Reduced cyclin D1 expression in the cerebella of nutritionally deprived rats correlates with developmental delay and decreased cellular DNA synthesis.
Nutritional deprivation in the early postnatal period severely inhibits cerebellar growth and development, which is related in part to reduced levels of growth factors. Cyclin D1 encodes a growth factor-inducible regulatory subunit of a serine/thereonine kinase that is capable of phosphorylating the tumor suppressor pRB, thereby allowing normal progression through the G1 phase of the cell-cycle. Because the abundance of cyclin D1 is rate limiting in this progression, we examined the regulation of cyclin D1 expression in vivo, using a model of nutritional deprivation. Cyclin D1 expression in cerebella of fed control rats was detected in the external granular layer and was associated with cellular proliferation within this layer. Nutritional deprivation of rats reduced cerebellar weight, as well as the thickness of the molecular layer that largely consists of cells migrating from the external granular layer. Refeeding partially restored cerebellar weight, molecular layer thickness and increased external granular layer cyclin D1 immunostaining. Since nutritional deprivation is accompanied by lower levels of circulating insulin-like growth factor-I (IGF-I), we determined whether IGF-I directly stimulated the cyclin D1 promoter. The human cyclin D1 promoter linked to the luciferase reporter gene was stably integrated into PC12 cells. IGF-I stimulated cyclin D1 promoter activity 4- to 6-fold at 6 hours (h). These findings are consistent with the notion that nutritional deprivation may affect proliferative growth by altering expression of cyclin D1 in the germinal cell layer and that regulation of cyclin D1 expression by growth factors may contribute to normal neonatal cerebellar development. The reduction in cyclin D1 expression as cells differentiate in the cerebellum is consistent with a potential role for cyclin D1 in this process.


Small-bowel malabsorption and gastrointestinal malignancy.
In addition to lymphoma, there is an increased incidence of gastrointestinal carcinoma in patients with malabsorption due to celiac disease. This is frequently manifested by a loss of response to gluten withdrawal. Four such cases are described: one patient had lymphoma and the other three had cancer of the esophagus, jejunum, and pancreas, respectively. The literature indicates that carcinoma of the esophagus and small bowel is particularly common in patients with celiac disease. These findings suggest that celiac disease should be considered a premalignant condition and that such patients should undergo a regular radiographic survey to detect early cancer.


Coexpression of acidic fibroblast growth factor enhances specific productivity and antibody titers in transiently transfected HEK293 cells.
Recombinant proteins are of great commercial and scientific interest. However, most current production methods using mammalian cells involve the time- and labor-intensive step of creating stable cell lines. Although production methods based on transient gene expression could offer a significant improvement, transient transfection is currently still limited by low titers and low specific productivity compared to stable cell lines. To overcome these bottlenecks, we have explored the use of various growth factors to enhance specific productivity and titers in the context of transient gene expression. For that purpose, several growth factors were cloned and screened for their effect on transient gene expression in HEK293E and CHO-DG44 cells. In particular, acidic fibroblast growth factor (aFGF) was able to increase specific productivity by 60% and recombinant protein titers by 80% in HEK293E cells, while FGF9 increased titers by 250% in CHO-DG44 cells.


[Thermodynamics of calmodulin and tubulin binding to the vinca-alkaloid vinorelbine].
Vinca-alkaloids, such as vinblastine, and some of their derivatives, as for example vinorelbine, are widely used in clinical therapy of leukemia and several types of tumors. Their effects are associated with the disfunctioning of the mitotic spindle, which leads to mitosis blockage and a shutdown of the cell cycle. Their primary target is tubulin, however recent research has shown that some of the vinca-alkaloids inhibit calmodulin binding to its targets. Vinka-alkaloids binding with other proteins could be responsible for their efficiency and neuroprotection. Here we investigated the thermodynamics of vinorelbine interactions with calmodulin and tubulin. It was determined that unlike the other vinca-alkaloids both vinorelbine binding sites are located in the C-domain of calmodulin, and characterized by association constants of 4.0 x 10(5) and 5.4 x 10(4) M(-1). At the same time the thermodynamics of vinorelbine binding to tubulin are not much different from that of other vinca-alkaloids. These results will allow getting a better insight on the reaction mechanisms of vinca-alkaloids on a secondary protein target.


Patient safety culture in nursing: a dimensional concept analysis.
This paper is a report of a dimensional concept analysis of patient safety culture in nursing. Patient safety is an important issue in healthcare organizations. As the release of Institute of Medicine reports in the United States of America, substantial interest has arisen in studying patient safety culture; however, the concept remains poorly defined. Multiple databases, including CINAHL, MEDLINE, PsycINFO and Anthropological Index Online, were searched from 1970 to 2006. A keyword search method was employed followed by a combined key word search. A concept analysis based on Caron and Bowers' method was carried out using 45 papers, three books and three theses after examination of the abstracts to identify definitions, dimensions, perspectives and consequences needed for content and dimensional analyses. Nurses' shared values, beliefs and behavioural norms towards patient safety were identified as the overarching dimensions of the patient safety culture. The four sub-dimensions of patient safety culture were synthesized as system, personal, task-associated and interaction. Two main philosophical perspectives, functional and interpretative, were added to the analysis and further clarification was provided. It is expected that understanding the nature, as well as the key elements of the concept, would assist with analysing the existing safety culture and help to determine the strategies to build or shape the safety culture.


