medical devices between the two countries. This study revealed that there were differences between Japan and the US in requiring the premarketing clinical trials for the hemodialyzers. Our findings could be useful for constructing sophisticated premarketing safety evaluation.


Distress among rural residents: does employment and occupation make a difference?
This study investigates the relationship between levels of mental health and well-being (in terms of self-reported levels of distress) with employment and occupational status of rural residents, to better inform the provision of mental health services to those in greatest need in rural communities. A stratified random sample of community residents in rural and remote New South Wales with over-sampling of remote areas as first stage of a cohort study. Psychological distress was measured using Kessler-10, inclusive of additional items addressing functional impairment (days out of role). Occupational data were classified using Australian and New Zealand Standard Classification of Occupations categories. A total of 2639 adults participated in this baseline phase. Among them, 57% were in paid employment, 30% had retired from the workforce, 6% were permanently unable to work and 2% were unemployed. The highest levels of distress and functional impairment were reported in those permanently unable to work and the unemployed group with rates of 'caseness' (likely mental health disorder) varying from 57% to 69%, compared with 34% of farmers and farm managers and 29% of health workers (P < 0.01). The rural unemployed suffer considerable psychological distress and 'disability', yet they are not the target of specific mental health promotion and prevention programs, which are often occasioned by rural adversity, such as drought, and delivered through work-based pathways. Policy-makers and health service providers need to consider the needs of the rural unemployed and those permanently unable to work and how they might be addressed.


Tooth counts through growth in diapsid reptiles: implications for interpreting individual and size-related variation in the fossil record.
Tooth counts are commonly recorded in fossil diapsid reptiles and have been used for taxonomic and phylogenetic purposes under the assumption that differences in the number of teeth are largely explained by interspecific variation. Although phylogeny is almost certainly one of the greatest factors influencing tooth count, the relative role of intraspecific variation is difficult, and often impossible, to test in the fossil record given the sample sizes available to palaeontologists and, as such, is best investigated using extant models. Intraspecific variation (largely manifested as size-related or ontogenetic variation) in tooth counts has been examined in extant squamates (lizards and snakes) but is poorly understood in archosaurs (crocodylians and dinosaurs). Here, we document tooth count variation in two species of extant crocodylians (Alligator mississippiensis and Crocodylus porosus) as well as a large varanid lizard (Varanus komodoensis). We test the hypothesis that variation in tooth count is driven primarily by growth and thus predict significant correlations between tooth count and size, as well as differences in the frequency of deviation from the modal tooth count in the premaxilla, maxilla, and dentary. In addition to tooth counts, we also document tooth allometry in each species and compare these results with tooth count change through growth. Results reveal no correlation of tooth count with size in any element of any species examined here, with the exception of the premaxilla of C. porosus, which shows the loss of one tooth position. Based on the taxa examined here, we reject the hypothesis, as it is evident that variation in tooth count is not always significantly correlated with growth. However, growth trajectories of smaller reptilian taxa show increases in tooth counts and, although current samples are small, suggest potential correlates between tooth count trajectories and adult size. Nevertheless, interspecific variation in growth patterns underscores the importance of considering and understanding growth when constructing taxonomic and phylogenetic characters, in particular for fossil taxa where ontogenetic patterns are difficult to reconstruct.


Artemisinin-Resistant Plasmodium falciparum Malaria.
For more than five decades, Southeast Asia (SEA) has been fertile ground for the emergence of drug-resistant Plasmodium falciparum malaria. After generating parasites resistant to chloroquine, sulfadoxine, pyrimethamine, quinine, and mefloquine, this region has now spawned parasites resistant to artemisinins, the world's most potent antimalarial drugs. In areas where artemisinin resistance is prevalent, artemisinin combination therapies (ACTs)-the first-line treatments for malaria-are failing fast. This worrisome development threatens to make malaria practically untreatable in SEA, and threatens to compromise global endeavors to eliminate this disease. A recent series of clinical, in vitro, genomics, and transcriptomics studies in SEA have defined in vivo and in vitro phenotypes of artemisinin resistance, identified its causal genetic determinant, explored its molecular mechanism, and assessed its clinical impact. Specifically, these studies have established that artemisinin resistance manifests as slow parasite clearance in patients and increased survival of early-ring-stage parasites in vitro; is caused by single nucleotide polymorphisms in the parasite's K13 gene, is associated with an upregulated "unfolded protein response" pathway that may antagonize the pro-oxidant activity of artemisinins, and selects for partner drug resistance that rapidly leads to ACT failures. In SEA, clinical studies are urgently needed to monitor ACT efficacy where K13 mutations are prevalent, test whether new combinations of currently available drugs cure ACT failures, and advance new antimalarial compounds through preclinical pipelines and into clinical trials. Intensifying these efforts should help to forestall the spread of artemisinin and partner drug resistance from SEA to sub-Saharan Africa, where the world's malaria transmission, morbidity, and mortality rates are highest.


