Celiac disease: management of persistent symptoms in patients on a gluten-free diet.
To investigate all patients referred to our center with non-responsive celiac disease (NRCD), to establish a cause for their continued symptoms. We assessed all patients referred to our center with non-responsive celiac disease over an 18-mo period. These individuals were investigated to establish the eitiology of their continued symptoms. The patients were first seen in clinic where a thorough history and examination were performed with routine blood work including tissue transglutaminase antibody measurement. They were also referred to a specialist gastroenterology dietician to try to identift any lapses in the diet and sources of hidden gluten ingestion. A repeat small intestinal biopsy was also performed and compared to biopsies from the referring hospital where possible. Colonoscopy, lactulose hydrogen breath testing, pancreolauryl testing and computed tomography scan of the abdomen were undertaken if the symptoms persisted. Their clinical progress was followed over a minimum of 2 years. One hundred and twelve consecutive patients were referred with NRCD. Twelve were found not to have celiac disease (CD). Of the remaining 100 patients, 45% were not adequately adhering to a strict gluten-free diet, with 24 (53%) found to be inadvertently ingesting gluten, and 21 (47%) admitting non-compliance. Microscopic colitis was diagnosed in 12% and small bowel bacterial overgrowth in 9%. Refractory CD was diagnosed in 9%. Three of these were diagnosed with intestinal lymphoma. After 2 years, 78 patients remained well, eight had continuing symptoms, and four had died. In individuals with NRCD, a remediable cause can be found in 90%: with continued gluten ingestion as the leading cause. We propose an algorithm for investigation.


Antibody response after hepatitis B immunisation in a group of health care workers.
Hepatitis B immunisation has been offered to staff of Hampstead Health Authority since 1982 and is now offered to all staff with clinical contact. Three doses of 20 micrograms of vaccine are given at zero, one, and six months and the antibody response is measured three months later. Results were analysed to seek for associations with the antibody response. At the time of analysis, 2739 people had started vaccination and 1067 had completed the course and had a measurement of antibody response. Vaccine injections were initially into the buttock and later into the arm; measurement of antibody levels was initially by radioimmunoassay (RIA) and later by enzyme immunoassay (EIA). A positive antibody response was defined as a positive/negative ratio of greater than 10 for RIA or a level of greater than 10 mIU/ml for EIA. Associations between antibody response and other variables were tested by chi 2 and a multiple logistic regression analysis was undertaken to examine the effects of variables in combination. The overall antibody response rate was 95%. Men and women did not respond differently but there were significantly more positive responses with the EIA testing method and a tendency for more positive responses with arm injections. The responders were significantly younger than the non-responders and had significantly lower values of body mass index (wt/ht2).(ABSTRACT TRUNCATED AT 250 WORDS)


Effect of a behavioural intervention in obese pregnant women (the UPBEAT study): a multicentre, randomised controlled trial.
Behavioural interventions might improve clinical outcomes in pregnant women who are obese. We aimed to investigate whether a complex intervention addressing diet and physical activity could reduce the incidence of gestational diabetes and large-for-gestational-age infants. The UK Pregnancies Better Eating and Activity Trial (UPBEAT) is a randomised controlled trial done at antenatal clinics in eight hospitals in multi-ethnic, inner-city locations in the UK. We recruited pregnant women (15-18 weeks plus 6 days of gestation) older than 16 years who were obese (BMI ≥30 kg/m(2)). We randomly assigned participants to either a behavioural intervention or standard antenatal care with an internet-based, computer-generated, randomisation procedure, minimising by age, ethnic origin, centre, BMI, and parity. The intervention was delivered once a week through eight health trainer-led sessions. Primary outcomes were gestational diabetes (diagnosed with an oral glucose tolerance test and by criteria from the International Association of Diabetes in Pregnancy Study Groups) and large-for-gestational-age infants (≥90th customised birthweight centile). Analysis was by intention to treat. This trial is registered with Current Controlled Trials, ISCRTN89971375. Recruitment and pregnancy outcomes are complete but childhood follow-up is ongoing. Between March 31, 2009, and June 2, 2014, we assessed 8820 women for eligibility and recruited 1555, with a mean BMI of 36·3 kg/m(2) (SD 4·8). 772 were randomly assigned to standard antenatal care and 783 were allocated the behavioural intervention, of which 651 and 629 women, respectively, completed an oral glucose tolerance test. Gestational diabetes was reported in 172 (26%) women in the standard care group compared with 160 (25%) in the intervention group (risk ratio 0·96, 95% CI 0·79-1·16; p=0·68). 61 (8%) of 751 babies in the standard care group were large for gestational age compared with 71 (9%) of 761 in the intervention group (1·15, 0·83-1·59; p=0·40). Thus, the primary outcomes did not differ between groups, despite improvements in some maternal secondary outcomes in the intervention group, including reduced dietary glycaemic load, gestational weight gain, and maternal sum-of-skinfold thicknesses, and increased physical activity. Adverse events included neonatal death (two in the standard care group and three in the intervention group) and fetal death in utero (ten in the standard care group and six in the intervention group). No maternal deaths were reported. Incidence of miscarriage (2% in the standard care group vs 2% in the intervention group), major obstetric haemorrhage (1% vs 3%), and small-for-gestational-age infants (≤5th customised birthweight centile; 6% vs 5%) did not differ between groups. A behavioural intervention addressing diet and physical activity in women with obesity during pregnancy is not adequate to prevent gestational diabetes, or to reduce the incidence of large-for-gestational-age infants. National Institute for Health Research, Guys and St Thomas' Charity, Chief Scientist Office Scotland, Tommy's Charity.


Predicted Impact of COVID-19 on Neglected Tropical Disease Programs and the Opportunity for Innovation.
Due to the COVID-19 pandemic, many key neglected tropical disease (NTD) activities have been postponed. This hindrance comes at a time when the NTDs are progressing towards their ambitious goals for 2030. Mathematical modelling on several NTDs, namely gambiense sleeping sickness, lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases (STH), trachoma, and visceral leishmaniasis, shows that the impact of this disruption will vary across the diseases. Programs face a risk of resurgence, which will be fastest in high-transmission areas. Furthermore, of the mass drug administration diseases, schistosomiasis, STH, and trachoma are likely to encounter faster resurgence. The case-finding diseases (gambiense sleeping sickness and visceral leishmaniasis) are likely to have fewer cases being detected but may face an increasing underlying rate of new infections. However, once programs are able to resume, there are ways to mitigate the impact and accelerate progress towards the 2030 goals.


PMEPA1 isoform a drives progression of glioblastoma by promoting protein degradation of the Hippo pathway kinase LATS1.
The Hippo signaling pathway controls organ development and is also known, in cancer, to have a tumor suppressing role. Within the Hippo pathway, we here demonstrate, in human gliomas, a functional interaction of a transmembrane protein, prostate transmembrane protein, androgen induced 1 (PMEPA1) with large tumor suppressor kinase 1 (LATS1). We show that PMEPA1 is upregulated in primary human gliomas. The PMEPA1 isoform PMEPA1a was predominantly expressed in glioma specimens and cell lines, and ectopic expression of the protein promoted glioma growth and invasion in vitro and in an orthotopic xenograft model in nude mice. In co-immunoprecipitation experiments, PMEPA1a associated with the Hippo tumor suppressor kinase LATS1. This interaction led to a proteasomal degradation of LATS1 through recruitment of the ubiquitin ligase, neural precursor cell expressed, developmentally downregulated 4 (NEDD4), which led to silencing of Hippo signaling. Alanine substitution in PMEPA1a at PY motifs resulted in failed LATS1 degradation. Targeting of a downstream component in the Hippo signaling pathway, YAP, with shRNA, interfered with the growth promoting activities of PMEPA1a in vitro and in vivo. In conclusion, the presented work shows that PMEPA1a contributes to glioma progression by a dysregulation of the Hippo signaling pathway and thus represents a promising target for the treatment of gliomas.


Adrenal myelolipoma: Controversies in its management.
Adrenal myelolipomas (AMLs) are rare, benign neoplasms of the adrenal gland with varied clinical presentations. The rarity of these tumors precludes any case-controlled or randomized study into their management. The available literature is limited to case reports and short series from referral centers. This review is an effort to put the available literature into perspective such that clinical decision making can be done with some clarity. The PubMed and Cochrane databases were searched with key words Adrenal Myelolipoma, Adrenal Incidentaloma (AI) and Adrenal Collision Tumor (ACT). From over 1300 search results, 547 relevant publications dating from 1954 to 2014 were reviewed. Details of about 1231 AMLs in the indexed literature were analyzed. Increasing usage of imaging studies has significantly increased the discovery of AMLs. Although AMLs are benign tumors, those measuring larger than 6 cm are prone to rupture and hemorrhage. Thorough endocrine work-up may benefit a selected group of patients, especially those who are hypertensive, diabetic/pre-diabetic, young patients (<50 years) and those with bilateral AML. Regular observation is needed for AML patients who are being treated non-operatively, as many of them may require surgery during follow-up. Although the AACE/AAES guidelines for AI (2009) exclude AML from mandatory metabolic work-up for a newly discovered AI, we feel that a significant number of patients with AML would benefit from metabolic work-up. In the literature, endocrine dysfunction in AML is 7% as compared with 11% in AI. Endocrine dysfunction in AML is probably underdiagnosed.


wingless refines its own expression domain on the Drosophila wing margin.
The imaginal discs of Drosophila, which give rise to the adult appendages, are patterned during a period of intense cell proliferation. The specification of differing regions occurs in some cases by subdividing the disc epithelium into lineage compartments. However, in most cases precise boundaries are formed between different cell types without early compartmentalization. One such boundary occurs between the wingless (wg)-expressing cells of the wing margin and the adjacent proneural cells, which give rise to margin sensory bristles. Here we show that this boundary arises in part by a mechanism of 'self-refinement', by which wingless protein (Wg) represses wg expression in adjacent cells. Cells unable to receive the Wg signal do not resolve the boundary between wg-expressing and proneural cells.