A polar filter in DNA polymerases prevents ribonucleotide incorporation.
The presence of ribonucleotides in DNA can lead to genomic instability and cellular lethality. To prevent adventitious rNTP incorporation, the majority of the DNA polymerases (dPols) possess a steric filter. The dPol named MsDpo4 (Mycobacterium smegmatis) naturally lacks this steric filter and hence is capable of rNTP addition. The introduction of the steric filter in MsDpo4 did not result in complete abrogation of the ability of this enzyme to incorporate ribonucleotides. In comparison, DNA polymerase IV (PolIV) from Escherichia coli exhibited stringent selection for deoxyribonucleotides. A comparison of MsDpo4 and PolIV led to the discovery of an additional polar filter responsible for sugar selectivity. Thr43 represents the filter in PolIV and this residue forms interactions with the incoming nucleotide to draw it closer to the enzyme surface. As a result, the 2'-OH in rNTPs will clash with the enzyme surface, and therefore ribonucleotides cannot be accommodated in the active site in a conformation compatible with productive catalysis. The substitution of the equivalent residue in MsDpo4-Cys47, with Thr led to a drastic reduction in the ability of the mycobacterial enzyme to incorporate rNTPs. Overall, our studies evince that the polar filter serves to prevent ribonucleotide incorporation by dPols.


Children with autism fail to orient to naturally occurring social stimuli.
Children with autism were compared to developmentally matched children with Down syndrome or typical development in terms of their ability to visually orient to two social stimuli (name called, hands clapping) and two nonsocial stimuli (rattle, musical jack-in-the-box), and in terms of their ability to share attention (following another's gaze or point). It was found that, compared to children with Down syndrome or typical development, children with autism more frequently failed to orient to all stimuli, and that this failure was much more extreme for social stimuli. Children with autism who oriented to social stimuli took longer to do so compared to the other two groups of children. Children with autism also exhibited impairments in shared attention. Moreover, for both children with autism and Down syndrome, correlational analyses revealed a relation between shared attention performance and the ability to orient to social stimuli, but no relation between shared attention performance and the ability to orient to nonsocial stimuli. Results suggest that social orienting impairments may contribute to difficulties in shared attention found in autism.


The relation of cortisol and sex hormone levels to results of psychological, performance, IQ and memory tests in military men and women.
Cortisol, along with other hormones of hypothalamo-pituitary-adrenal axis, belongs to one of the main factors influencing psychological and pathognomic factors, intelligence, and memory. The aim of our study was to review a large battery of psychological, performance, IQ and memory tests as to their relation with cortisol, testosterone and estrogen levels in groups of 100 men and 93 women who attended the Central Military Hospital in Prague for regular entrance psychological examinations for military personnel. In men, we detected positive correlations between cortisol and emotional lability, and negative correlations with impulsivity, while in women hypochondria and psychopathology were negatively correlated, and aggression measured with the Meili selective memory test had a positive relation to cortisol level. Testosterone correlated positively with emotional liability and negatively with impulsivity in men, and negatively with hypochondria and psychasteny, indirect aggression, irritability and paranoia in women. Estradiol correlated positively with psychopathology in men, and negatively with phobia. It was positively correlated with negativism in women. No clear correlation was observed between the concentration of steroid hormones and psychomotor performance or intelligence. Concentrations of steroid hormones correlate with results of several psychological tests, the sign and magnitude of these correlations, however, very often differ in military men and women.


Oxidative stress in patients with obstructive sleep apnoea syndrome.
Obstructive sleep apnoea syndrome (OSAS) is a disorder that leads to metabolic abnormalities and increased cardiovascular risk. The aim of this study was to identify early laboratory markers of cardiovascular disease through analysis of oxidative stress in normal subjects and patients with OSAS. A prospective study was designed to compare outcomes of oxidative stress laboratory tests in 20 adult patients with OSAS and a control group of 20 normal subjects. Laboratory techniques for detecting and quantifying free radical damage must be targeted to assess the pro-oxidant component and the antioxidant in order to obtain an overall picture of oxidative balance. No statistical differences in age, sex distribution, or BMI were found between the two groups (p>0.05). There were significant differences in the apnoea/hypopnoea index (AHI) between OSAS patients and the control group (p<0.05). Statistically significant differences in isoprostane, advanced oxidation protein products (AOPP) and non-protein bound iron (NPBI) levels were found between the study and control groups. No significant difference in the levels of thiol biomarkers was found between the two groups. The main finding of the present study was increased production of oxidative stress biomarkers in OSAS patients. The major difference between thiols and other oxidative stress biomarkers is that thiols are antioxidants, while the others are expressions of oxidative damage. The findings of the present study indicate that biomarkers of oxidative stress in OSAS may be used as a marker of upper airway obstructive episodes due to mechanical trauma, as well as a marker of hypoxaemia causing local oropharyngeal inflammation.


Fatty acid oxidation in mitochondria from needle biopsy samples of human skeletal muscle.
Activities for the oxidation of palmitoylcarnitine, of palmitoyl-CoA and of carnitine palmitoyltransferase were measured in mitochondria prepared from needle biopsy samples of human skeletal muscle. Results are presented for nine normal subjects and 18 patients in whom there was evidence of mitochondrial abnormality. Palmitoylcarnitine and palmitoyl-CoA oxidation were measured spectrophotometrically by following the reduction of added cytochrome c in the presence of cyanide. Because of large variations in the activities between subjects it was essential to express the three activities per unit of cytochrome c oxidase activity to demonstrate unambiguous specific alterations in the activities. In most of the patients the order of the three activities was similar to that in the normal subjects. However, in five cases the activity for palmitoylcarnitine oxidation was less than 4% of the mean normal value. In two of these patients, the low activity could be accounted for by very low (less than 10% normal) activity of carnitine palmitoyltransferase (CPT). In another two patients the activity of CPT was normal but that of palmitoyl-CoA dehydrogenase (a measure of beta-oxidation) was very low.