Pepper mild mottle virus: A plant pathogen with a greater purpose in (waste)water treatment development and public health management.
An enteric virus surrogate and reliable domestic wastewater tracer is needed to manage microbial quality of food and water as (waste)water reuse becomes more prevalent in response to population growth, urbanization, and climate change. Pepper mild mottle virus (PMMoV), a plant pathogen found at high concentrations in domestic wastewater, is a promising surrogate for enteric viruses that has been incorporated into over 29 water- and food-related microbial quality and technology investigations around the world. This review consolidates the available literature from across disciplines to provide guidance on the utility of PMMoV as either an enteric virus surrogate and/or domestic wastewater marker in various situations. Synthesis of the available research supports PMMoV as a useful enteric virus process indicator since its high concentrations in source water allow for identifying the extent of virus log-reductions in field, pilot, and full-scale (waste)water treatment systems. PMMoV reduction levels during many forms of wastewater treatment were less than or equal to the reduction of other viruses, suggesting this virus can serve as an enteric virus surrogate when evaluating new treatment technologies. PMMoV excels as an index virus for enteric viruses in environmental waters exposed to untreated domestic wastewater because it was detected more frequently and in higher concentrations than other human viruses in groundwater (72.2%) and surface waters (freshwater, 94.5% and coastal, 72.2%), with pathogen co-detection rates as high as 72.3%. Additionally, PMMoV is an important microbial source tracking marker, most appropriately associated with untreated domestic wastewater, where its pooled-specificity is 90% and pooled-sensitivity is 100%, as opposed to human feces where its pooled-sensitivity is only 11.3%. A limited number of studies have also suggested that PMMoV may be a useful index virus for enteric viruses in monitoring the microbial quality of fresh produce and shellfish, but further research is needed on these topics. Finally, future work is needed to fill in knowledge gaps regarding PMMoV's global specificity and sensitivity.


Specific complex formation between proteins encoded by the yeast DNA repair and recombination genes RAD1 and RAD10.
The RAD1 and RAD10 genes of Saccharomyces cerevisiae are required for excision repair of ultraviolet light-damaged DNA, and they also function in a mitotic recombination pathway that is distinct from the double-strand-break recombination pathway controlled by RAD52. Here, we show that the RAD1 and RAD10 proteins are complexed with each other in vivo. Immunoprecipitation of yeast cell extracts with either anti-RAD1 antibody or anti-RAD10 antibody coprecipitated quantitative amounts of both RAD1 and RAD10 proteins. The level of coprecipitable RAD1 and RAD10 increased when both proteins were overproduced together, but not if only one of the proteins was overproduced. The RAD1/RAD10 complex is highly stable, being refractory to 1 M NaCl and to low concentrations of SDS. By hydroxylamine mutagenesis, we have identified a rad1 mutant allele whose encoded protein fails to complex with RAD10. The interaction-defective rad1 mutant resembles the rad1 or rad10 null mutant in defective DNA repair and recombination, implying that complex formation is essential for the expression of biological activities controlled by RAD1 and RAD10.


Nipah virus: a recently emergent deadly paramyxovirus.
A paramyxovirus virus termed Nipah virus has been identified as the etiologic agent of an outbreak of severe encephalitis in people with close contact exposure to pigs in Malaysia and Singapore. The outbreak was first noted in late September 1998 and by mid-June 1999, more than 265 encephalitis cases, including 105 deaths, had been reported in Malaysia, and 11 cases of encephalitis or respiratory illness with one death had been reported in Singapore. Electron microscopic, serologic, and genetic studies indicate that this virus belongs to the family Paramyxoviridae and is most closely related to the recently discovered Hendra virus. We suggest that these two viruses are representative of a new genus within the family Paramyxoviridae. Like Hendra virus, Nipah virus is unusual among the paramyxoviruses in its ability to infect and cause potentially fatal disease in a number of host species, including humans.


Langerhans' cells in hair follicles of the depigmenting C57Bl/Ler-vit.vit mouse. A model for human vitiligo.
The C57Bl/Ler-vit.vit mouse grows a black pelage after birth. During successive hair molts, the fur loses its pigmentation. By 6 months of age, most of the fur of the animal is white. The epidermis of the ears and tail also loses its pigmentation. Histologic studies confirm that in the epidermis and hair follicles there is an absence of pigment cells identifiable by various histochemical or electron microscopic techniques. This mouse may be an excellent model in which to study the role of Langerhans' cells and the immune response in the pathogenesis of vitiligo, a study not easily done in humans. From results of prior studies, we postulated that if Langerhans' cells were involved in the destruction of melanocytes, they would be abnormal (either more or less numerous) in number during the active phase of depigmentation and normal in number after depigmentation was complete. To determine whether the Langerhans cell (Ia+/adenosine triphosphatase dendritic epidermal cell) might be involved in destruction of pigment cells, we quantified the number of Ia+ and adenosine triphosphatase dendritic cells in the hair follicles in skin from the ear, abdomen, back, and tail from male C57Bl/Ler-vit.vit mice while the fur and skin were depigmenting and after depigmentation was almost completed. We found that Langerhans' cells were normal in number during depigmentation and were most numerous after depigmentation. Previous studies indicate that Langerhans' cells in these mice are functionally defective and respond poorly to some contact allergens. From these morphologic and functional data, we conclude that Langerhans' cells probably are uninvolved in causing depigmentation in these mice. We also observed that the epithelium of hair follicles has a significantly higher (up to 1600/mm2) population density of Langerhans' cells than interfollicular skin.


Thermodynamically reengineering the listerial invasion complex InlA/E-cadherin.
Biological processes essentially all depend on the specific recognition between macromolecules and their interaction partners. Although many such interactions have been characterized both structurally and biophysically, the thermodynamic effects of small atomic changes remain poorly understood. Based on the crystal structure of the bacterial invasion protein internalin (InlA) of Listeria monocytogenes in complex with its human receptor E-cadherin (hEC1), we analyzed the interface to identify single amino acid substitutions in InlA that would potentially improve the overall quality of interaction and hence increase the weak binding affinity of the complex. Dissociation constants of InlA-variant/hEC1 complexes, as well as enthalpy and entropy of binding, were quantified by isothermal titration calorimetry. All single substitutions indeed significantly increase binding affinity. Structural changes were verified crystallographically at < or =2.0-A resolution, allowing thermodynamic characteristics of single substitutions to be rationalized structurally and providing unique insights into atomic contributions to binding enthalpy and entropy. Structural and thermodynamic data of all combinations of individual substitutions result in a thermodynamic network, allowing the source of cooperativity between distant recognition sites to be identified. One such pair of single substitutions improves affinity 5,000-fold. We thus demonstrate that rational reengineering of protein complexes is possible by making use of physically distant hot spots of recognition.