Serum apoptotic caspase activity as a marker of severity in HBeAg-negative chronic hepatitis B virus infection.
In chronic hepatitis C and non-alcoholic fatty liver disease, apoptotic caspases are activated in liver, and serum caspase activity has been suggested as a sensitive marker of early liver injury. An investigation was carried out into whether the serum levels of caspase-generated fragments of cytokeratin-18 (CK-18) are associated with the severity of liver lesions in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B virus (HBV) infection. Patients/ CK-18 fragment serum levels were determined in 115 treatment-naive, consecutive HBV patients and 30 healthy controls. Hepatic-expression of CK-18 fragments was evaluated by immunocytochemistry in chronic hepatitis B patients. CK-18 fragment levels (U/l) were significantly lower in healthy controls (mean (SD), 154 (31)) than in 53 inactive carriers (172 (24), p = 0.003) and in 62 chronic hepatitis B patients (474 (488), p<0.001). The receiver operating characteristic curve showed excellent diagnostic accuracy (c-statistic: 0.87) for differentiating inactive carriers from chronic hepatitis B patients. A CK-18 fragment cut-off level of 240 U/l gave a sensitivity of 60%, and a specificity and positive predictive value of 100% for chronic hepatitis B diagnosis. CK-18 fragment levels were also lower in inactive carriers than in 16 chronic hepatitis B patients with transiently normal alanine aminotransferase (ALT; 327 (256), p = 0.001), offering good accuracy for such a differentiation (c-statistic: 0.78). In chronic hepatitis B patients, serum CK-18 fragments correlated positively with ALT/aspartate aminotransferase (AST), viraemia, grading score and their immunohistochemical hepatic expression, and negatively with platelet counts, but not with fibrosis or steatosis severity. Serum apoptotic caspase activity is strongly associated with the presence of liver injury in patients with HBeAg-negative chronic HBV infection. CK-18 fragment levels seem to be a very useful marker for differentiation between the inactive HBV carrier state and HBeAg-negative chronic hepatitis B, but not for estimation of the severity of liver histological lesions among HBeAg-negative chronic hepatitis B patients.


The viability of an ecologically valid chronic sleep restriction and circadian timing protocol: An examination of sample attrition, compliance, and effectiveness at impacting sleepiness and mood.
Chronic sleep restriction (SR) increases sleepiness, negatively impacts mood, and impairs a variety of cognitive performance measures. The vast majority of work establishing these effects are tightly controlled in-lab experimental studies. Examining commonly-experienced levels of SR in naturalistic settings is more difficult and generally involves observational methods, rather than active manipulations of sleep. The same is true for analyzing behavioral and cognitive outcomes at circadian unfavorable times. The current study tested the ability of an at-home protocol to manipulate sleep schedules (i.e., impose SR), as well as create a mismatch between a subject's circadian preference and time of testing. Viability of the protocol was assessed via completion, compliance with the SR, and success at manipulating sleepiness and mood. An online survey was completed by 3630 individuals to assess initial eligibility, 256 agreed via email response to participate in the 3-week study, 221 showed for the initial in-person session, and 184 completed the protocol (175 with complete data). The protocol consisted of 1 week at-home SR (5-6 hours in bed/night), 1 week wash-out, and 1 week well-rested (WR: 8-9 hours in bed/night). Sleep was monitored with actigraphy, diary, and call-ins. Risk management strategies were implemented for subject safety. At the end of each experimental week, subjects reported sleepiness and mood ratings. Protocol completion was 83%, with lower depression scores, higher anxiety scores, and morning session assignment predicting completion. Compliance with the sleep schedule was also very good. Subjects spent approximately 2 hours less time in bed/night and obtained an average of 1.5 hours less nightly sleep during SR, relative to WR, with 82% of subjects obtaining at least 60 minutes less average nightly sleep. Sleepiness and mood were impacted as expected by SR. These findings show the viability of studying experimental chronic sleep restriction outside the laboratory, assuming appropriate safety precautions are taken, thus allowing investigators to significantly increase ecological validity over strictly controlled in-lab studies.


Modal properties and thermal behaviors of high quality factor quasi-photonic crystal microcavity.
We investigate the variations of modal properties of 12-fold quasi-photonic crystal microcavities sustaining whispering-gallery (WG) mode with different central post sizes both in simulations and experiments. We realize our design by a series of dry- and wet-etching processes. WG mode lasing actions are obtained with high quality (Q) factor of 8,400 from microcavity with effective post size 420 nm in diameter. Loss and thermal behaviors are analyzed by measured Q factors, thresholds, and rolling-off effects from light-in light-out curves of microcavities with increased post size. By finite-element simulations, we also address the heat sink improvement due to presence of larger central post that is observed in measurements.


Systematic analysis of Plasmodium myosins reveals differential expression, localisation, and function in invasive and proliferative parasite stages.
The myosin superfamily comprises of actin-dependent eukaryotic molecular motors important in a variety of cellular functions. Although well studied in many systems, knowledge of their functions in Plasmodium, the causative agent of malaria, is restricted. Previously, six myosins were identified in this genus, including three Class XIV myosins found only in Apicomplexa and some Ciliates. The well characterized MyoA is a Class XIV myosin essential for gliding motility and invasion. Here, we characterize all other Plasmodium myosins throughout the parasite life cycle and show that they have very diverse patterns of expression and cellular location. MyoB and MyoE, the other two Class XIV myosins, are expressed in all invasive stages, with apical and basal locations, respectively. Gene deletion revealed that MyoE is involved in sporozoite traversal, MyoF and MyoK are likely essential in the asexual blood stages, and MyoJ and MyoB are not essential. Both MyoB and its essential light chain (MCL-B) are localised at the apical end of ookinetes but expressed at completely different time points. This work provides a better understanding of the role of actomyosin motors in Apicomplexan parasites, particularly in the motile and invasive stages of Plasmodium during sexual and asexual development within the mosquito.


Dizziness reported by elderly patients in family practice: prevalence, incidence, and clinical characteristics.
Although dizziness in elderly patients is very common in family practice, most prevalence studies on dizziness are community-based and include a study population that is not representative of family practice. The aim of this study was to investigate the prevalence and incidence of dizziness reported by elderly patients in family practice, to describe their final diagnoses as recorded by the family physician, and to compare the clinical characteristics of dizzy patients with those of non-dizzy patients. Data were obtained from the Second Dutch National Survey of General Practice, a prospective registration study which took place over a 12-month period in 2001. We developed a search strategy consisting of 15 truncated search terms (based on Dutch synonyms for dizziness), and identified all patients aged 65 or older who visited their family physician because of dizziness (N = 3,990). We used the mid-time population as denominator to calculate the prevalence and incidence, and for group comparisons we used the Student's t and Chi-square test, and logistic regression analysis. The one-year prevalence of dizziness in family practice in patients aged 65 or older was 8.3%, it was higher in women than in men, and it increased with age. In patients aged 85 or older the prevalence was similar for men and women. The incidence of dizziness was 47.1 per 1000 person-years. For 39% of the dizzy patients the family physicians did not specify a diagnosis, and recorded a symptom diagnosis as the final diagnosis. Living alone, lower level of education, pre-existing cerebrovascular disease, and pre-existing hypertension were independently associated with dizziness. Dizziness in family practice patients increases with age. It is more common in women than in men, but this gender difference disappears in the very old. Because a large proportion of dizzy elderly patients in family practice remains undiagnosed, it would be worthwhile to carry out more diagnostic research on dizziness in a family practice setting.


Benign breast and gynecologic conditions, reproductive and hormonal factors, and risk of thyroid cancer.
The higher incidence of thyroid cancer in women compared with men suggests an influence of sex steroid hormones in the etiology of this malignancy. We investigated a comprehensive set of potential indicators of lifetime sex steroid hormone exposure in relation to thyroid cancer risk. Using data from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, which enrolled 70,047 women, 50 to 78 years old, we prospectively examined associations of self-reported history of benign breast and gynecologic conditions, reproductive factors, and exogenous sex hormone use with thyroid cancer risk. Multivariable-adjusted HRs and 95% confidence intervals (CI) were calculated in models using age as the time metric. During follow-up (median, 11 years), 127 women were diagnosed with first primary thyroid cancer. Older age at natural menopause (≥55 vs. <50 years; HR, 2.24; 95% CI, 1.20-4.18), greater estimated lifetime number of ovulatory cycles (≥490 vs. <415 cycles; HR, 2.40; 95% CI, 1.33-4.30), greater number of live births (≥5 vs. 1-2; HR, 1.72; 95% CI, 1.05-2.82), and history of uterine fibroids (HR, 1.72; 95% CI, 1.18-2.50) were associated with an increased risk of thyroid cancer. Earlier age at menarche, greater number of reproductive years, history of a tubal ligation, and history of ovarian cysts were nonsignificantly associated with increased thyroid cancer risk. No associations were observed for oral contraceptive use, menopausal hormone therapy, or history of benign breast disease or endometriosis. In general, we found that factors reflecting a greater length of exposure to endogenous hormones, particularly during the reproductive years, were associated with risk of postmenopausal thyroid cancer.


Glycogen availability and skeletal muscle adaptations with endurance and resistance exercise.
It is well established that glycogen depletion affects endurance exercise performance negatively. Moreover, numerous studies have demonstrated that post-exercise carbohydrate ingestion improves exercise recovery by increasing glycogen resynthesis. However, recent research into the effects of glycogen availability sheds new light on the role of the widely accepted energy source for adenosine triphosphate (ATP) resynthesis during endurance exercise. Indeed, several studies showed that endurance training with low glycogen availability leads to similar and sometimes even better adaptations and performance compared to performing endurance training sessions with replenished glycogen stores. In the case of resistance exercise, a few studies have been performed on the role of glycogen availability on the early post-exercise anabolic response. However, the effects of low glycogen availability on phenotypic adaptations and performance following prolonged resistance exercise remains unclear to date. This review summarizes the current knowledge about the effects of glycogen availability on skeletal muscle adaptations for both endurance and resistance exercise. Furthermore, it describes the role of glycogen availability when both exercise modes are performed concurrently.