Family-centred care for hospitalised children aged 0-12 years.
This is an update of the Cochrane systematic review of family-centred care published in 2007 (Shields 2007). Family-centred care (FCC) is a widely used model in paediatrics, is thought to be the best way to provide care to children in hospital and is ubiquitous as a way of delivering care. When a child is admitted, the whole family is affected. In giving care, nurses, doctors and others must consider the impact of the child's admission on all family members. However, the effectiveness of family-centred care as a model of care has not been measured systematically. To assess the effects of family-centred models of care for hospitalised children aged from birth (unlike the previous version of the review, this update excludes premature neonates) to 12 years, when compared to standard models of care, on child, family and health service outcomes. In the original review, we searched up until 2004. For this update, we searched: the Cochrane Central Register of Controlled Trials (CENTRAL,The Cochrane Library, Issue 12 2011); MEDLINE (Ovid SP); EMBASE (Ovid SP); PsycINFO (Ovid SP); CINAHL (EBSCO Host); and Sociological Abstracts (CSA). We did not search three that were included in the original review: Social Work Abstracts, the Australian Medical Index and ERIC. We searched EMBASE in this update only and searched from 2004 onwards. There was no limitation by language. We performed literature searches in May and June 2009 and updated them again in December 2011. We searched for randomised controlled trials (RCTs) including cluster randomised trials in which family-centred care models are compared with standard models of care for hospitalised children (0 to 12 years, but excluding premature neonates). Studies had to meet criteria for family-centredness. In order to assess the degree of family-centredness, we used a modified rating scale based on a validated instrument, (same instrument used in the initial review), however, we decreased the family-centredness score for inclusion from 80% to 50% in this update. We also changed several other selection criteria in this update: eligible study designs are now limited to randomised controlled trials (RCTs) only; single interventions not reflecting a FCC model of care have been excluded; and the selection criterion whereby studies with inadequate or unclear blinding of outcome assessment were excluded from the review has been removed. Two review authors undertook searches, and four authors independently assessed studies against the review criteria, while two were assigned to extract data. We contacted study authors for additional information. Six studies found since 2004 were originally viewed as possible inclusions, but when the family-centred score assessment was tested, only one met the minimum score of family-centredness and was included in this review. This was an unpublished RCT involving 288 children post-tonsillectomy in a care-by-parent unit (CBPU) compared with standard inpatient care.The study used a range of behavioural, economic and physical measures. It showed that children in the CBPU were significantly less likely to receive inadequate care compared with standard inpatient admission, and there were no significant differences for their behavioural outcomes or other physical outcomes. Parents were significantly more satisfied with CBPU care than standard care, assessed both before discharge and at 7 days after discharge. Costs were lower for CPBU care compared with standard inpatient care. No other outcomes were reported. The study was rated as being at low to unclear risk of bias. This update of a review has found limited, moderate-quality evidence that suggests some benefit of a family-centred care intervention for children's clinical care, parental satisfaction, and costs, but this is based on a small dataset and needs confirmation in larger RCTs. There is no evidence of harms. Overall, there continues to be little high-quality quantitative research available about the effects of family-centred care. Further rigorous research on the use of family-centred care as a model for care delivery to children and families in hospitals is needed. This research should implement well-developed family-centred care interventions, ideally in randomised trials. It should investigate diverse participant groups and clinical settings, and should assess a wide range of outcomes for children, parents, staff and health services.


Which Benefits Are Mentioned Most Often in Drug Development Publications?
The aim was to identify theoretically expected as well as actually reported benefits from drug development and the importance of individual patient benefits compared to the collective benefits to society in general. Ethical guidelines require that clinical research involving humans offer the potential for benefit. A number of characteristics can be applied to define research benefit. Often benefit is categorized as being either direct or indirect. Indirect benefits can involve collective benefits for society rather than any benefits to the trial patient or subject. The purpose of this review was to examine which potential individual and societal benefits were mentioned as being expected in publications from government experts and which were mentioned in publications describing completed drug development trial results. Literature on research benefit was first identified by searching the PubMed database using several combinations of the key words benefit and clinical research. The search was limited to articles published in English. A Google search with the same combinations of key words but without any language limitation was then performed. Additionally, the reference lists of promising articles were screened for further thematically related articles. Finally, a narrative review was performed of relevant English- and German-language articles published between 1996 and 2016 to identify which of several potential benefits were either theoretically expected or which were mentioned in publications on clinical drug development trial results. The principal benefits from drug development discussed included 2 main types of benefit, namely individual benefits for the patients and collective benefits for society. Twenty-one of an overall total of 26 articles discussing theoretically expected benefits focused on individual patient benefits, whereas 17 out of 26 articles mentioned collective benefits to society. In these publications, the most commonly mentioned theoretically expected individual patient benefit was the chance to receive up-to-date care (38.1%). A general increase in knowledge about health care, treatments, or drugs (70.6%) was the most commonly mentioned theoretically expected benefit for society. In contrast, all 13 publications reporting actual benefits of clinical drug development trials focused on personal benefits and only 1 of these publications also mentioned a societal benefit. The most commonly mentioned individual benefit was an increased quality of life (53.9%), whereas the only mentioned collective benefit to society was a general gain of knowledge (100.0%). Both theoretically expected and actually reported benefits in the majority of the included publications emphasized the importance of individual patient benefits from drug development rather than the collective benefits to society in general. The authors of these publications emphasized the right of each individual patient or subject to look for and expect some personal benefit from participating in a clinical trial rather than considering societal benefit as a top priority. From an ethical point of view, the benefits each individual patient receives from his or her participation in a clinical trial might also be seen as a societal benefit, especially when the drug or device tested, if approved for marketing, would eventually be made available for other similar patients from the country in which the clinical trial was conducted.