Treatment and outcomes of melanoma in acral location in Korean patients.
A retrospective study was conducted to review the treatment and outcomes of mainly melanomas in acral location in a single institution in Korea, and to evaluate the prognostic significance of anatomic locations of the tumor. A retrospective review was completed on 40 patients between 2001 and 2006 to obtain pertinent demographic data, tumor data, treatment characteristics, and follow-up data. Forty melanoma patients were identified and analyzed. Of these, 18 were male and 22 were female patients and the mean age at the time of diagnosis was 55.9 years. Of the tumors, 65% were located on the hands and feet with acral lentiginous melanoma being the most common histological subtype. Univariate analysis for the overall melanoma survival revealed that the thickness of the tumor and the clinical stage have prognostic significances. The most significant factor as analyzed by a multivariate analysis was shown to be the advanced clinical stage. Acral melanomas did not show statistically significant differences in the age at diagnosis, thickness of the tumor, stage, ulceration, and survival rates compared to non-acral melanomas. There was also no significant difference in the survival rate between the patients treated by amputation versus wide local excision in acral melanomas. In Korean melanoma patients, thickness and advanced stages are significant factors for poorer prognosis. However, the location of melanoma did not have a significant prognostic value. In treating the melanomas in acral location, local wide excisions resulted in a similar prognosis compared to amputations.


The Epstein-Barr virus nuclear antigen 2 transactivator is directed to response elements by the J kappa recombination signal binding protein.
Epstein-Barr virus nuclear antigen 2 (EBNA-2) plays an essential role in primary B-lymphocyte growth transformation. EBNA-2 is an acidic transcriptional transactivator that is brought to virus and cell EBNA-2 response elements by interaction with a factor that recognizes the double-stranded sequence MNYYGTGGGAA, where M is A or C, N is any nucleotide, and Y is a pyrimidine. A 63-kDa protein that recognizes this DNA sequence has now been purified by S-Sepharose and oligonucleotide affinity chromatography. p63 peptide sequence is identical to the predicted amino acid sequence for the human J kappa immunoglobulin recombination signal binding protein. Purified or recombinant in vitro-translated J kappa binds to the MNYYGTGGGAA EBNA-2 response element sequence and interacts with EBNA-2. Surprisingly, J kappa does not bind to the J kappa 1 heptamer recombination signal sequence (CACTGTG), and its prior identification as a heptamer binding protein was most likely due to the addition of a BamHI restriction site to the native heptamer creating a near EBNA-2 response element consensus (CACTGTGGGAT).


Historical control clinical trial to assess the effectiveness of teflubenzuron for treating sea lice on Atlantic salmon.
A historical control clinical trial was performed to assess the effectiveness of teflubenzuron in controlling sea lice Lepeoptheirus salmonis burdens on farmed Atlantic salmon Salmo salar over time. The study site comprised 9 sea cages, all of which were treated. The teflubenzuron was administered in the feed, at a dosage of 10 mg kg(-1) biomass d(-1), over a treatment period of 7 d. At 1 wk post-treatment, sea lice chalimus and mobile stages were reduced by 92 and 74% (both p < 0.001), respectively. At 2 wk post-treatment, chalimus stages were reduced by 41% and mobile stages 61% (both p < 0.001) compared to pre-treatment levels. At 3 wk post-treatment, chalimus stages were still 36% (p < 0.001) lower than pre-treatment levels, but mobile stages had increased to above pre-treatment levels. Our results show that the effects of teflubenzuron are limited to a 3 wk duration, but that with appropriate management, farms could benefit from these reduced lice burdens for longer periods.


Genetic influences on vitamin D status and forearm fracture risk in African American children.
We sought to investigate the relationship between newly identified genetic variants and vitamin D levels and fracture risk in healthy African American (black) children. This case-control study included children of both sexes, ages 5 to 9 years, with and without forearm fractures. Serum 25-hydroxy vitamin D levels, bone mineral density, body mass index, and calcium/vitamin D intake were measured in 130 individuals (n = 60 cases and n = 70 controls). The 5 variants tested were located in the GC gene (rs2282679), in the NADSYN1 gene (rs12785878 and rs3829251), and in the promoter region of the CYP2R1 gene (rs2060793 and rs104741657). Associations between single nucleotide polymorphisms (SNPs) and vitamin D levels were tested using an analysis of covariance. Associations between SNPs and fracture status were tested using logistic regression. The GC gene variant was associated with vitamin D levels (P = 0.038). None of the SNPs were associated with fracture status in young blacks. These results suggest that the variants tested, which are associated with circulating vitamin D levels in whites, are not associated with fracture status in healthy black children. Additional research is required to discover the genetics of fracture risk in blacks.


Genetic impact dominates over environmental effects in development of carotid artery stiffness: a twin study.
Arterial stiffness is an independent predictor of cardiovascular, cerebrovascular and all-cause mortality. Quantifying the genetic influence on the stiff arterial phenotype allows us to better predict the development of arterial stiffness. In this study, we aimed to determine the heritability of carotid artery stiffness in healthy twins. We studied 98 twin pairs of both sexes. We determined carotid artery stiffness locally using echo tracking and applanation tonometry. We estimated the heritability of stiffness parameters using structural equation modeling. The carotid distensibility coefficient showed the highest heritability (64%, 95% confidence interval 45-77%). The incremental elastic modulus, compliance and stiffness index β also showed substantial heritability (62%, 61% and 58%, respectively). The remaining 36-42% phenotypic variance was attributed to unshared environmental effects. Genetic influence appears to dominate over environmental factors in the development of carotid artery stiffness. Environmental factors may have an important role in favorably influencing the genetic predisposition for accelerated arterial stiffening.