A PY-NLS nuclear targeting signal is required for nuclear localization and function of the Saccharomyces cerevisiae mRNA-binding protein Hrp1.
Proteins destined for import into the nucleus contain nuclear localization signals (NLSs) that are recognized by import receptors termed karyopherins or importins. Until recently, the only nuclear import sequence that had been well defined and characterized was the classical NLS (cNLS), which is recognized by importin alpha. However, Chook and coworkers (Lee, B. J., Cansizoglu, A. E., Süel, K. E., Louis, T. H., Zhang, Z., and Chook, Y. M. (2006) Cell 126, 543-558) have provided new insight into nuclear targeting with their identification of a novel NLS, termed the PY-NLS, that is recognized by the human karyopherin beta2/transportin (Kapbeta2) receptor. Here, we demonstrate that the PY-NLS is conserved in Saccharomyces cerevisiae and show for the first time that the PY-NLS is a functional nuclear targeting sequence in vivo. The apparent ortholog of Kapbeta2 in yeast, Kap104, has two known cargos, the mRNA-binding proteins Hrp1 and Nab2, which both contain putative PY-NLS-like sequences. We find that the PY-NLS-like sequence within Hrp1, which closely matches the PY-NLS consensus, is both necessary and sufficient for nuclear import and is also required for receptor binding and protein function. In contrast, the PY-NLS-like sequences in Nab2, which vary from the PY-NLS consensus, are not required for proper import or protein function, suggesting that Kap104 may interact with different cargos using multiple mechanisms. Dissection of the PY-NLS consensus reveals that the minimal PY-NLS in yeast consists of the C-terminal portion of the human consensus, R/H/KX(2-5)PY, with upstream basic or hydrophobic residues enhancing the targeting function. Finally, we apply this analysis to a bioinformatic search of the yeast proteome as a preliminary search for new potential Kap104 cargos.


Bridging the gap between single molecule and ensemble methods for measuring lateral dynamics in the plasma membrane.
The lateral dynamics of proteins and lipids in the mammalian plasma membrane are heterogeneous likely reflecting both a complex molecular organization and interactions with other macromolecules that reside outside the plane of the membrane. Several methods are commonly used for characterizing the lateral dynamics of lipids and proteins. These experimental and data analysis methods differ in equipment requirements, labeling complexities, and further oftentimes give different results. It would therefore be very convenient to have a single method that is flexible in the choice of fluorescent label and labeling densities from single molecules to ensemble measurements, that can be performed on a conventional wide-field microscope, and that is suitable for fast and accurate analysis. In this work we show that k-space image correlation spectroscopy (kICS) analysis, a technique which was originally developed for analyzing lateral dynamics in samples that are labeled at high densities, can also be used for fast and accurate analysis of single molecule density data of lipids and proteins labeled with quantum dots (QDs). We have further used kICS to investigate the effect of the label size and by comparing the results for a biotinylated lipid labeled at high densities with Atto647N-strepatvidin (sAv) or sparse densities with sAv-QDs. In this latter case, we see that the recovered diffusion rate is two-fold greater for the same lipid and in the same cell-type when labeled with Atto647N-sAv as compared to sAv-QDs. This data demonstrates that kICS can be used for analysis of single molecule data and furthermore can bridge between samples with a labeling densities ranging from single molecule to ensemble level measurements.


Differential Effects of Lithium Chloride on In Vitro Growth of Clavibacter michiganense subsp. nebraskense Depending upon Inoculum Source.
The bacterium Clavibacter michiganense subsp. nebraskense (Corynebacterium michiganense subsp. nebraskense) was grown in broth cultures and inoculated into corn plants. The plating efficiency of cells from broth cultures was essentially the same on nutrient broth-yeast extract and the semiselective medium for this bacterium, CNS. However, when cells were isolated from Goss bacterial wilt- and blight-infected corn, very few were recovered on CNS compared with the amount recovered on nutrient broth-yeast extract agar. When lithium chloride was omitted from the CNS, recoveries from infected corn were nearly the same as on nutrient broth-yeast extract agar. No other ingredient of CNS was inhibitory, nor did substitution of other salts for lithium chloride cause equal inhibition. The amount of inhibition was proportional to lithium chloride concentration. The inhibition by lithium chloride occurred with several strains of the bacterium isolated from one corn cultivar and with one of the strains recovered from three different cultivars of infected corn.


Effect of balneotherapy in sulfurous water on an in vivo murine model of osteoarthritis.
Osteoarthritis (OA) is a chronic joint disease that results in progressive cartilage destruction and subsequently joint dysfunction. Growing evidence indicates beneficial impact of balneological interventions in OA; however, their mechanisms of action are still unclear. Here, we evaluate the effect of balneotherapy in sulfurous water in an OA experimental model. Experimental OA was induced in Wistar rats by transection of the medial collateral ligament and removal of the medial meniscus of the left knee. Animals were randomized into three groups: non-treated (control) and balneotherapy using sulfurous water (SW) or tap water (TW). Macroscopic evaluation was performed, as well as evaluation of pain levels and analysis of motor function by rotarod test. Histopathological changes in articular cartilage and synovium were also evaluated. The presence of matrix metalloproteinase-13 (MMP-13) and oxidative damage markers was assessed by immunohistochemistry. Joint destabilization induced joint thickening, loss of joint flexion, and increased levels of pain. At day 40, animals from SW group presented lower pain levels than those from control group. Experimental OA also affected motor function. Balneotherapy in sulfur-rich water significantly improved joint mobility in relation to that in tap water. Besides, we observed that cartilage deterioration was lower in SW group than in the other two groups. Likewise, SW group showed reduced levels of MMP-13 in the cartilage. Conversely, we failed to observe any modulation on synovial inflammation. Finally, balneotherapy in sulfurous water diminished the presence of oxidative damage markers. Our results suggest the beneficial effect of balneotherapy in sulfur-rich water on an experimental model of OA, showing a reduced cartilage destruction and oxidative damage. Thus, these findings support the use of balneotherapy as a non-pharmacological treatment in OA.


Consequences of defaunation for a tropical tree community.
Hunting affects a considerably greater area of the tropical forest biome than deforestation and logging combined. Often even large remote protected areas are depleted of a substantial proportion of their vertebrate fauna. However, understanding of the long-term ecological consequences of defaunation in tropical forests remains poor. Using tree census data from a large-scale plot monitored over a 15-year period since the approximate onset of intense hunting, we provide a comprehensive assessment of the immediate consequences of defaunation for a tropical tree community. Our data strongly suggest that over-hunting has engendered pervasive changes in tree population spatial structure and dynamics, leading to a consistent decline in local tree diversity over time. However, we do not find any support for suggestions that over-hunting reduces above-ground biomass or biomass accumulation rate in this forest. To maintain critical ecosystem processes in tropical forests increased efforts are required to protect and restore wildlife populations.


The key role of vitamin A in spermatogenesis.
Spermatogenesis in adult mammals is highly organized, with the goal being continual sperm production. Vertebrate testes are arranged into recurring cellular associations that vary with time and distance along the tubule. These changes over time and distance are designated the cycle of the seminiferous epithelium and the spermatogenic wave, respectively. In this Review, we briefly outline the roles that follicle-stimulating hormone (FSH) and testosterone play in regulating spermatogenesis and describe our current understanding of how vitamin A regulates germ cell differentiation and how it may lead to the generation of both the cycle of the seminiferous epithelium and the spermatogenic wave.


A quantitative test to estimate neutralizing antibodies to the hepatitis C virus: cytofluorimetric assessment of envelope glycoprotein 2 binding to target cells.
Hepatitis C virus (HCV) is a major cause of chronic hepatitis. The virus does not replicate efficiently in cell cultures, and it is therefore difficult to assess infection-neutralizing antibodies and to evaluate protective immunity in vitro. To study the binding of the HCV envelope to cell-surface receptors, we developed an assay to assess specific binding of recombinant envelope proteins to human cells and neutralization thereof. HCV recombinant envelope proteins expressed in various systems were incubated with human cells, and binding was assessed by flow cytometry using anti-envelope antibodies. Envelope glycoprotein 2 (E2) expressed in mammalian cells, but not in yeast or insect cells, binds human cells with high affinity (Kd approximately 10(-8) M). We then assessed antibodies able to neutralize E2 binding in the sera of both vaccinated and carrier chimpanzees, as well as in the sera of humans infected with various HCV genotypes. Vaccination with recombinant envelope proteins expressed in mammalian cells elicited high titers of neutralizing antibodies that correlated with protection from HCV challenge. HCV infection does not elicit neutralizing antibodies in most chimpanzees and humans, although low titers of neutralizing antibodies were detectable in a minority of infections. The ability to neutralize binding of E2 derived from the HCV-1 genotype was equally distributed among sera from patients infected with HCV genotypes 1, 2, and 3, demonstrating that binding of E2 is partly independent of E2 hypervariable regions. However, a mouse monoclonal antibody raised against the E2 hypervariable region 1 can partially neutralize binding of E2, indicating that at least two neutralizing epitopes, one of which is hypervariable, should exist on the E2 protein. The neutralization-of-binding assay described will be useful to study protective immunity to HCV infection and for vaccine development.


Effect of acute ammonia intoxication on cerebral metabolism in rats with portacaval shunts.
Rats were made chronically hyperammonemic by portal-systemic shunting and, 8 wk later, were subjected to acute ammonia intoxication by the intraperitoneal injection of 5.2 mmol/kg of ammonium acetate. In free-ranging animals, ammonia treatment induced a brief period of precoma (10-15 min) that progressed into deep, anesthetic coma lasting for several hours and was associated with a high mortality. In paralyzed, artificially ventilated animals that were lightly anesthetized with nitrous oxide, acute ammonia intoxication caused major disturbances of cerebral carbohydrate, amino acid, and energy metabolism that correlated in time with the change in functional state. At 10 min after injection (precoma), the concentrations of most glycolytic intermediates were increased, as was the lactate/pyruvate ratio. Citrate declined, despite a twofold rise in pyruvate, suggesting that the conversion of pyruvate to citrate had been impaired. Concentrations of phosphocreatine, and of the putative neurotransmitters, glutamate and aspartate, declined during precoma, but the concentrations of the adenine nucleotides in the cerebral hemispheres, cerebellum, and brain stem remained within normal limits. At 60 min after injection (coma), ATP declined in all regions of brain; the reduction in total high-energy phosphates was most notable in the brain stem. The findings indicate that cerebral dysfunction in chronic, relapsing ammonia intoxication is not due to primary energy failure. Rather, it is suggested that ammonia-induced depletion of glutamic and aspartic acids, and inhibition of the malate-asparate hydrogen shuttle are the dominant neurochemical lesions.


Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism.
Accumulating evidence suggests that progenitor cells may decrease destructive inflammation and reduce tissue loss by antiapoptotic mechanisms. However, they remain poorly characterized, and many questions remain regarding the mechanisms by which they may positively affect wound healing, tissue remodeling, or tissue regeneration. It has been speculated that various growth factors are responsible, but what components of the wound milieu stimulate progenitor cell production of growth factors and by what mechanisms? We hypothesized that tumor necrosis factor-alpha (TNF-alpha) stimulated progenitor cell secretion of vascular endothelial growth factor (VEGF), hepatocyte growth factor (HGF), and insulin-like growth factor I (IGF-I) by a p38 mitogen-activated protein kinase (MAPK)-dependent mechanism. Human mesenchymal stem cells (hMSCs) and human adipose progenitor cells (hAPCs) were divided into four groups: control, p38 MAPK inhibitor (p38MKI), TNF, and TNF + p38MKI. After 24 h of incubation, supernatants were harvested for ELISA of VEGF, HGF, and IGF-I. Cells were collected for Western blot analysis of p38 MAPK activation. Secretion of VEGF, HGF, and IGF-I in hMSCs and hAPCs was significantly increased by stimulation with TNF and was associated with increased activation of p38 MAPK. The p38 MAPK inhibitor decreased production of TNF-stimulated VEGF, HGF, and IGF-I in hMSCs and hAPCs. However, p38 MAPK inhibitor alone had no effect on production of growth factors. These data demonstrate that progenitor cells are potent sources of VEGF, HGF, and IGF-I. TNF, a prominent tissue cytokine, strongly stimulated production of growth factors by hMSCs and hAPCs via a p38 MAPK-dependent mechanism.


EphrinB2 signaling in osteoblasts promotes bone mineralization by preventing apoptosis.
Cells that form bone (osteoblasts) express both ephrinB2 and EphB4, and previous work has shown that pharmacological inhibition of the ephrinB2/EphB4 interaction impairs osteoblast differentiation in vitro and in vivo. The purpose of this study was to determine the role of ephrinB2 signaling in the osteoblast lineage in the process of bone formation. Cultured osteoblasts from mice with osteoblast-specific ablation of ephrinB2 showed delayed expression of osteoblast differentiation markers, a finding that was reproduced by ephrinB2, but not EphB4, RNA interference. Microcomputed tomography, histomorphometry, and mechanical testing of the mice lacking ephrinB2 in osteoblasts revealed a 2-fold delay in bone mineralization, a significant reduction in bone stiffness, and a 50% reduction in osteoblast differentiation induced by anabolic parathyroid hormone (PTH) treatment, compared to littermate sex- and age-matched controls. These defects were associated with significantly lower mRNA levels of late osteoblast differentiation markers and greater levels of osteoblast and osteocyte apoptosis, indicated by TUNEL staining and transmission electron microscopy of bone samples, and a 2-fold increase in annexin V staining and 7-fold increase in caspase 8 activation in cultured ephrinB2 deficient osteoblasts. We conclude that osteoblast differentiation and bone strength are maintained by antiapoptotic actions of ephrinB2 signaling within the osteoblast lineage.


Pharmacodynamics of doxorubicin in human bladder tumors.
Intravesical doxorubicin treatment delivers high drug concentrations to the bladder wall, yet the treatment produces only a variable and incomplete response in superficial bladder cancer and insignificant activity in muscle-invading disease. This study evaluated the pharmacological basis for the clinical observations and potential prognostic indicators of tumor sensitivity to doxorubicin. The pharmacodynamics of doxorubicin were studied using histocultures of surgical specimens of seven superficial (Ta and T1) and nine invasive (T2-T4) tumors. After a 2-h exposure, drug treatment caused a concentration-dependent inhibition of proliferation, as measured by bromodeoxyuridine incorporation into DNA. Extensive cell death was observed at high concentrations (>10 micrometer) in sensitive tumors. The IC50 values ranged from 0.14 to 5.2 micrometer for superficial tumors and from 1.4 to >100 micrometer for invasive tumors. A comparison of the IC50 and IC90 values with the drug concentrations previously determined in human bladder walls showed that IC50 was achieved in all Ta tumors, 67-100% of T1 tumors, and one of the nine invasive tumors, whereas IC90 was achieved in all Ta tumors but none of the other tumors. To determine the biological basis of variable doxorubicin sensitivity among different tumors, we examined the relationship of chemosensitivity with tumor pathology and with expression of multidrug resistance p-glycoprotein (Pgp) and p53 protein. The invasive, high-grade, highly proliferative, p53- and Pgp-positive tumors were more resistant than the superficial, lower-grade, p53- and Pgp-negative tumors. All tumors were negative for bcl-2. The rank order of these factors was p53 expression > tumor stage > grade > bromodeoxyuridine labeling index > Pgp. Statistical analysis using the Akaike Information Criterion indicates that the two-parameter combination of p53 expression with stage further improved the predictive value. The present study shows that: (a) there was a >700-fold difference in doxorubicin sensitivity among superficial and invasive tumors; (b) the variable and incomplete response of superficial bladder cancer to intravesical doxorubicin therapy is likely due to the 35-fold variability in tumor chemosensitivity and, to a lesser degree, the 4-fold variability in tissue pharmacokinetics; (c) the lack of response of invasive cancer to intravesical doxorubicin therapy is likely the result of the inadequate drug concentrations presented to the deep muscle layers and the low chemosensitivity of the more aggressive tumors; and (d) the combination of p53 expression and high stage was the most significant predictor of doxorubicin sensitivity, whereas Pgp expression was the least important.


Active Gaming Among High School Students--United States, 2010.
Our study is the first to describe the prevalence and correlates (demographics, body mass index [BMI], sedentary behaviors, and physical activity) of high school youth who report active videogame playing (active gaming) in a U.S. representative sample. The National Youth Physical Activity and Nutrition Study of 2010 provided data for this study. Active gaming was assessed as the number of days in the 7 days prior to the survey that students in grades 9-12 (14-18 years of age) reported participating in active videogames (e.g., "Wii™ Fit" [Nintendo, Kyoto, Japan], "Dance Dance Revolution" [Konami, Osaka, Japan]). Students reporting ≥1 days were classified as active gamers. Logistic regression was used to examine the association among active gaming and demographic characteristics, BMI, sedentary behaviors, and physical activity. Among 9125 U.S. high school students in grades 9-12 surveyed, 39.9 percent (95 percent confidence interval=37.9 percent, 42.0 percent) reported active gaming. Adjusting for covariates, the following characteristics were positively associated (P<0.05) with active gaming: being in 9th and 10th grades compared with being in 12th grade; being of black, non-Hispanic race/ethnicity; being overweight or obese; watching DVDs >0 hours/day; watching TV >0 hours/day; and meeting guidelines for aerobic and muscle-strengthening physical activity. Four out of 10 U.S. high school students report participating in active gaming. Active gamers tend to spend more time watching DVDs or TV, meet guidelines for physical activity, and/or be overweight or obese compared with nonactive gamers. These findings may serve to provide a baseline to track active gaming in U.S. youth and inform interventions that target sedentary behaviors and/or physical activity.


Current trends in etiology, prognosis and therapeutic aspects of Parkinson's disease: a review.
Parkinson's disease (PD) is a movement disorder, mainly affecting population consisting of the aged. PD occurs chiefly due to progressive loss of dopaminergic neurons in nigrostriatal pathway. Largely, PD patients suffer from non-motor symptoms, such as depression, anxiety, fatigue, and sleep disorders, that needs further investigation and addressing during PD research. Depression in PD is a predominant and complex symptom, and its pathology exists extrinsic to the nigrostriatal system. This disease can ultimately be managed by a combination of regular physiotherapy and proper medication. Taking together the present scenario of PD, including the nature of disease, characteristics, treatment, diagnosis of the patients with PD, these outcomes were reviewed to be explored along with many speech-based solutions to PD in this study. This neurodegenerative disorder needs advancement in research and development which can help patients with PD to lead a normal life.


Caries prevalence in 2-year-old children in the city of Zurich.
To establish caries prevalence in 2-year-olds in the city of Zurich; and to investigate the relationship between caries prevalence and dietary habits, and oral hygiene practices in native children and children with immigrant background. 1,000 randomly selected 2-year-olds were invited to participate in a clinical examination, at which parents were interviewed about the child's oral hygiene and dietary habits. Caries diagnosis was based on visual inspection of all tooth surfaces and included both initial (d1) and cavitated (d2) lesions. Univariate and multivariate logistic regressions for two subgroups of children (children of Swiss and foreign-born mothers) were performed in order to assess the association between predictor variables and caries. 771 children were examined (participation rate 78%; mean age 2.4 years (age range 2.06-2.90 years)). Although the majority (94%) was born in Switzerland, 61% of children had immigrant backgrounds (mother not born in Switzerland). Cavitated teeth (d2mft) were observed in 12.6% of children (95% CI: 10.4-15.1%). Caries including initial lesions (dl2mft) affected 25.3% of children (95% CI: 22.4-28.5%). There were 34 (4.4%) children with severe caries (all maxillary incisors cavitated). For children with caries, the mean d2mft was 4.3 (+/- 2.8). Children with foreign-born mothers (mothers not born in Switzerland) exhibited a significantly higher caries prevalence than those with Swiss-born mothers (17.4% versus 5.0% with d2mft > 0). Children with foreign-born mothers exhibited significantly higher caries prevalence rates than those with Swiss-born mothers. Poor oral hygiene and night-time bottle use were identified as risk indicators for caries in all children. Further risk indicators identified in children of foreign-born mothers were a preference for sugar-containing non-milk drinks, no pacifier use, child's age and male gender.


Surgeon Procedure Volume and Complication Rates in Anterior Cervical Discectomy and Fusions: Analysis of a National Longitudinal Database.
Retrospective study using the MarketScan longitudinal database (2006-2010). Compare complication rates between groups of patients undergoing anterior cervical discectomy and fusion (ACDF) procedures performed by surgeons with high versus low mean annual ACDF volume. Over the past decade the volume of ACDFs performed has increased, concurrent with greater appreciation of potential for associated complications. The effect of surgeon procedure volume on adverse events occurrence in the postoperative period has not been described. We evaluated the relationship between surgeon procedure volume and postoperative incidence of any complication using a multivariate logistic regression model. A total of 24,461 patients undergoing single and multiple level ACDFs were identified in the MarketScan database by Current Procedural Terminology coding. Annual surgeon volume was determined by tracking of anonymized surgeon identification numbers, with high-volume surgeons defined as those performing an average of at least 30 ACDF procedures annually. Over 50% of unique surgeon identifiers reported <9 ACDF operations per year, whereas the highest decile reported a range of 44-101. High surgeon volume was protective for any complication [odds ratio (OR), 72; 95% confidence interval, 0.65-0.81; P<0.0001], with an adjusted number needed to harm of 44. Patients treated by high-volume physicians specifically had lower odds of dysphagia (2.22% vs. 3.08%; OR, 0.71; P<0.0013), neurological complications (0.33% vs. 0.64%; OR, 0.52; P<0.0107), new diagnosis of chronic pain (0.48% vs. 0.82%; OR, 0.58; P<0.0119), pulmonary complications (1.10% vs. 1.58%; OR, 0.69; P<0.0138), and other wound complications (0.06% vs. 0.22%; OR, 0.28; P<0.0242). We demonstrate a possible association between higher surgeon procedure volume and decreased postoperative complications after ACDF. There was no difference observed in need for revision surgery or readmission rates.