NS3 is a serine protease required for processing of hepatitis C virus polyprotein.
Hepatitis C virus (HCV) possesses a positive-sense RNA genome which encodes a large polyprotein of 3,010 amino acids. Previous data and sequence analysis have indicated that this polyprotein is processed by cellular proteases and possibly by a virally encoded serine protease localized in the N-terminal domain of nonstructural protein NS3. To characterize the molecular aspects of HCV protein biogenesis and to clearly identify the protein products derived from the HCV genome, we have examined HCV polyprotein expression by using the vaccinia virus T7 transient expression system in transfected cells and by cell-free translation studies. HCV proteins were identified by immunoprecipitation with region-specific antisera. Here we show that the amino-terminal region of the HCV polyprotein is processed in vitro by cellular proteases releasing three structural proteins: p21 (core), gp37 (E1), and gp61 (E2). Processing of the nonstructural region of HCV was evident in transfected cells. Two proteins of 24 and 68 kDa were immunoprecipitated with anti-NS2 and NS3 antisera, respectively. Antiserum against NS4 recognized three proteins of 6, 26, and 31 kDa, while antisera specific for NS5 immunoprecipitated two polypeptides of 56 and 65 kDa, indicating that each of these two genes encodes at least two different proteins. When the NS3 protease domain was inactivated by replacing the proposed catalytic Ser-1165 with Ala, processing at several sites was abolished. When Ser-1164 was mutated to Ala, no effect on the processing was observed. Cleavage activities at three of the four sites affected by NS3 were shown to occur in trans, while processing at the carboxy terminus of NS3 could not be mediated in trans. These results provide a detailed description of the protein products obtained from the processing of the HCV polyprotein. Furthermore, the data obtained implicate NS3 as a serine protease and demonstrate that a catalytically active NS3 is necessary for cleavage of the nonstructural region of HCV.


Low frequency temporal modulation of light promotes a myopic shift in refractive compensation to all spectacle lenses.
Emmetropization, the process by which ocular growth of young animals adapts to ensure focussed retinal images, can be disrupted by high frequency flicker, causing a hypermetropic shift. Emmetropization can also be disrupted differentially, in a sign dependent manner, by pharmacological alteration of the balance of activation of the ON and OFF retinal sub-systems in normal light or by rearing in an environment with a moving spatiotemporally varied diamond pattern (yielding local sawtooth illumination on the retina). Thus the aim of this experiment was to determine whether low frequency temporal modulation alone was sufficient to cause defocus sign-dependent interference with compensation. Chicks were reared for 6 or 7 days with monocular +/-10 D, 0 D, or No Lenses in a 12h light/dark cycle. Luminance of the environment was temporally modulated during the light cycle with a non-square wave profile pulse of 250 msec duration, with the illumination fluctuating between 1.5 and 180 lux at 1 Hz, 2 Hz, 4 Hz or with no flicker (0 Hz-180 lux). Final refractive state and ocular dimensions, measured using retinoscopy and A-scan ultrasonography, demonstrated that in the absence of temporal luminance modulation (0 Hz), chicks compensated to induced defocus in the expected sign-dependent manner. However, under 1, 2 and 4 Hz flickering light conditions, there was an overall myopic offset of approximately 6D across lens groups with refractive compensation to positive lenses more strongly inhibited. This myopic offset was reflected by increases in the depth of both vitreous and anterior chambers. However, luminance modulation had no effect on refraction or ocular parameters in the No Lens conditions. This is a hitherto unreported strong interaction between lens wear and low frequency temporally modulated light, with the refractive compensation mechanism being overridden by a generalized myopic shift.


Interleukin 21 (IL-21) regulates chronic allograft vasculopathy (CAV) in murine heart allograft rejection.
IL-21 is the most recently discovered common gamma-chain cytokine that promotes persistent T-cell responses in chronic infections, autoimmunity and cancer. However, the therapeutic potential of inhibiting the IL-21-BATF signaling axis, particularly in transplant rejection, remains unclear. We used heart transplant models to examine the effects of IL-21 blockade in prevention of chronic cardiac allograft vasculopathy (CAV) using genetic knock-out and therapeutic approaches. Both wild-type C57BL/6 and IL-21-/- strains acutely rejected Balb/c skin grafts and once immunized with this skin graft, rejected Balb/c heart allografts in an accelerated fashion. However, when transplanted with heart grafts from the class-II major histocompatibility complex mutant, B6bm12 mice; wild-type recipients developed CAV, while IL-21-/- recipients were protected, even at day 100 post-transplant. Similarly, BATF-/- recipients, lacking the transcription factor BATF responsible for IL-21 production, did not develop CAV in B6-bm12 heart allografts. Strikingly, in a transient treatment protocol, the development of CAV in wild-type recipients of B6-bm12 hearts allografts was blocked by the administration of IL-21 receptor fusion protein (R-Fc). Thus, we demonstrate that CAV is regulated at least in part by IL-21 signaling and its blockade by genetic approaches or therapy with IL-21R-Fc prevents CAV in mice.


River biofilms adapted to anthropogenic disturbances are more resistant to WWTP inputs.
The sensitivity and spatial recovery of river sediment biofilms along 1 km after the input of two wastewater treatment plants (WWTPs) located in two river reaches with different degrees of anthropogenic influence were investigated. First, at the upper reach, we observed an inhibition of some microbial functions (microbial respiration and extracellular enzyme activities) and strong shifts in bacterial community composition (16S rRNA gene), whereas an increase in microbial biomass and activity and less pronounced effect on microbial diversity and community composition were seen at the lower reach. Second, at the lower reach we observed a quick spatial recovery (around 200 m downstream of the effluent) as most of the functions and community composition were similar to those from reference sites. On the other hand, bacterial community composition and water quality at the upper reach was still altered 1 km from the WWTP effluent. Our results indicate that biofilms in the upstream sites were more sensitive to the effect of WWTPs due to a lower degree of tolerance after a disturbance than communities located in more anthropogenically impacted sites.