Evaluation of a model of nursing care for older patients using participatory action research in an acute medical ward.
The main aim of this study was to improve the quality of nursing care for older acutely ill hospitalized medical patients through developing, implementing and evaluating a new model of care using a participatory action research process. One of the challenges of nursing today is to meet the health-care needs of the growing older population. It is important to consider what quality of nursing care means to older patients if nurses are to address gaps between their own perceptions and those of older patients themselves and to consider conceptual models of care appropriate for older patients care in order to improve the quality of care provided. This study is a mixed method triangulated study, involving the use of both quantitative and qualitative methods through participatory action research methodology to establish an evidence-base for an evolving model of care. The model was tested on 60 acutely ill patients aged at least 65 years. The medical ward nurses selected a key reference group including the researcher to facilitate the participatory action research process to develop, implement and evaluate a new model of care based on Orem's self-care model incorporating the Nurses Improving Care to Health System Elders Faculty (Am J Nurs 1994; 94:21) medication protocol to improve the nursing care provided for acutely ill older patients. The participatory action research process resulted in improved heath-care outcomes for the patients, such as significant improvements in activities of daily living capabilities between admission to discharge, significant improvements in knowledge levels regarding their medication regimes, as well as increased satisfaction with nursing care activities as perceived by older patients and nursing staff. The implementation of educational sessions during the model of care improved the older patient's functional activities and knowledge levels of their medication regime prior to discharge. In addition, by repeatedly explaining procedures, nurses became more involved with their individual patient's care, developing a patient-centred care relationship based on Orem's self-care model. This study demonstrates the efficacy of a new model of nursing care in improving the quality of nursing care for older patients in the acute medical ward setting. This study is significant because of its evidence-base and demonstrates how the participatory action research process empowered nurses to make sustainable changes to their practice. The nurses in the study wanted to affect change. The planned change was not dictated by management, but was driven by the clinical nursing staff at the 'grass roots' level. Therefore, being involved in the decision-making process provided an incentive to actively implement change.


A Developmental Framework for Embodiment Research: The Next Step Toward Integrating Concepts and Methods.
Embodiment research is at a turning point. There is an increasing amount of data and studies investigating embodiment phenomena and their role in mental processing and functions from across a wide range of disciplines and theoretical schools within the life sciences. However, the integration of behavioral data with data from different biological levels is challenging for the involved research fields such as movement psychology, social and developmental neuroscience, computational psychosomatics, social and behavioral epigenetics, human-centered robotics, and many more. This highlights the need for an interdisciplinary framework of embodiment research. In addition, there is a growing need for a cross-disciplinary consensus on level-specific criteria of embodiment. We propose that a developmental perspective on embodiment is able to provide a framework for overcoming such pressing issues, providing analytical tools to link timescales and levels of embodiment specific to the function under study, uncovering the underlying developmental processes, clarifying level-specific embodiment criteria, and providing a matrix and platform to bridge disciplinary boundaries among the involved research fields.


Squamous cell carcinoma of the palatine tonsils: FDG standardized uptake value ratio as a biomarker to differentiate tonsillar carcinoma from physiologic uptake.
To quantify fluorine 18 ((18)F) fluorodeoxyglucose (FDG) uptake in the palatine tonsils to identify a sensitive and specific metric for distinguishing physiologic asymmetric uptake from squamous cell carcinoma (SCC). This HIPAA-compliant retrospective study was approved by institutional review board. Informed consent requirements were waived. Twenty-six patients (seven female, 19 male; mean age, 53.46 years + or - 10.45 [standard deviation]) with tonsillar SCC were included. Twenty-six patients (seven female, 19 male; mean age, 61.77 years + or - 10.12) with head and neck carcinomas not involving the tonsils were included as control subjects. Tonsil standardized uptake values (SUVs) were measured bilaterally in each group. Independent-samples t test was used to compare mean SUVs, and Pearson correlation was used to evaluate association of FDG uptake between tonsils within control subjects. The mean maximum SUV (SUV(max)) of tonsil tumors was 9.36 + or - 4.54, which was significantly higher than that of contralateral cancer-free tonsils (2.54 + or - 0.88; P < .0001) and tonsils in control subjects (2.98 + or - 1.08; P < .0001). In patients with tonsillar cancer, the mean difference in SUV(max) between tonsils was 10.43 + or - 7.07, which was significantly greater than that in control subjects (0.62 + or - 0.54; P < .0001). The mean SUV(max) ratio between tonsils in patients with carcinoma was 3.79 + or - 1.69, which was threefold higher than in control subjects (1.18 + or - 0.13; P < .0001). For receiver operating characteristic analysis using SUV(max) ratio to differentiate benign uptake from SCC, the area under the curve was 1.00 (95% confidence interval: 1.00, 1.00). A cutoff ratio of 1.48 had 100% sensitivity and specificity. The SUV(max) ratio represents an accurate imaging biomarker for differentiating tonsillar SCC from physiologic (18)F-FDG uptake.