Increased CYFIP1 dosage alters cellular and dendritic morphology and dysregulates mTOR.
Rare maternally inherited duplications at 15q11-13 are observed in ~1% of individuals with an autism spectrum disorder (ASD), making it among the most common causes of ASD. 15q11-13 comprises a complex region, and as this copy number variation encompasses many genes, it is important to explore individual genotype-phenotype relationships. Cytoplasmic FMR1-interacting protein 1 (CYFIP1) is of particular interest because of its interaction with Fragile X mental retardation protein (FMRP), its upregulation in transformed lymphoblastoid cell lines from patients with duplications at 15q11-13 and ASD and the presence of smaller overlapping deletions of CYFIP1 in patients with schizophrenia and intellectual disability. Here, we confirm that CYFIP1 is upregulated in transformed lymphoblastoid cell lines and demonstrate its upregulation in the post-mortem brain from 15q11-13 duplication patients for the first time. To investigate how increased CYFIP1 dosage might predispose to neurodevelopmental disease, we studied the consequence of its overexpression in multiple systems. We show that overexpression of CYFIP1 results in morphological abnormalities including cellular hypertrophy in SY5Y cells and differentiated mouse neuronal progenitors. We validate these results in vivo by generating a BAC transgenic mouse, which overexpresses Cyfip1 under the endogenous promotor, observing an increase in the proportion of mature dendritic spines and dendritic spine density. Gene expression profiling on embryonic day 15 suggested the dysregulation of mammalian target of rapamycin (mTOR) signaling, which was confirmed at the protein level. Importantly, similar evidence of mTOR-related dysregulation was seen in brains from 15q11-13 duplication patients with ASD. Finally, treatment of differentiated mouse neuronal progenitors with an mTOR inhibitor (rapamycin) rescued the morphological abnormalities resulting from CYFIP1 overexpression. Together, these data show that CYFIP1 overexpression results in specific cellular phenotypes and implicate modulation by mTOR signaling, further emphasizing its role as a potential convergent pathway in some forms of ASD.


A qualitative analysis of virtual patient descriptions in healthcare education based on a systematic literature review.
Virtual Patients (VPs) have been in the focus of research in healthcare education for many years. The aim of our study was to analyze how virtual patients are described in the healthcare education literature, and how the identified concepts relate to each other. We performed a literature review and extracted 185 descriptions of virtual patients from the articles. In a qualitative content analysis approach we inductively-deductively developed categories and deducted subcategories. We constructed a concept map to illustrate these concepts and their interrelations. We developed the following five main categories: Patient, Teacher, Virtual Patient, Curriculum, and Learner. The concept map includes these categories and highlights aspects such as the under-valued role of patients in shaping their virtual representation and opposing concepts, such as standardization of learner activity versus learner-centeredness. The presented concept map synthesizes VP descriptions and serves as a basis for both, VP use and discussions of research topics related to virtual patients.


Limits on the high-energy gamma and neutrino fluxes from the SGR 1806-20 giant flare of 27 December 2004 with the AMANDA-II detector.
On 27 December 2004, a giant gamma flare from the Soft Gamma-Ray Repeater 1806-20 saturated many satellite gamma-ray detectors, being the brightest transient event ever observed in the Galaxy. AMANDA-II was used to search for down-going muons indicative of high-energy gammas and/or neutrinos from this object. The data revealed no significant signal, so upper limits (at 90% C.L.) on the normalization constant were set: 0.05(0.5) TeV-1 m;{-2} s;{-1} for gamma=-1.47 (-2) in the gamma flux and 0.4(6.1) TeV-1 m;{-2} s;{-1} for gamma=-1.47 (-2) in the high-energy neutrino flux.


Isolation of Brucella ceti from a Long-finned Pilot Whale (Globicephala melas) and a Sowerby's Beaked Whale (Mesoploden bidens).
Brucella ceti is an emerging zoonotic pathogen that has been recovered from several species of cetaceans in the world's oceans over the past 20 yr. We report the recovery of B. ceti from a Sowerby's beaked whale (Mesoploden bidens) and a long-finned pilot whale (Globicehala melas). Recovery from the testis of a long-finned pilot whale provides further evidence of potential for B. ceti infection to impact the reproductive success of cetaceans, many of which are threatened species. The addition of another two cetacean species to the growing number from which B. ceti has been recovered also further emphasizes the concern for human infections with this organism.


Exploring opportunities to project a "responsible man" image: gatekeepers views of young men's sexual and reproductive health needs in Uttaranchal, India.
Increase in extramarital sex among youths, gender-based violence, lack of contraceptive knowledge among newly married couples and lack of knowledge of protection against diseases like STIs/HIV are the information and service needs of young people that need to be addressed urgently in order to make them future knowledgeable, responsible, and non-violent partners. In addressing these needs the gatekeepers, including parents, formal and informal community leaders and teachers, play a critical role, by facilitating/hindering access to appropriate and correct information about sexual and reproductive health to young people. The study was conducted in a district of Uttaranchal, India. The specific objective was to understand the social context and gatekeepers' views on family planning and sexual and reproductive health needs of young men. Thirty-two in-depth interviews and four focus group discussions were conducted with parents, formal and informal community leaders, teachers, and selected development officials. The findings indicate that gatekeepers are worried about rapid changes in the aspiration, expectation, and behavior of young men. Most of them were seriously concerned about the increasing drinking habit, use of drugs, and changing values of sexuality leading to various risk behaviors among young men. They felt that many of these changes are consequences of wider societal changes, rising aspirations, explosion of electronic media, and globalization of a new youth culture where extramarital sex, alcohol consumption, and violence are expressions of different facets of masculinity and symbols of the affluent class. Overall, there was a feeling that TV/films and their peers now influence more the socialization of young people and parents are losing control in guidance and mentoring of their children.


Performance of simultaneous cardiac-respiratory self-gated three-dimensional MR imaging of the heart: initial experience.
This study was approved by the local institutional ethics committee, and informed consent was obtained from all volunteers and patients. The objective of the present study was to assess the performance of high-spatial-resolution three-dimensional prospective cardiac-respiratory self-gated (CRSG) magnetic resonance (MR) imaging for determining left ventricular (LV) volumes and mass, as well as right ventricular (RV) volumes, in comparison with standard electrocardiography (ECG)-triggered, two-dimensional multisection, multiple-breath-hold cine imaging. The self-gated method derives cardiac triggering and respiratory gating information prospectively on the basis of additional MR imaging signals acquired in every repetition time and, thereby, eliminates the need for ECG triggering and multiple-breath-hold procedures. Data were acquired in 15 healthy volunteers (mean age, 27.2 years +/- 7.2 [standard deviation]) and 11 patients (mean age, 60.7 years +/- 11.3). The bias between the self-gating and the reference imaging techniques was minimal for all LV and RV parameters (mean values: LV end-diastolic volume, 2.0 mL; LV end-systolic volume, 0.6 mL; RV end-diastolic volume, 2.2 mL; and RV end-systolic volume, 0.8 mL). Prospective CRSG is a valuable alternative to ECG-triggered, multisection, multiple-breath-hold cine imaging of the heart and holds considerable promise for simplifying functional imaging of the heart, particularly in patients who are unable to hold their breath for a long period and patients who show ECG signal disturbances.


Life-history variation in a seed beetle: adult egg-laying vs. larval competitive ability.
Populations of the seed beetle Callosobruchus maculatus differ genetically in several traits that mediate intraspecific competition. This study examined competitive interactions between larvae from two strains that differed in their propensity to oviposit on occupied hosts. In a strain (S) where females avoided laying >1 egg/seed, larvae were highly competitive; if two larvae entered a small host simultaneously, only one adult emerged. In a strain (I) whose females were "sloppier" in their egg-laying decisions, more than half of the seeds bearing two larvae yielded two adults. If seeds contained one larva from each strain, only one adult emerged per seed, and 70% of these adults belonged to the more competitive S strain. A larva's probability of emergence could be increased if it entered the seed before its competitor. A two-day headstart was needed merely for I larvae to compete equally with S larvae. Competition also affected development time and adult weight, but its effect was highly strain- and sex-specific. Adult life-history traits also differed substantially between strains. Compared to I beetles, S beetles exhibited decreased longevity, lower fecundity, a truncated period of oviposition, and larger egg and body size. Fecundity was linearly related to body size in the I strain, but was largely independent of size in the S strain. When faced with a shortage of hosts, S females (whose progeny are highly competitive) "withheld" eggs and died without depositing 40% of their lifetime supply. In contrast, the fecundity of I females was independent of seed availability. Comparisons with previous studies suggest that both highly uniform egg-laying and strong interference among larvae may be a consequence of chronic association with a relatively small host. Results from the larval competition experiments were used as parameter estimates for a simple, game-theoretic model that postulates interference vs. exploitative strategies. Fitness comparisons suggest that a strategy employing interference competition cannot be invaded by a more exploitative form of competition in a small host.


PT symmetry via electromagnetically induced transparency.
We propose a scheme to realize parity-time (PT) symmetry via electromagnetically induced transparency (EIT). The system we consider is an ensemble of cold four-level atoms with an EIT core. We show that the cross-phase modulation contributed by an assisted field, the optical lattice potential provided by a far-detuned laser field, and the optical gain resulted from an incoherent pumping can be used to construct a PT-symmetric complex optical potential for probe field propagation in a controllable way. Comparing with previous study, the present scheme uses only a single atomic species and hence is easy for the physical realization of PT-symmetric Hamiltonian via atomic coherence.