OPTN/SRTR 2012 Annual Data Report: liver.
Liver transplant in the us remains a successful life-saving procedure for patients with irreversible liver disease. In 2012, 6256 adult liver transplants were performed, and more than 65,000 people were living with a transplanted liver. The number of adults who registered on the liver transplant waiting list decreased for the first time since 2002; 10,143 candidates were added, compared with 10,359 in 2011. However, the median waiting time for active wait-listed adult candidates increased, as did the number of candidates removed from the list because they were too sick to undergo transplant. The overall deceased donor transplant rate decreased to 42.3 per 100 patient-years, and varied geographically from 18.9 to 228.0 per 100 patient-years. Graft survival continues to improve, especially for donation after circulatory death livers. The number of new active pediatric candidates added to the waiting list also decreased. Almost 75% of pediatric candidates listed in 2009 underwent transplant within 3 years; the 2012 rate of deceased donor transplants among active pediatric wait-listed candidates was 136 per 100 patient-years. Graft survival for deceased donor pediatric transplants was 92.8% at 30 days. Medicare paid for some or all of the care for more than 30% of liver transplants in 2010.


Entrepreneurship.
High-tech businesses are the driving force behind global knowledge-based economies. Academic institutions have positioned themselves to serve the high-tech industry through consulting, licensing, and university spinoffs. The awareness of commercialization strategies and building an entrepreneurial culture can help academics to efficiently transfer their inventions to the market to achieve the maximum value. Here, the concept of high-tech entrepreneurship is discussed from lab to market in technology-intensive sectors such as nanotechnology, photonics, and biotechnology, specifically in the context of lab-on-a-chip devices. This article provides strategies for choosing a commercialization approach, financing a startup, marketing a product, and planning an exit. Common reasons for startup company failures are discussed and guidelines to overcome these challenges are suggested. The discussion is supplemented with case studies of successful and failed companies. Identifying a market need, assembling a motivated management team, managing resources, and obtaining experienced mentors lead to a successful exit.


Andrographolide sensitizes prostate cancer cells to TRAIL-induced apoptosis.
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising agent for anticancer therapy. The identification of small molecules that can establish the sensitivity of prostate cancer (PCa) cells to TRAIL-induced apoptosis is crucial for the targeted treatment of PCa. PC3, DU145, JAC-1, TsuPr1, and LNCaP cells were treated with Andrographolide (Andro) and TRAIL, and the apoptosis was measured using the Annexin V/PI double staining method. Real time-polymerase chain reaction (PCR) and Western blot analysis were performed to measure the expression levels of target molecules. RNA interference technique was used to down-regulate the expression of the target protein. We established a nude mouse xenograft model of PCa, which was used to measure the caspase-3 activity in the tumor cells using flow cytometry. In this research study, our results demonstrated that Andro preferentially increased the sensitivity of PCa cells to TRAIL-induced apoptosis at subtoxic concentrations, and the regulation mechanism was related to the up-regulation of DR4. In addition, it also increased the p53 expression and led to the generation of reactive oxygen species (ROS) in the cells. Further research revealed that the DR4 inhibition, p53 expression, and ROS generation can significantly reduce the apoptosis induced by the combination of TRAIL and Andro in PCa cells. In conclusion, Andro increases the sensitivity of PCa cells to TRAIL-induced apoptosis through the generation of ROS and up-regulation of p53 and then promotes PCa cell apoptosis associated with the activation of DR4.


Exploring the Predictors of Post-Clerkship USMLE Step 1 Scores.
Theory: We used two theoretical frameworks for this study: a) experiential learning, whereby learners construct new knowledge based on prior experience, and learning grows out of a continuous process of reconstructing experience, and b) deliberate practice, whereby the use of testing (test-enhanced learning) promotes learning and produces better long-term retention. Hypothesis: We hypothesized that moving the USMLE Step 1 exam to follow the clerkship year would provide students with a context for basic science learning that may enhance exam performance. We also hypothesized that examination performance variables, specifically National Board of Medical Examiners (NBME) Customized Basic Science Examinations and NBME subject examinations in clinical disciplines would account for a moderate to large amount of the variance in Step 1 scores. Thus we examined predictors of USMLE Step 1 scores when taken after the core clerkship year. Method: In 2011, we revised our medical school curriculum and moved the timing of Step 1 to follow the clerkship year. We performed descriptive statistics, an ANCOVA to compare Step 1 mean scores for three graduating classes of medical students before and after the curriculum changes, and stepwise linear regression to investigate the association between independent variables and the primary outcome measure after curriculum changes. Results: 993 students took the Step 1 exam, which included graduating classes before (2012-2014, N = 491) and after (2015-2017, N = 502) the curriculum change. Step 1 scores increased significantly following curricular revision (mean 218, SD 18.2, vs. 228, SD 16.7, p < 0.01) after controlling for MCAT and undergraduate GPA. Overall, 66.4% of the variance in Step 1 scores after the clerkship year was explained by: the mean score on fourteen pre-clerkship customized NBME exams (p < 0.01, 57.0% R2); performance on the surgery NBME subject exam (p < 0.01, 3.0% R2); the pediatrics NBME subject exam (p < 0.01, 2.0% R2); the Comprehensive Basic Science Self-Assessment (p < .01, 2.0% R2) ; the internal medicine NBME subject exam (p < 0.01, 0.03% R2), pre-clerkship Integrated Clinical Skills score (p < 0.01, 0.05% R2), and the pre-matriculation MCAT (p < 0.01, 0.01% R2). Conclusion: In our institution, nearly two-thirds of the variance in performance on Step 1 taken after the clerkship year was explained mainly by pre-clerkship variables, with a smaller contribution emanating from clerkship measures. Further study is needed to uncover the specific aspects of the clerkship experience that might contribute to success on high stakes licensing exam performance.