Anti-Helicobacter pylori activity of herbal medicines.
The extracts of Coptidis japonica (rhizoma), Eugenia caryophyllata (flower), Rheum palmatum (rhizoma), Magnolia officinalis (cortex) and Rhusjavanica (galla rhois) potently inhibited the growth of Helicobacter pylori (HP). However, these herbal extracts showed no inhibitory effect on HP urease except Galla rhois. Among the components separated from active herbal extracts by silica gel column chromatography, the inhibitory effects of decursinol angelate and decursin on the growth of HP were the most potent, followed by magnolol, berberine, cinnamic acid, decursinol and gallic acid. Minimum inhibitory concentrations (MICs) of decursin and decursinol angelate were 6-20 microg/ml.


Missed Opportunities: Screening and Brief Intervention for Risky Alcohol Use in Women's Health Settings.
Although women's health settings could provide access to women for screening, brief intervention, and referral to treatment (SBIRT) for risky alcohol use, little is known about rates of alcohol use or associated risk for alcohol-exposed pregnancy (AEP) among women's health patients, receipt of SBIRT services in these settings, or patient attitudes towards SBIRT services. This study reports the results of a self-administered survey to a convenience sample of women's health patients attending public clinics for family planning or sexually transmitted infection visits. Surveys were analyzed for 199 reproductive-aged women who had visited the clinic within the past year. The rate of risky drinking among the sample was (44%) and risk for AEP was (17%). Despite this, many patients did not receive SBIRT services, with more than half of risky drinking patients reporting that they were not advised about safe drinking limits (59%) and similar rates of patients at risk for AEP reporting that their medical provider did not discuss risk factors of AEP (53%). Patient attitudes towards receipt of SBIRT services were favorable; more than 90% of women agreed or strongly agreed that if their drinking was affecting their health, their women's health provider should advise them to cut down. Women's health clinics may be an ideal setting to implement SBIRT and future research should address treatment efficacy in these settings.


A single domestication for potato based on multilocus amplified fragment length polymorphism genotyping.
The cultivated potato, Solanum tuberosum, ultimately traces its origin to Andean and Chilean landraces developed by pre-Colombian cultivators. These Andean landraces exhibit tremendous morphological and genetic diversity, and are distributed throughout the Andes, from western Venezuela to northern Argentina, and in southern Chile. The wild species progenitors of these landraces have long been in dispute, but all hypotheses center on a group of approximately 20 morphologically very similar tuber-bearing (Solanum section Petota) wild taxa referred to as the S. brevicaule complex, distributed from central Peru to northern Argentina. We present phylogenetic analyses based on the representative cladistic diversity of 362 individual wild (261) and landrace (98) members of potato (all tuber-bearing) and three outgroup non-tuber-bearing members of Solanum section Etuberosum, genotyped with 438 robust amplified fragment length polymorphisms. Our analyses are consistent with a hypothesis of a "northern" (Peru) and "southern" (Bolivia and Argentina) cladistic split for members of the S. brevicaule complex, and with the need for considerable reduction of species in the complex. In contrast to all prior hypotheses, our data support a monophyletic origin of the landrace cultivars from the northern component of this complex in Peru, rather than from multiple independent origins from various northern and southern members.


Silver nanoparticle plasmonic enhanced förster resonance energy transfer (FRET) imaging of protein-specific sialylation on the cell surface.
A large amount of proteins are post-translationally modified with a sialic acid terminal oligosaccharide, and sialylation directly affects the function of glycoproteins and adjusts relevant biological processes. Herein, we developed a method for imaging analysis of protein-specific sialylation on the cell surface via silver nanoparticle (AgNPs) plasmonic enhanced Förster resonance energy transfer (FRET). In this strategy, the target monosaccharide was labelled with the FRET acceptor of Cy5 via bioorthogonal chemistry. In addition, aptamer linked AgNPs were combined with the Cy3 fluorophore by DNA hybridization as the FRET donor probe, which could be conjugated to the target glycoprotein based on specific aptamer-protein recognition. The Cy5 fluorescence signal was obtained under the Cy3 excitation wavelength via FRET. Moreover, the FRET fluorescence signal was obviously enhanced owing to the plasmonic effect of AgNPs at an appropriate distance to Cy3 on the cell surface. Hence, the protein-specific sialic acids were detected with high contrast. The results showed that the AgNP plasmonic enhanced FRET method was not only superior to the bare FRET method but also can be used to evaluate the expression of sialoglycoproteins in different cell types under pharmacological treatments. The AgNP plasmonic enhanced FRET method provides a valuable tool in the research of glycan metabolism biological processes, the active site of glycoproteins and drug screening.


Water Quality Conditions Associated with Cattle Grazing and Recreation on National Forest Lands.
There is substantial concern that microbial and nutrient pollution by cattle on public lands degrades water quality, threatening human and ecological health. Given the importance of clean water on multiple-use landscapes, additional research is required to document and examine potential water quality issues across common resource use activities. During the 2011 grazing-recreation season, we conducted a cross sectional survey of water quality conditions associated with cattle grazing and/or recreation on 12 public lands grazing allotments in California. Our specific study objectives were to 1) quantify fecal indicator bacteria (FIB; fecal coliform and E. coli), total nitrogen, nitrate, ammonium, total phosphorus, and soluble-reactive phosphorus concentrations in surface waters; 2) compare results to a) water quality regulatory benchmarks, b) recommended maximum nutrient concentrations, and c) estimates of nutrient background concentrations; and 3) examine relationships between water quality, environmental conditions, cattle grazing, and recreation. Nutrient concentrations observed throughout the grazing-recreation season were at least one order of magnitude below levels of ecological concern, and were similar to U.S. Environmental Protection Agency (USEPA) estimates for background water quality conditions in the region. The relative percentage of FIB regulatory benchmark exceedances widely varied under individual regional and national water quality standards. Relative to USEPA's national E. coli FIB benchmarks-the most contemporary and relevant standards for this study-over 90% of the 743 samples collected were below recommended criteria values. FIB concentrations were significantly greater when stream flow was low or stagnant, water was turbid, and when cattle were actively observed at sampling. Recreation sites had the lowest mean FIB, total nitrogen, and soluble-reactive phosphorus concentrations, and there were no significant differences in FIB and nutrient concentrations between key grazing areas and non-concentrated use areas. Our results suggest cattle grazing, recreation, and provisioning of clean water can be compatible goals across these national forest lands.