Genomic organization of human arylamine N-acetyltransferase Type I reveals alternative promoters that generate different 5'-UTR splice variants with altered translational activities.
In humans, a polymorphic gene encodes the drug-metabolizing enzyme NAT1 (arylamine N-acetyltransferase Type 1), which is widely expressed throughout the body. While the protein-coding region of NAT1 is contained within a single exon, examination of the human EST (expressed sequence tag) database at the NCBI revealed the presence of nine separate exons, eight of which were located in the 5' non-coding region of NAT1. Differential splicing produced at least eight unique mRNA isoforms that could be grouped according to the location of the first exon, which suggested that NAT1 expression occurs from three alternative promoters. Using RT (reverse transcriptase)-PCR, we identified one major transcript in various epithelial cells derived from different tissues. In contrast, multiple transcripts were observed in blood-derived cell lines (CEM, THP-1 and Jurkat), with a novel variant, not identified in the EST database, found in CEM cells only. The major splice variant increased gene expression 9-11-fold in a luciferase reporter assay, while the other isoforms were similar or slightly greater than the control. We examined the upstream region of the most active splice variant in a promoter-reporter assay, and isolated a 257 bp sequence that produced maximal promoter activity. This sequence lacked a TATA box, but contained a consensus Sp1 site and a CAAT box, as well as several other putative transcription-factor-binding sites. Cell-specific expression of the different NAT1 transcripts may contribute to the variation in NAT1 activity in vivo.


Tumor blood flow measured by PET dynamic imaging of first-pass 18F-FDG uptake: a comparison with 15O-labeled water-measured blood flow.
PET molecular imaging of 15O-labeled water is the gold standard for measuring blood flow in humans. However, this requires an on-site cyclotron to produce the short-lived 15O tracer, which is cost-prohibitive for most clinical PET centers. The purpose of this study was to determine if the early uptake of 18F-FDG could be used to measure regional blood flow in tumors in the absence of 15O-water. PET scans were obtained in patients being evaluated for tumor perfusion and glucose metabolism in a phase I dose-escalating protocol for endostatin, a novel antiangiogenic agent. A 2-min perfusion scan was performed with a bolus injection of 2,220 MBq (60 mCi) of 15O-water, which was followed by a 370-MBq (10 mCi) dose of 18F-FDG. Four sequential scans of 18F-FDG uptake were acquired, consisting of an early 2-min uptake scan-or first-pass scan-and 3 sequential 15-min late 18F-FDG uptake scans. Regions of interest (ROIs) were drawn on 2 or more tumor sites and on back muscle, as a control ROI, for each patient. Arterial blood concentration was derived from the PET scans by drawing an ROI over a large artery in the field of view. Blood flow was computed with a simple 1-compartment blood flow model using the first 2 min of data after injection. Blood flow estimated from the early uptake of 18F-FDG was linearly correlated with 15O-measured blood flow, with an intercept of 0.01, a slope of 0.86, and an R2 regression coefficient of 0.74 (r = 0.86). The 18F-FDG tumor extraction fraction relative to 15O-water averaged 0.86. A preliminary case study of a patient with prostate cancer confirms the utility of the first-pass 18F-FDG blood flow analysis in tumor diagnosis. These results suggest that the first-pass uptake of 18F-FDG may provide an estimate of perfusion in a tumor within the limitations of incomplete extraction of 18F-FDG compared with 15O-water.


Therapeutic effects of short-term monochromatic infrared energy therapy on patients with knee osteoarthritis: a double-blind, randomized, placebo-controlled study.
Randomized, double-blind, placebo-controlled study. To examine the short-term therapeutic effects of monochromatic infrared energy (MIRE) on participants with knee osteoarthritis (OA). Patients were assessed according to the International Classification of Functioning, Disability and Health. MIRE is commonly used in therapy for patients with peripheral neuropathies. However, research has not focused intensively on the therapeutic effects of MIRE in patients with knee OA. This study enrolled 73 participants with knee OA. Participants received six 40-minute sessions of active or placebo MIRE treatment (890-nm wavelength; power, 6.24 W; energy density, 2.08 J/cm2/min; total energy, 83.2 J/cm2) over the knee joints for 2 weeks. International Classification of Functioning, Disability and Health-related outcomes were collected weekly over 4 weeks using the Knee injury and Osteoarthritis Outcome Score, Lysholm Knee Scale, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Inventory, Chronic Pain Grade questionnaire, World Health Organization Quality of Life-brief version, and OA Quality of Life Questionnaire. Data were analyzed by repeated-measures analysis of variance. No statistically significant differences were found for the interaction of group by time for Knee injury and Osteoarthritis Outcome Score scores, including pain, other symptoms, function in daily living, function in sport and recreation, and knee-related quality of life. Scores on the Lysholm Knee Scale, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Inventory, Chronic Pain Grade questionnaire, World Health Organization Quality of Life-brief version, and OA Quality of Life Questionnaire also showed no significant differences between the 2 groups at any of the 4 follow-up assessments. Short-term MIRE therapy provided no beneficial effects to body functions, activities, participation, and quality of life in patients with knee OA.


Cutaneous manifestations in patients with mastocytosis: Consensus report of the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology.
Cutaneous lesions in patients with mastocytosis are highly heterogeneous and encompass localized and disseminated forms. Although a classification and criteria for cutaneous mastocytosis (CM) have been proposed, there remains a need to better define subforms of cutaneous manifestations in patients with mastocytosis. To address this unmet need, an international task force involving experts from different organizations (including the European Competence Network on Mastocytosis; the American Academy of Allergy, Asthma & Immunology; and the European Academy of Allergology and Clinical Immunology) met several times between 2010 and 2014 to discuss the classification and criteria for diagnosis of cutaneous manifestations in patients with mastocytosis. This article provides the major outcomes of these meetings and a proposal for a revised definition and criteria. In particular, we recommend that the typical maculopapular cutaneous lesions (urticaria pigmentosa) should be subdivided into 2 variants, namely a monomorphic variant with small maculopapular lesions, which is typically seen in adult patients, and a polymorphic variant with larger lesions of variable size and shape, which is typically seen in pediatric patients. Clinical observations suggest that the monomorphic variant, if it develops in children, often persists into adulthood, whereas the polymorphic variant may resolve around puberty. This delineation might have important prognostic implications, and its implementation in diagnostic algorithms and future mastocytosis classifications is recommended. Refinements are also suggested for the diagnostic criteria of CM, removal of telangiectasia macularis eruptiva perstans from the current classification of CM, and removal of the adjunct solitary from the term solitary mastocytoma.


Microbial contributions to coupled arsenic and sulfur cycling in the acid-sulfide hot spring Champagne Pool, New Zealand.
Acid-sulfide hot springs are analogs of early Earth geothermal systems where microbial metal(loid) resistance likely first evolved. Arsenic is a metalloid enriched in the acid-sulfide hot spring Champagne Pool (Waiotapu, New Zealand). Arsenic speciation in Champagne Pool follows reaction paths not yet fully understood with respect to biotic contributions and coupling to biogeochemical sulfur cycling. Here we present quantitative arsenic speciation from Champagne Pool, finding arsenite dominant in the pool, rim and outflow channel (55-75% total arsenic), and dithio- and trithioarsenates ubiquitously present as 18-25% total arsenic. In the outflow channel, dimethylmonothioarsenate comprised ≤9% total arsenic, while on the outflow terrace thioarsenates were present at 55% total arsenic. We also quantified sulfide, thiosulfate, sulfate and elemental sulfur, finding sulfide and sulfate as major species in the pool and outflow terrace, respectively. Elemental sulfur concentration reached a maximum at the terrace. Phylogenetic analysis of 16S rRNA genes from metagenomic sequencing revealed the dominance of Sulfurihydrogenibium at all sites and an increased archaeal population at the rim and outflow channel. Several phylotypes were found closely related to known sulfur- and sulfide-oxidizers, as well as sulfur- and sulfate-reducers. Bioinformatic analysis revealed genes underpinning sulfur redox transformations, consistent with sulfur speciation data, and illustrating a microbial role in sulfur-dependent transformation of arsenite to thioarsenate. Metagenomic analysis also revealed genes encoding for arsenate reductase at all sites, reflecting the ubiquity of thioarsenate and a need for microbial arsenate resistance despite anoxic conditions. Absence of the arsenite oxidase gene, aio, at all sites suggests prioritization of arsenite detoxification over coupling to energy conservation. Finally, detection of methyl arsenic in the outflow channel, in conjunction with increased sequences from Aquificaceae, supports a role for methyltransferase in thermophilic arsenic resistance. Our study highlights microbial contributions to coupled arsenic and sulfur cycling at Champagne Pool, with implications for understanding the evolution of microbial arsenic resistance in sulfidic geothermal systems.


Human gene therapy and slippery slope arguments.
Any suggestion of altering the genetic makeup of human beings through gene therapy is quite likely to provoke a response involving some reference to a 'slippery slope'. In this article the author examines the topography of two different types of slippery slope argument, the logical slippery slope and the rhetorical slippery slope argument. The logical form of the argument suggests that if we permit somatic cell gene therapy then we are committed to accepting germ line gene therapy in the future because there is no logically sustainable distinction between them. The rhetorical form posits that allowing somatic cell therapy now will be taking the first step on a slippery slope which will ultimately lead to the type of genocide perpetrated by the Nazis. The author tests the validity of these lines of argument against the facts of human gene therapy and concludes that because of their dependence on probabilities that cannot be empirically proven they should be largely disregarded in the much more important debate on moral line-drawing in gene therapy.


Wigner function for nonparaxial wave fields.
The generalized optical transfer function and the spectral correlation function are investigated for nonparaxial two-dimensional wave fields. The angle-impact marginal of the four-dimensional Wigner function is derived directly. For focused wave fields of semiangle greater than 90 degrees, the spectral correlation function exhibits overlapping and interference. For focused wave fields for which the semiangle is known to be less than 180 degrees, the magnitude and phase can be recovered directly from knowledge of the intensity in the focal region.


Impact of Red Blood Cells on Function and Metabolism of Porcine Deceased Donor Kidneys During Normothermic Machine Perfusion.
Normothermic machine perfusion (NMP) protocols using blood-based solutions are commonly used in the assessment of kidneys before transplantation. This procedure is, nevertheless, limited by blood availability and warrants the search for alternatives. We compared a blood-based solution with a serum-like preservation solution (Aqix) enriched with colloids with and without red blood cells (RBCs). Porcine kidneys retrieved from an abattoir were subjected to 30 min of warm ischemia, followed by 3 h of hypothermic oxygenated machine perfusion at 4 °C. Subsequently, kidneys (n = 6 per group) were evaluated with NMP for 4 h with 5 different solutions: diluted blood, Aqix with BSA ± RBCs, or Aqix with dextran 40 ± RBCs. Throughout NMP, markers of renal function and tubular metabolism were favorable in groups with RBCs. The addition of RBCs resulted in 4- to 6-fold higher oxygen consumption rates. Controls had significantly higher ATP levels post-NMP, exhibited decreased production of oxidative stress markers, and had the highest creatinine clearance. In conclusion, this study shows that the addition of RBCs during NMP reduced renal injury, improved function, and was associated with increased renal metabolism. Although the RBC-BSA-supplemented Aqix solution was also able to support metabolism and renal function, a blood-based perfusion solution remains superior.