Automated Pulmonary Nodule Classification in Computed Tomography Images Using a Deep Convolutional Neural Network Trained by Generative Adversarial Networks.
Lung cancer is a leading cause of death worldwide. Although computed tomography (CT) examinations are frequently used for lung cancer diagnosis, it can be difficult to distinguish between benign and malignant pulmonary nodules on the basis of CT images alone. Therefore, a bronchoscopic biopsy may be conducted if malignancy is suspected following CT examinations. However, biopsies are highly invasive, and patients with benign nodules may undergo many unnecessary biopsies. To prevent this, an imaging diagnosis with high classification accuracy is essential. In this study, we investigate the automated classification of pulmonary nodules in CT images using a deep convolutional neural network (DCNN). We use generative adversarial networks (GANs) to generate additional images when only small amounts of data are available, which is a common problem in medical research, and evaluate whether the classification accuracy is improved by generating a large amount of new pulmonary nodule images using the GAN. Using the proposed method, CT images of 60 cases with confirmed pathological diagnosis by biopsy are analyzed. The benign nodules assessed in this study are difficult for radiologists to differentiate because they cannot be rejected as being malignant. A volume of interest centered on the pulmonary nodule is extracted from the CT images, and further images are created using axial sections and augmented data. The DCNN is trained using nodule images generated by the GAN and then fine-tuned using the actual nodule images to allow the DCNN to distinguish between benign and malignant nodules. This pretraining and fine-tuning process makes it possible to distinguish 66.7% of benign nodules and 93.9% of malignant nodules. These results indicate that the proposed method improves the classification accuracy by approximately 20% in comparison with training using only the original images.


Regulation of calcium signalling in T lymphocytes by the second messenger cyclic ADP-ribose.
Cyclic ADP-ribose (cADPR) is a natural compound that mobilizes calcium ions in several eukaryotic cells. Although it can lead to the release of calcium ions in T lymphocytes, it has not been firmly established as a second messenger in these cells. Here, using high-performance liquid chromatography analysis, we show that stimulation of the T-cell receptor/CD3 (TCR/CD3) complex results in activation of a soluble ADP-ribosyl cyclase and a sustained increase in intracellular levels of cADPR. There is a causal relation between increased cADPR concentrations, sustained calcium signalling and activation of T cells, as shown by inhibition of TCR/CD3-stimulated calcium signalling, cell proliferation and expression of the early- and late-activation markers CD25 and HLA-DR by using cADPR antagonists. The molecular target for cADPR, the type-3 ryanodine receptor/calcium channel, is expressed in T cells. Increased cADPR significantly and specifically stimulates the apparent association of [3H]ryanodine with the type-3 ryanodine receptor, indicating a direct modulatory effect of cADPR on channel opening. Thus we show the presence, causal relation and biological significance of the major constituents of the cADPR/calcium-signalling pathway in human T cells.


Profiling of temperature-induced changes in Borrelia burgdorferi gene expression by using whole genome arrays.
Borrelia burgdorferi is the etiologic agent of Lyme disease, the most prevalent arthropod-borne disease in the United States. The genome of the type strain, B31, consists of a 910,725-bp linear chromosome and 21 linear and circular plasmids comprising 610,694 bp. During its life cycle, the spirochete exists in distinctly different environments, cycling between a tick vector and a mammalian host. Temperature is one environmental factor known to affect B. burgdorferi gene expression. To identify temperature-responsive genes, genome arrays containing 1,662 putative B. burgdorferi open reading frames (ORFs) were prepared on nylon membranes and employed to assess gene expression in B. burgdorferi B31 grown at 23 and 35 degrees C. Differences in expression of more than 3.5 orders of magnitude could be readily discerned and quantitated. At least minimal expression from 91% of the arrayed ORFs could be detected. A total of 215 ORFs were differentially expressed at the two temperatures; 133 were expressed at significantly greater levels at 35 degrees C, and 82 were more significantly expressed at 23 degrees C. Of these 215 ORFs, 134 are characterized as genes of unknown function. One hundred thirty-six (63%) of the differentially expressed genes are plasmid encoded. Of particular interest is plasmid lp54 which contains 76 annotated putative genes; 31 of these exhibit temperature-regulated expression. These findings underscore the important role plasmid-encoded genes may play in adjustment of B. burgdorferi to growth under diverse environmental conditions.


Clinical presentation of leptospirosis: a retrospective study of 201 patients in a metropolitan city of Brazil.
leptospirosis is a zoonosis of worldwide importance. The disease is endemic in Brazil. This study was conducted to describe the clinical and laboratory presentation of leptospirosis in a metropolitan city of Brazil. this is a retrospective study including 201 consecutive patients with leptospirosis admitted to tertiary hospitals in Fortaleza, Brazil, between 1985 and 2006. All patients had clinical and epidemiological data suggestive of leptospirosis, and positive laboratorial test for leptospirosis (microscopic agglutination test, MAT, higher than 1:800). a total of 201 patients were included, with mean age of 38.9 + or - 15.7 years; 79.1% were male. The mean length from onset of symptoms to admission was 7 + or - 3 days. The main clinical signs and symptoms at admission were fever (96.5%), jaundice (94.5%), myalgia (92.5%), headache (74.6%), vomiting (71.6%) and dehydration (63.5%). Hemorrhagic manifestations were present in 35.8%. Acute kidney injury was found in 87% of the patients. Platelet count was less than 100,000/mm(3) in 74.3%. Hematuria was found in 42.9%. Death occurred in 31 cases (15.4%). leptospirosis is a globally relevant disease with potential fatal outcome. Signs and symptoms suggestive of leptospirosis must be known by any physician in order to institute early adequate treatment to improve outcome. Early indication and daily hemodialysis seems to be beneficial in this group of patients.