Parsing with probabilistic strictly locally testable tree languages.
Probabilistic k-testable models (usually known as k-gram models in the case of strings) can be easily identified from samples and allow for smoothing techniques to deal with unseen events during pattern classification. In this paper, we introduce the family of stochastic k-testable tree languages and describe how these models can approximate any stochastic rational tree language. The model is applied to the task of learning a probabilistic k-testable model from a sample of parsed sentences. In particular, a parser for a natural language grammar that incorporates smoothing is shown.


Dementia-Related Functional Disability in Moderate to Advanced Parkinson's Disease: Assessment Using the World Health Organization Disability Assessment Schedule 2.0.
Dementia is a common nonmotor condition among people with moderate or advanced Parkinson's disease (PD). Undoubtedly, profound motor symptoms cause remarkable impairment in daily activities; however, dementia-related disabilities have not been thoroughly investigated, especially not with consideration of differences according to sex. The present study used the World Health Organization Disability Assessment Schedule 2.0 (WHODAS 2.0) to compare the functional disability between men and women with PD (PwP) with and without dementia. This study employed a registry of disability evaluation and functional assessment using the Taiwan Data Bank of Persons with Disability between July 2012 and October 2018. To investigate dementia-related disability in PwP, 1:1 matching by age and Hoehn-Yahr stage was conducted, which resulted in the inclusion of 1605 study participants in each group. The present study demonstrated that among the six major domains of WHODAS 2.0, the section of "Getting alone with others" was significantly worse in both genders of PwP with dementia; however, a greater disability in fulfilling activities of daily living was only noted in male PwP with dementia but not in their female counterparts. Neither the inability to provide self-care nor participation were significantly different between the sexes. Our findings suggested that deteriorating social relationships were a dementia-related disability in all PwP at the moderate and advanced disease stages. Regarding the performance of activities of daily living, deterioration was related to dementia only in male PwP. Such disabilities could indicate cognitive impairment in people with moderate or advanced PD and could be used as an indicator for the early detection of dementia in PwP by healthcare professionals through the easier functional assessment of the WHODAS 2.0.


Elevated snail expression mediates tumor progression in areca quid chewing-associated oral squamous cell carcinoma via reactive oxygen species.
Snail is an important transcription factor implicated in several tumor progression and can be induced by reactive oxygen species (ROS). Areca quid chewing is a major risk factor of oral squamous cell carcinoma (OSCC). Therefore, we hypothesize that the major areca nut alkaloid arecoline may induce Snail via ROS and involve in the pathogenesis of areca quid chewing-associated OSCC. Thirty-six OSCC and ten normal oral epithelium specimens were examined by immunohistochemistry and analyzed by the clinico-pathological profiles. Cytotoxicity, 2', 7'-dichlorofluorescein diacetate assay, and western blot were used to investigate the effects of arecoline in human oral keratinocytes (HOKs) and oral epithelial cell line OECM-1 cells. In addition, antioxidants N-acetyl-L-cysteine (NAC), curcumin, and epigallocatechin-3 gallate (EGCG) were added to find the possible regulatory mechanisms. Initially, Snail expression was significantly higher in OSCC specimens (p<0.05). Elevated Snail expression was associated with lymph node metastasis (p = 0.031) and poor differentiation (p = 0.017). Arecoline enhanced the generation of intracellular ROS at the concentration higher than 40 µg/ml (p<0.05). Arecoline was also found to induced Snail expression in a dose- and time-dependent manner (p<0.05). Treatment with NAC, curcumin, and EGCG markedly inhibited arecoline induced Snail expression (p<0.05). Our results suggest that Snail overexpression in areca quid chewing-associated OSCC is associated with tumors differentiation and lymph node metastasis. Arecoline-upregulated Snail expression may be mediated by ROS generation. In addition, arecoline induced Snail expression was downregulated by NAC, curcumin, and EGCG.


Reach out to enhance wellness home-based diet-exercise intervention promotes reproducible and sustainable long-term improvements in health behaviors, body weight, and physical functioning in older, overweight/obese cancer survivors.
Diet and exercise interventions have been tested in cancer survivors as a means to reduce late effects and comorbidity, but few have assessed adherence and health outcomes long term. Between July 2005 and May 2007, the Reach Out to Enhance Wellness (RENEW) trial accrued 641 locoregionally staged, long-term (≥ 5 years from diagnosis) colorectal, breast, and prostate cancer survivors in the United States (21 states), Canada, and the United Kingdom. All participants were sedentary (< 150 minutes of physical activity [PA] a week), overweight or obese (body mass index, 25 to 40 kg/m(2)), and over age 65 years. The trial tested a diet-exercise intervention delivered via mailed print materials and telephone counseling. RENEW used a wait-list control, cross-over design (ie, participants received the year-long intervention immediately or after a 1-year delay), which allowed the opportunity to assess program efficacy (previously reported primary outcome), durability, and reproducibility (reported herein). Measures included diet quality (DQ), PA, BMI, and physical function (PF). No significant relapse was observed in the immediate-intervention arm for DQ, PA, and BMI; however, rates of functional decline increased when the intervention ceased. From year 1 to year 2, significant improvements were observed in the delayed-intervention arm; mean change scores in behaviors and BMI and PF slopes were as follows: DQ score, 5.2 (95% CI, 3.4 to 7.0); PA, 45.8 min/wk (95% CI, 26.9 to 64.6 min/wk); BMI, -0.56 (95% CI, -0.75 to -0.36); and Short Form-36 PF, -1.02 versus -5.52 (P < .001 for all measures). Overall, both arms experienced significant improvements in DQ, PA, and BMI from baseline to 2-year follow-up (P < .001). Older cancer survivors respond favorably to lifestyle interventions and make durable changes in DQ and PA that contribute to sustained weight loss. These changes positively reorient functional decline trajectories during intervention delivery.