Relationships of diabetes-specific emotional distress, depression, anxiety, and overall well-being with HbA1c in adult persons with type 1 diabetes.
Emotional problems are common in adults with diabetes, and knowledge about how different indicators of emotional problems are related with glycemic control is required. The aim was to examine the relationships of diabetes-specific emotional distress, depression, anxiety, and overall well-being with glycosylated hemoglobin (HbA1c). Of the 319 adults with type 1 diabetes attending the endocrinology outpatient clinic at a university hospital in Norway, 235 (74%) completed the Diabetes Distress Scale, the Problem Areas in Diabetes Survey, the Hospital Anxiety and Depression Scale, and the World Health Organization-Five Well-Being Index. Blood samples were taken at the time of data collection to determine HbA1c. Regression analyses examined associations of diabetes-specific emotional distress, anxiety, depression, and overall well-being with HbA1c. The relationship between diabetes-specific emotional distress and HbA1c was tested for nonlinearity. Diabetes-specific emotional distress was related to glycemic control (DDS total: unstandardized coefficient=0.038, P<.001; PAID total: coefficient=0.021, P=.007), but depression, anxiety, and overall well-being were not. On the DDS, only regimen-related distress was independently related to HbA1c (coefficient=0.056, P<.001). A difference of 0.5 standard deviation of baseline regimen distress is associated with a difference of 0.6 in HbA1c. No significant nonlinearity was detected in the relationship between diabetes-specific distress and HbA1c. To stimulate adequate care strategies, health personnel should acknowledge depression and diabetes-specific emotional distress as different conditions in clinical consultations. Addressing diabetes-specific emotional distress, in particular regimen distress, in clinical consultation might improve glycemic control.


Altered interorgan response to feeding in patients with chronic obstructive pulmonary disease.
Previously, we reported increased values for whole-body protein turnover in patients with chronic obstructive pulmonary disease (COPD) in the postabsorptive state. The objective was to investigate whether intake of a carbohydrate-protein meal influences whole-body protein turnover differently in COPD patients and control subjects. Eight normal-weight patients with moderate COPD and 8 healthy control subjects were examined in the postabsorptive state and after 2 h of repeatedly ingesting a maltodextrin casein-based protein meal (0.02 g x kg body wt(-1) x 20 min(-1)). Combined simultaneous, continuous, intravenous infusion of L-[ring-2H5]-phenylalanine and L-[ring-2H2]-tyrosine tracer and oral repeated ingestion of 1-13C-phenylalanine were performed to measure whole-body protein synthesis (WbPS) and first-pass splanchnic extraction of phenylalanine. Endogenous rate of appearance of phenylalanine as the measure of whole-body protein breakdown (WbPB) and netWbPS was calculated as WbPS--WbPB. Arterialized venous blood was sampled for amino acid enrichment and concentration analyses. Feeding induced an increase in WbPS and a reduction in WbPB. The reduction in WbPB was larger in the COPD group than in the control group (P < 0.05) and was related to the lower splanchnic extraction of phenylalanine in the patients. Consequently, netWbPS increased more after feeding in the COPD group than in the control group (P < 0.05). Feeding induces more protein anabolism in normal-weight patients with moderate COPD than in healthy control subjects. This is probably because these COPD patients are characterized by an adaptive interorgan response to feeding to prevent or delay weight loss at this disease stage.


A scoping review to explore the experiences and outcomes of younger people with disabilities in residential aged care facilities.
In Australia, over 6,000 adults younger than 65 have been inappropriately placed in nursing homes designed to accommodate older adults. The primary aim of this review was to map the literature on the experiences and outcomes of young people with disability who are placed in aged care. A scoping review of the published literature from 2009-2018 was conducted using Embase, Medline, PsycINFO and Scopus. Eleven articles were identified (7 qualitative, 3 mixed methods, 1 quantitative). Results demonstrated the inability of aged care facilities to meet the basic human needs of young people (e.g., privacy, physical, sexual, social, nutritional, emotional need) and highlighted the lack of choice young people with disability have in regards to rehabilitation and housing. There was limited data relating to the trajectory and support needs of young people placed in aged care facilities. This review highlights the negative outcomes young people experience while living in aged care. Future research should investigate the trajectory and support needs of young people in aged care facilities. Systemic changes are required to meet the needs of young people with complex needs at risk of admission to aged care including timely rehabilitation and housing and support options.


Menarcheal age of girls from dysfunctional families.
The objective of the present study was to determine median age at menarche and the influence of familial instability on maturation. The sample included 7047 girls between the ages of 9 and 17 years from Tuzla Canton. The girls were divided into two groups. Group A (N=5230) comprised girls who lived in families free of strong traumatic events. Group B (N=1817) included girls whose family dysfunction exposed them to prolonged distress. Probit analysis was performed to estimate mean menarcheal age using the Probit procedure of SAS package. The mean menarcheal age calculated by probit analysis for all the girls studied was 13.07 years. In girls from dysfunctional families a very clear shift toward earlier maturation was observed. The mean age at menarche for group B was 13.0 years, which was significantly lower that that for group A, 13.11 years (t=2.92, P<0.01). The results surveyed here lead to the conclusion that girls from dysfunctional families mature not later but even earlier than girls from normal families. This supports the hypothesis that stressful childhood life events accelerate maturation of girls.


Outcomes of paediatric patients ventilated in a high-care area outside an intensive care unit.
Limited availability of paediatric intensive care beds in the public sector is a major challenge in South Africa. It often results in patients being ventilated in a high-care area (HCA) outside an intensive care setting. The outcomes of paediatric patients ventilated outside a paediatric intensive care unit (ICU) are not well documented. To describe characteristics and outcomes of patients ventilated in a paediatric HCA. A retrospective chart review of children (0 - 16 years) requiring mechanical ventilation in the HCA at Chris Hani Baragwanath Academic Hospital, Johannesburg, between 1 February and 31 October 2015 was performed. A total of 214 patients required mechanical ventilation during the study period. Fifty-four percent were male and 91.1% were HIV-negative. The most common diagnoses were acute lower respiratory tract infections (59.3% of the post-neonatal group, 28.8% of the neonatal group) and sepsis (6.8% of the post-neonatal group, 28.8% of the neonatal group). The ultimate rate of acceptance to an ICU was 69.0%. Only 41.6% of cases referred to an ICU were initially accepted, with limited bed availability being the main reason for refusal. Patients with respiratory illnesses were more likely and those with neurological illness less likely to be accepted to an ICU. Patients with low-risk diagnoses were more likely to be accepted than those with very high-risk diagnoses. The overall mortality rate was 32.2%, with 52.2% of these deaths occurring in the HCA. Patients aged 1 - 5 years had the highest mortality rate (48.0%). Lower respiratory tract infections (36.8%) and sepsis (20.6%) were the main causes of death. The mortality rate of suitable ICU candidates in the HCA was higher than that in an ICU (33.3% v. 24.3%). The standardised mortality ratio (SMR), as predicted by the Paediatric Index of Mortality 3 score, for all patients who died in the HCA was 3.3, while the SMR for patients who died in an ICU was 1.3. The odds ratio for mortality of suitable candidates ventilated in the HCA v. patients who were ventilated in an ICU was 1.80 (95% confidence interval 1.39 - 6.03). Although a reasonable number of paediatric patients ventilated in an HCA survive, survival is lower than in those ventilated in an ICU. However, offering life-supporting therapies in an HCA may offer benefit where ICU care is unavailable. Emphasis needs to be placed on improving access to ICU care as well as optimising the use of available resources.


The Role of GnRH Analogues in Improving Outcome in Women Undergoing Superovulation and Intrauterine Insemination after Surgical Correction of Mild Endometriosis: A Randomized Controlled Trial.
Treatment with laparoscopic surgery, gonadotropin-releasing hormone analog (GnRHa) therapy, superovulation (SO), and intrauterine insemination (IUI) have individual benefits in improving fertility outcomes in women with endometriosis. The aim of the study was to evaluate the role of GnRHa in improving outcome in women undergoing SO and IUI after surgical correction of mild endometriosis. This was a randomized controlled trial conducted in the Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, New Delhi, India, over a period of 2 years and 6 months. Ninety women who were diagnosed with mild endometriosis on laparoscopy using the revised American Society for Reproductive Medicine criteria were included in the study. The patients in the study group (n=45) received a single dose of 3.75 mg GnRHa subcutaneously within 48 h of the surgery, and those in the control group (n=45) did not receive GnRHa. Thereafter, patients in both arms received SO and IUI from the next menstrual cycle. Four patients in the study group and three patients in the control group were lost to follow-up before the first cycle of ovulation induction. Primary outcomes measured in our study were live birth rates and clinical pregnancy rate. Secondary outcome measures were number of follicles >18 mm, endometrial thickness, dose and days of gonadotropin stimulation. Baseline characteristics, such as age and body mass index, were comparable in both groups. The SO and IUI cycles were comparable between the two groups with regard to the secondary outcome parameters. Pregnancy rate in the first cycle was 17.1% in the study group and 19.1% in the control group (p=0.81). The overall pregnancy rate was similar in both groups (study group=21.9%, control group=23.8%; p=1). As no patient had miscarriage or any other complication during pregnancy, live birth rate was similar to the clinical pregnancy rate. Adding GnRHa for the suppression of mild endometriosis has shown no significant improvement in the surgical management of women undergoing SO and IUI.