[Infective endocarditis in the elderly].
The influence of age on the clinical presentation and on the prognosis of infective endocarditis (IE) is unclear. Our aim was to analyse the epidemiologic, clinical and bacteriological characteristics of IE in the elderly compared with younger adult patients. PATIENTS AND METHODS A retrospective study of all patients with IE non intravenous drug users diagnosed in our hospital during the period from 1990 to 2000. We used the Duke criteria to compare the characteristics of 46 episodes of definitive IE in elderly patients (>65 years old ) and of 46 episodes in younger adult patients (20-64 years of age ). No significant differences were observed among the two groups with respect to the delay in diagnosed, possible source of infection, the frequency of positive blood cultures and the type of infective organism, clinical presentation and evolution of the IE. Elderly patients more often had risk factors predisposing (degenerative valvular disease, prosthetic valve and pacemaker ), which decreased the sensitivity of transthoracic echocardiography to 46.5% compared with 64.4% in the younger patients. Transesophageal echocardiography improved the diagnostic of IE in the 37.2% in elderly patients. The patients in the both groups underwent surgical therapy with similar frequency (36.9% in the elderly and the 39.1% in the younger adult patient ) and the mortality rate not was significantly higher in the elderly (19.5%) than in the younger adult patients (10.8%). The age itself is not a poor prognostic, and should not be used prejudicially in denying a early and aggressive treatment of the patients with IE.


Macular measurements using optical coherence tomography in healthy Chinese school age children.
To evaluate macular thickness/volume in a Chinese population of primary school children using optical coherence tomography (OCT), and assess its association with age, sex, spherical equivalent refraction (SE), body mass index (BMI), and intraocular pressure (IOP). Healthy Chinese children (n = 806) from six randomly selected primary schools in Chongming County, Shanghai, China, were enrolled. Comprehensive standardized ophthalmic examinations included visual acuity, cycloplegic refraction, IOP, and fast macular scans using Stratus OCT. Mean values for the nine Early Treatment Diabetic Retinopathy Study (ETDRS) areas, foveal minimum thickness, and macular volume were calculated. OCT data from right eyes with high-quality scans were evaluated in 720 children (89.3% of total participants; 46.5% boys). Macular thickness and volume were normally distributed. The mean foveal minimum thickness was 140.0 ± 12.3 μm. There were significant differences between the boys and the girls in mean foveal volume (P = 0.023) and sectoral macular thickness in all the quadrants of the inner ring (P < 0.001 and P = 0.001) and temporal outer quadrant (P = 0.009). SE refraction correlated positively with inner and outer macular thickness and total macular volume (P < 0.001) and negatively with central macular volume (P = 0.012). BMI correlated significantly only with outer macular thickness (r = 0.074, P = 0.048). No age- and IOP-related differences were found in the macular parameters. OCT demonstrated that macular thickness/volume was normally distributed in this sample of Chinese children, with variations in sex and SE. The variables in macular thickness/volume should be considered when diagnosing and monitoring school-aged children with diseases that affect the macula.


A ten year review of atrioventricular septal defects.
To review all cases of atrioventricular septal defects in Northern Ireland from January 1990 to February 1999, examining clinical and morphological features, management, and outcome. A retrospective case note analysis of 106 subjects with comparisons between subgroups. An atrioventricular septal defect was part of a more complex abnormality in 50 of the patients (47%). Down's syndrome was present in 57 (54%). Cardiac surgery was performed in 81%. The defects were unrestrictive in 69 patients (65%), 45 of whom had Down's syndrome. Complex associated abnormalities existed in 36 patients, and 10 of these died without cardiac surgery. Operative mortality was 9.5% for those with co-existing Down's syndrome group, and 14.3% for the chromosomally normal patients. The ventricular components of the septal defect were restrictive in 23 patients (22%), with 9 having Down's syndrome. Spontaneous closure occurred in more than half of these patients. Mortality was zero. The septal defect was exclusively at atrial level in 14 patients ("primum" defects--13%), and 3 of these had Down's syndrome. Operative mortality was again zero. Median duration of postoperative follow-up was 3 and a half years. Overall, moderate to severe left atrioventricular valvar regurgitation was observed postoperatively in 23% at follow-up. Mortality was highest in the atrioventricular septal defects with an unrestrictive ventricular component. Uncomplicated cases had good outcomes. Patients without Down's syndrome tended to have more associated cardiac abnormalities, and to have more postoperative arrhythmias. Approximately half of the defects with restrictive ventricular components closed spontaneously. Moderate postoperative left atrioventricular valvar regurgitation was commonest in patients with the defect exclusively at atrial level.