Towards Fully Mobile 3D Face, Body, and Environment Capture Using Only Head-worn Cameras.
We propose a new approach for 3D reconstruction of dynamic indoor and outdoor scenes in everyday environments, leveraging only cameras worn by a user. This approach allows 3D reconstruction of experiences at any location and virtual tours from anywhere. The key innovation of the proposed ego-centric reconstruction system is to capture the wearer's body pose and facial expression from near-body views, e.g. cameras on the user's glasses, and to capture the surrounding environment using outward-facing views. The main challenge of the ego-centric reconstruction, however, is the poor coverage of the near-body views - that is, the user's body and face are observed from vantage points that are convenient for wear but inconvenient for capture. To overcome these challenges, we propose a parametric-model-based approach to user motion estimation. This approach utilizes convolutional neural networks (CNNs) for near-view body pose estimation, and we introduce a CNN-based approach for facial expression estimation that combines audio and video. For each time-point during capture, the intermediate model-based reconstructions from these systems are used to re-target a high-fidelity pre-scanned model of the user. We demonstrate that the proposed self-sufficient, head-worn capture system is capable of reconstructing the wearer's movements and their surrounding environment in both indoor and outdoor situations without any additional views. As a proof of concept, we show how the resulting 3D-plus-time reconstruction can be immersively experienced within a virtual reality system (e.g., the HTC Vive). We expect that the size of the proposed egocentric capture-and-reconstruction system will eventually be reduced to fit within future AR glasses, and will be widely useful for immersive 3D telepresence, virtual tours, and general use-anywhere 3D content creation.


Investigation of fMRI neurofeedback of differential primary motor cortex activity using kinesthetic motor imagery.
Functional MRI neurofeedback (fMRI NF) is an emerging technique that trains subjects to regulate their brain activity while they manipulate sensory stimulus representations of fMRI signals in "real-time". Here we report an fMRI NF study of brain activity associated with kinesthetic motor imagery (kMI), analyzed using partial least squares (PLS), a multivariate analysis technique. Thirteen healthy young adult subjects performed kMI involving each hand separately, with NF training targeting regions of interest (ROIs) in the left and right primary motor cortex (M1). Throughout, subjects attempted to maximize a laterality index (LI) of brain activity-the difference in activity between the contralateral ROI (relative to the hand involved in kMI) and the ipsilateral M1 ROI-while receiving real-time updates on a visual display. Six of 13 subjects were successful in increasing the LI value, whereas the other 7 were not successful and performed similarly to 5 control subjects who received sham NF training. Ability to suppress activity in the ipsilateral M1 ROI was the primary driver of successful NF performance. Multiple PLS analyses depicted activated networks of brain regions involved with imagery, self-awareness, and feedback processing, and additionally showed that activation of the task positive network was correlated with task performance. These results indicate that fMRI NF of kMI is capable of modulating brain activity in primary motor regions in a subset of the population. In the future, such methods may be useful in the development of NF training methods for enhancing motor rehabilitation following stroke.


A Multistrain Mathematical Model To Investigate the Role of Pyrazinamide in the Emergence of Extensively Drug-Resistant Tuberculosis.
Several infectious diseases of global importance-e.g., HIV infection and tuberculosis (TB)-require prolonged treatment with combination antimicrobial regimens typically involving high-potency core agents coupled with additional companion drugs that protect against the de novo emergence of mutations conferring resistance to the core agents. Often, the most effective (or least toxic) companion agents are reused in sequential (first-line, second-line, etc.) regimens. We used a multistrain model of Mycobacterium tuberculosis transmission in Southeast Asia to investigate how this practice might facilitate the emergence of extensive drug resistance, i.e., resistance to multiple core agents. We calibrated this model to regional TB and drug resistance data using an approximate Bayesian computational approach. We report the proportion of data-consistent simulations in which the prevalence of pre-extensively drug-resistant (pre-XDR) TB-defined as resistance to both first-line and second-line core agents (rifampin and fluoroquinolones)-exceeds predefined acceptability thresholds (1 to 2 cases per 100,000 population by 2035). The use of pyrazinamide (the most effective companion agent) in both first-line and second-line regimens increased the proportion of simulations in which the prevalence exceeded the pre-XDR acceptability threshold by 7-fold compared to a scenario in which patients with pyrazinamide-resistant TB received an alternative drug. Model parameters related to the emergence and transmission of pyrazinamide-resistant TB and resistance amplification were among those that were the most strongly correlated with the projected pre-XDR prevalence, indicating that pyrazinamide resistance acquired during first-line treatment subsequently promotes amplification to pre-XDR TB under pyrazinamide-containing second-line treatment. These findings suggest that the appropriate use of companion drugs may be critical to preventing the emergence of strains resistant to multiple core agents.