Efficacy and optimization of palivizumab injection regimens against respiratory syncytial virus infection.
Infection with the respiratory syncytial virus (RSV) is the leading cause of hospitalizations in children, accounting for more than 90,000 hospitalizations every year in the United States. For children who are at risk for severe RSV infections, the American Academy of Pediatrics recommends immunoprophylaxis with a series of up to 5 injections of the antibody palivizumab administered monthly, beginning on November 1 of each year. However, many practitioners initiate injections at the onset of RSV season as indicated by local surveillance. To evaluate the effectiveness of current regimens for palivizumab injections across different cities and to design an optimized regimen. We performed a mathematical modeling study of the risk for hospitalization due to RSV infection. The model accounted for the pharmacokinetics of the antibody, the timing of the injections, and seasonal patterns of RSV, including geographic and year-to-year variability. We used the model to estimate the efficacy of current regimens, including the American Academy of Pediatrics recommendation, and to design a more effective injection regimen, the optimized fixed start (OFS), which uses city-specific initiation dates. Participants were the approximately 700,000 individuals who had specimens tested for RSV by National Respiratory and Enteric Virus Surveillance System laboratories in 18 US cities from July 1, 1994, through June 30, 2011 (a total of 725,741 tests). Different palivizumab injection regimens. The primary outcome measure was reduction in hospitalizations due to RSV infections. The secondary measures were cost (number of palivizumab doses) and duration of protection (in days). The American Academy of Pediatrics-recommended 5-injection regimen is expected to reduce hospitalization risk by a median of 2.7% (range, -2.2% to 6.1%) compared with the conventional regimen based on RSV surveillance. The 5-injection OFS regimen is expected to further reduce risk by a median of 6.8% (range, 4.9% to 14.8%), and the 4-injection OFS regimen is expected to achieve efficacy comparable to that of the conventional 5-injection regimen while reducing costs by 20%. Modified palivizumab regimens can improve protection for children at risk for severe outcomes of RSV infection and thereby lower rates of hospitalization due to RSV.


High-intensity non-invasive positive pressure ventilation for stable hypercapnic COPD.
The objective of the present analysis is to describe the outcomes of high-intensity non-invasive positive pressure ventilation (NPPV) aimed at maximally decreasing PaCO(2) as an alternative to conventional NPPV with lower ventilator settings in stable hypercapnic COPD patients. Physiological parameters, exacerbation rates and long-term survival were assessed in 73 COPD patients (mean FEV(1) 30+/-12 %predicted) who were established on high-intensity NPPV due to chronic hypercapnic respiratory failure between March 1997 and May 2006. Controlled NPPV with breathing frequencies of 21+/-3 breath/min and mean inspiratory/expiratory positive airway pressures of 28+/-5/5+/-1 cmH(2)O led to significant improvements in blood gases, lung function and hematocrit after two months. Only sixteen patients (22%) required hospitalisation due to exacerbation during the first year, with anaemia increasing the risk for exacerbation. Two- and five-year survival rates of all patients were 82% and 58%, respectively. The five year survival rate was 32% and 83% in patients with low (< or =39%) and high (> or =55%) hematocrit, respectively. High-intensity NPPV improves blood gases, lung function and hematocrit, and is also associated with low exacerbation rates and a favourable long-term outcome. The current report strongly emphasises the need for randomised controlled trials evaluating the role of high-intensity NPPV in stable hypercapnic COPD patients.


Vitamin D Deficiency, hypocalcemia, and increased skeletal muscle degradation in rats.
The myopathy associated with vitamin D deficiency was examined in vitamin D-deficient and vitamin D-supplemented rats. When compared with either vitamin D-supplemented ad lib. or pair-fed rats, weight gain and muscle mass were decreased in vitamin D-deficient hypocalcemic animals. With the exception of a modest decrease in muscle creatine phosphate levels, muscle composition was unchanged by vitamin D deficiency. Muscle protein turnover rates were determined in both in vivo and in vitro studies and demonstrated that myofibrillar protein degradation was increased in vitamin D deficiency. Normal growth rates could be maintained be feeding the rats vitamin D-deficient diets containing 1.6% calcium, which maintained plasma calcium within the normal range. In addition to its role in maintaining plasma calcium, vitamin D-supplemented rats had significantly higher levels of the anabolic hormone insulin. Vitamin D supplementation may affect muscle protein turnover by preventing hypocalcemia, as well as directly stimulating insulin secretion, rather than by a direct effect within skeletal muscle.


Examining the repeatable battery for the assessment of neuropsychological status validity indices in people with schizophrenia spectrum disorders.
Objective: We examined the frequency of possible invalid test scores on the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) in patients with schizophrenia spectrum disorders, and whether there was an association between scores on the embedded RBANS performance validity tests (PVTs) and self-reported symptoms of apathy as measured by the Initiate Scale of the Behavior Rating Inventory of Executive Function-Adult Version (BRIEF-A). Methods: Participants included 250 patients (M = 24.4 years-old, SD = 5.7) with schizophrenia spectrum disorders. Base rates of RBANS Effort Index (EI), Effort Scale (ES), and Performance Validity Index (PVI) test scores were computed. Spearman correlations were used to examine the associations between the RBANS PVTs, the RBANS Index scores, and the BRIEF-A Initiate Scale. Regression analyses were used to investigate how well the RBANS PVTs predicted scores on the BRIEF-A Initiate Scale. Results: The frequency of invalid scores on the EI (>3) and the PVI (<42) in participants with schizophrenia spectrum disorders was 6%. The frequency of invalid ES scores (<12) was 28% in the patients compared to 15% in the U.S. standardization sample. There was a small significant correlation between the EI and the BRIEF-A Initiate Scale (rho=.158, p<.05). Conclusions: The rates of invalid scores were similar to previously published studies. Invalid scores on the BRIEF-A were uncommon. Apathy measured with the BRIEF-A Initiate Scale was not associated with performance on the RBANS validity measures or with measures of cognition.


Narrow band imaging for detection of dysplasia in colitis: a randomized controlled trial.
In ulcerative colitis surveillance, chromoendoscopy improves dysplasia detection 3 – 5-fold compared with white light endoscopy (WLE). The aim of this study was to investigate whether narrow band imaging (NBI) can improve dysplasia detection compared with WLE. This was a randomized, parallel-group trial. A total of 220 patients were needed to be recruited to detect a threefold increase in dysplasia detection. In all, 112 patients with long-standing ulcerative colitis were randomized to colonoscopic extubation with NBI (56) or WLE (56) (1:1 ratio) at two tertiary endoscopy units in the United Kingdom. Targeted biopsies of suspicious areas and quadrantic random biopsies every 10 cm were taken in both groups. The primary outcome measure was the proportion of patients with at least one area of dysplasia detected. In a prespecified mid-point analysis, the criteria for trial discontinuation were met and the trial was stopped and analyzed at this point. There was no difference in the primary outcome between the two groups, with 5 patients having at least one dysplastic lesion in each group (odds ratio (OR) 1.00, 95 % confidence interval (95 % CI) 0.27 – 3.67, P = 1.00). This remained unchanged when adjusted for other variables (OR 0.69, 95 % CI 0.16 – 2.96, P = 0.62). Overall, dysplasia detection was 9 % in each arm. Yield of dysplasia from random nontargeted biopsies was 1 / 2,707 (0.04 % ). Overall, in this multicenter parallel-group trial, there was no difference in dysplasia detection when using NBI compared with high-definition WLE colonoscopy. Random background biopsies were ineffective in detecting dysplasia.


Control mechanism of the circadian clock for timing of cell division in vivo.
Cell division in many mammalian tissues is associated with specific times of day, but just how the circadian clock controls this timing has not been clear. Here, we show in the regenerating liver (of mice) that the circadian clock controls the expression of cell cycle-related genes that in turn modulate the expression of active Cyclin B1-Cdc2 kinase, a key regulator of mitosis. Among these genes, expression of wee1 was directly regulated by the molecular components of the circadian clockwork. In contrast, the circadian clockwork oscillated independently of the cell cycle in single cells. Thus, the intracellular circadian clockwork can control the cell-division cycle directly and unidirectionally in proliferating cells.


Prevalence of Atypical Pathogens in Patients With Cough and Community-Acquired Pneumonia: A Meta-Analysis.
Community-acquired pneumonia (CAP), acute cough, bronchitis, and lower respiratory tract infections (LRTI) are often caused by infections with viruses or Streptococcus pneumoniae. The prevalence of atypical pathogens Mycoplasma pneumoniae, Chlamydophila pneumoniae, Legionella pneumophila, and Bordetella pertussis among patients with these illnesses in the ambulatory setting has not been previously summarized. We set out to derive prevalence information from the existing literature. We performed a systematic review of MEDLINE for prospective, consecutive-series studies reporting the prevalence of M pneumoniae, C pneumoniae, L pneumophila and/or B pertussis in outpatients with cough, acute bronchitis, LRTI, or CAP. Articles were independently reviewed by 2 authors for inclusion and abstraction of data; discrepancies were resolved by consensus discussion. A meta-analysis was performed on each pathogen to calculate the pooled prevalence estimates using a random effects model of raw proportions. Fifty studies met our inclusion criteria. While calculated heterogeneity was high, most studies reported prevalence for each pathogen within a fairly narrow range. In patients with CAP, the overall prevalences of M pneumoniae and C pneumoniae were 10.1% (95% CI, 7.1%-13.1%) and 3.5% (95% CI, 2.2%-4.9%), respectively. Consistent with previous reports, M pneumoniae prevalence peaked in roughly 6-year intervals. Overall prevalence of L pneumophila was 2.7% (95% CI, 2.0%-3.4%), but the organism was rare in children, with only 1 case in 1,765. In patients with prolonged cough in primary care, the prevalence of B pertussis was 12.4% (95% CI, 4.9%-19.8%), although it was higher in studies that included only children (17.6%; 95% CI, 3.4%-31.8%). Atypical bacterial pathogens are relatively common causes of lower respiratory diseases, including cough, bronchitis, and CAP. Where surveillance data were available, we found higher prevalences in studies where all patients are tested for these pathogens. It is likely that these conditions are underreported, underdiagnosed, and undertreated in current clinical practice.


Morphological, behavioral and cellular analyses revealed different phenotypes in Wolfram syndrome wfs1a and wfs1b zebrafish mutant lines.
Wolfram syndrome (WS) is a rare genetic disease characterized by diabetes, optic atrophy and deafness. Patients die at 35 years of age, mainly from respiratory failure or dysphagia. Unfortunately, there is no treatment to block the progression of symptoms and there is an urgent need for adequate research models. Here, we report on the phenotypical characterization of two loss-of-function zebrafish mutant lines: wfs1aC825X and wfs1bW493X. We observed that wfs1a deficiency altered the size of the ear and the retina of the fish. We also documented a decrease in the expression level of unfolded protein response (UPR) genes in basal condition and in stress condition, i.e. after tunicamycin treatment. Interestingly, both mutants lead to a decrease in their visual function measured behaviorally. These deficits were associated with a decrease in the expression level of UPR genes in basal and stress conditions. Interestingly, basal, ATP-linked and maximal mitochondrial respirations were transiently decreased in the wfs1b mutant. Taken together, these zebrafish lines highlight the critical role of wfs1a and wfs1b in UPR, mitochondrial function and visual physiology. These models will be useful tools to better understand the cellular function of Wfs1 and to develop novel therapeutic approaches for WS.