High latitude and marine diet: vitamin D status in elderly Faroese.
Human subjects obtain their vitamin D from the diet, especially from marine food, and from endogenous synthesis following cutaneous sun exposure. The risk of an insufficient vitamin D synthesis is increased in northern populations, but it may be counteracted by a high intake of marine food in fishing populations, e.g. at the Faroe Islands. We examined the vitamin D status and its statistical determinants in a cross-sectional study of 713 elderly Faroese aged 70-74 years, about two-thirds of all the eligible residents in this age group. Clinical examination included measurement of body weight and height, and marine food intake was estimated using a questionnaire. We measured serum 25-hydroxyvitamin D3 (S-25(OH)D3) by LC-MS/MS in 669 of the 713 subjects in whom sufficient serum was available. Of the population, 19% had S-25(OH)D3 concentrations < 25 nmol/l, and only 10.3% of the population had S-25(OH)D3 concentrations >80 nmol/l. In a logistic regression analysis, BMI < 30 kg/m2, blood sampling in summer season, eating pilot whale blubber more than once per month and female sex were positively associated with vitamin D levels >80 nmol/l. The high prevalence of low vitamin D levels among the elderly Faroese population reflects the low skin synthesis during most months of the year, which is caused by the limited sun exposure and insufficient benefits from marine diet. Thus, even in a population with a high intake of marine food, the northern latitude causes a low vitamin D status. Efforts to improve vitamin D status in this population are warranted.


Sirolimus therapy in a child with partially diazoxide-responsive hyperinsulinaemic hypoglycaemia.
Hyperinsulinaemic hypoglycaemia (HH), which causes persistent neonatal hypoglycaemia, can result in neurological damage and it's management is challenging. Diazoxide is the first-line treatment, albeit not all patients will fully respond to it, as episodes of hypoglycaemia may persist and it entails unpleasant adverse effects. Sirolimus, an mTOR inhibitor, has reportedly been successful in treating children with severe diffuse HH, thus obviating the need for pancreatectomy. We report a girl with HH, with a novel heterozygous ABCC8 gene missense mutation (c.4154A>T/ p.Lys1385Thr), who was initially responsive to diazoxide therapy. After 11 months of diazoxide treatment, she developed intermittent, unpredictable breakthrough episodes of hypoglycaemia, in addition to generalized hypertrichosis and weight gain from enforced feeding to avoid hypoglycaemia. Sirolimus, which was commenced at 15 months of age, gradually replaced diazoxide, with significant reduction and abolition of hypoglycaemia. The hypertrichosis resolved and there was less weight gain given the reduced need for enforced feeding. Sirolimus, which was administered over the next 15 months, was well tolerated with no significant side effects and was gradually weaned off. After stopping sirolimus, apart from hypoglycaemia developing during an episode of severe viral gastroenteritis, the capillary glucose concentrations were maintained >3.5 mmol/L, even after a 10 h fast. Sirolimus may have a role in the treatment of partially diazoxide-responsive forms of HH who experience breakthrough hypoglycaemia, but the long-term safety and efficacy of sirolimus are not established. Conventional treatment of diffuse HH with diazoxide is not always effective in controlling hypoglycaemia and can be associated with unpleasant side effects.Sirolimus was successfully used to abolish recurrent hypoglycaemia in partially diazoxide-responsive HH, with resolution of unacceptable diazoxide-associated side effects.Sirolimus was well tolerated with no clinically significant side effects.Shortly after stopping sirolimus, the capillary glucose levels remained normoglycemic.


Fine morphological assessment of quality of human mature oocytes after slow freezing or vitrification with a closed device: a comparative analysis.
Human mature oocytes are very susceptible to cryodamage. Several reports demonstrated that vitrification might preserve oocyte better than slow freezing. However, this is still controversial. Thus, larger clinical, biological and experimental trials to confirm this concept are necessary. The aim of the study was to evaluate and compare fine morphological features in human mature oocytes cryopreserved with either slow freezing or vitrification. We used 47 supernumerary human mature (metaphase II) oocytes donated by consenting patients, aged 27-32 years, enrolled in an IVF program. Thirtyfive oocytes were cryopreserved using slow freezing with 1.5 M propanediol +0.2 M sucrose concentration (20 oocytes) or a closed vitrification system (CryoTip Irvine Scientific CA) (15 oocytes). Twelve fresh oocytes were used as controls. All samples were prepared for light and transmission electron microscopy evaluation. Control, slow frozen/thawed and vitrified/warmed oocytes (CO, SFO and VO, respectively) were rounded, 90-100 μm in diameter, with normal ooplasm showing uniform distribution of organelles. Mitochondria-smooth endoplasmic reticulum (M-SER) aggregates and small mitochondria-vesicle (MV) complexes were the most numerous structures found in all CO, SFO and VO cultured for 3-4 hours. M-SER aggregates decreased, and large MV complexes increased in those SFO and VO maintained in culture for a prolonged period of time (8-9 hours). A slight to moderate vacuolization was present in the cytoplasm of SFO. Only a slight vacuolization was present in VO, whereas vacuoles were almost completely absent in CO. Amount and density of cortical granules (CG) appeared abnormally reduced in SFO and VO, irrespective of the protocol applied. Even though, both slow freezing and vitrification ensured a good overall preservation of the oocyte, we found that: 1) prolonged culture activates an intracellular membrane "recycling" that causes the abnormal transformation of the membranes of the small MV complexes and of SER into larger rounded vesicles; 2) vacuolization appears as a recurrent form of cell damage during slow freezing and, at a lesser extent, during vitrification using a closed device; 3) premature CG exocytosis was present in both SFO and VO and may cause zona pellucida hardening.