An immunoglobulin heavy-chain gene is altered in two T-cell clones.
Thymus-derived lymphocytes (T cells) show a high degree of discrimination in their responses to various antigens, very similar to the specificity repertoire of antibody-producing B cells. The nature of the T-cell receptor which mediates antigen recognition is obscure, but the ability to discriminate between antigenic specificities implies a range of receptor specificities. Many serological and genetic data suggest that T-cell receptors use the immunoglobulin heavy (H)-chain variable (V) region genes but do not carry the antigenic determinants of the immunoglobulin H-chain constant (C) regions; they also do not seem to carry conventional light (L)-chain V- or C-region determinants. In B cells and derivatives the expression of immunoglobulin genes is manifested, at the DNA level, by an alteration of the restriction enzyme patterns of both the H and L immunoglobulin genes. Specifically, V-gene integration involves joining of a V gene with a J segment (in the case of the H chain probably through an intermediate D segment) so that sites for restriction enzymes will undergo changes in cells in which V-J joining has occurred. Here, we describe Southern filter hybridization experiments using C mu and C kappa probes on the DNA of individual T-cell clones from mice, and present evidence for alteration of sequences adjacent to the C mu gene in the cells.


Inside the "Black Box" of a Knowledge Translation Program in Applied Health Research.
In this article, we present the findings of a participatory realistic evaluation of a 5-year program of health care research intended to promote the translation of knowledge into routine clinical practice. The program was one of the nine pilot Collaborations for Leadership in Applied Health Research and Care funded by the English National Institute for Health Research between 2008 and 2013. Our aim was to delineate the mechanisms by which, and circumstances in which, some projects carried out under the program achieved success in knowledge translation while others were frustrated. Using qualitative methods, we examined how closer collaboration between academics and clinicians worked in four purposefully chosen case studies. In a synthesis of the findings, we produced a "black box" model of how knowledge translation was enabled by the activation of nine mechanisms. These are summarized in the form of five simple rules for promoting knowledge translation through collaborations based on principles of coproduction.


Salt Mediated Self-Assembly of Poly(ethylene glycol)-Functionalized Gold Nanorods.
Although challenging, assembling and orienting non-spherical nanomaterials into two- and three-dimensional (2D and 3D) ordered arrays can facilitate versatile collective properties by virtue of their shape-dependent properties that cannot be realized with their spherical counterparts. Here, we report on the self-assembly of gold nanorods (AuNRs) into 2D films at the vapor/liquid interface facilitated by grafting them with poly(ethylene glycol) (PEG). Using surface sensitive synchrotron grazing incidence small angle X-ray scattering (GISAXS) and specular X-ray reflectivity (XRR), we show that PEG-AuNRs in aqueous suspensions migrate to the vapor/liquid interface in the presence of salt, forming a uniform monolayer with planar-to-surface orientation. Furthermore, the 2D assembled PEG functionalized AuNRs exhibit short range order into rectangular symmetry with side-by-side and tail-to-tail nearest-neighbor packing. The effect of PEG chain length and salt concentration on the 2D assembly are also reported.


Suture, synthetic, or biologic in contaminated ventral hernia repair.
Data are lacking to support the choice between suture, synthetic mesh, or biologic matrix in contaminated ventral hernia repair (VHR). We hypothesize that in contaminated VHR, suture repair is associated with the lowest rate of surgical site infection (SSI). A multicenter database of all open VHR performed at from 2010-2011 was reviewed. All patients with follow-up of 1 mo and longer were included. The primary outcome was SSI as defined by the Centers for Disease Control and Prevention. The secondary outcome was hernia recurrence (assessed clinically or radiographically). Multivariate analysis (stepwise regression for SSI and Cox proportional hazard model for recurrence) was performed. A total of 761 VHR were reviewed for a median (range) follow-up of 15 (1-50) mo: there were 291(38%) suture, 303 (40%) low-density and/or mid-density synthetic mesh, and 167(22%) biologic matrix repair. On univariate analysis, there were differences in the three groups including ethnicity, ASA, body mass index, institution, diabetes, primary versus incisional hernia, wound class, hernia size, prior VHR, fascial release, skin flaps, and acute repair. The unadjusted outcomes for SSI (15.1%; 17.8%; 21.0%; P = 0.280) and recurrence (17.8%; 13.5%; 21.5%; P = 0.074) were not statistically different between groups. On multivariate analysis, biologic matrix was associated with a nonsignificant reduction in both SSI and recurrences, whereas synthetic mesh associated with fewer recurrences compared to suture (hazard ratio = 0.60; P = 0.015) and nonsignificant increase in SSI. Interval estimates favored biologic matrix repair in contaminated VHR; however, these results were not statistically significant. In the absence of higher level evidence, surgeons should carefully balance risk, cost, and benefits in managing contaminated ventral hernia repair.


Genetic variants associated with exercise performance in both moderately trained and highly trained individuals.
Adaptation to exercise training is a complex trait that may be influenced by genetic variants. We identified 36 single nucleotide polymorphisms (SNPs) that had been previously associated with endurance or strength performance, exercise-related phenotypes or exercise intolerant disorders. A MassARRAY multiplex genotyping assay was designed to identify associations with these SNPs against collected endurance fitness phenotype parameters obtained from two exercise cohorts (Gene SMART study; n = 58 and Hawaiian Ironman Triathlon 2008; n = 115). These parameters included peak power output (PP), a time trial (TT), lactate threshold (LT), maximal oxygen uptake (VO2 max) in recreationally active individuals and a triathlon time-to-completion (Hawaiian Ironman Triathlon cohort only). A nominal significance threshold of α < 0.05 was used to identify 17 variants (11 in the Gene SMART population and six in the Hawaiian Ironman Triathlon cohort) which were significantly associated with performance gains in highly trained individuals. The variant rs1474347 located in Interleukin 6 (IL6) was the only variant with a false discovery rate < 0.05 and was found to be associated with gains in VO2 max (additional 4.016 mL/(kg min) for each G allele inherited) after training in the Gene SMART cohort. In summary, this study found further evidence to suggest that genetic variance can influence training response in a moderately trained cohort and provides an example of the potential application of genomic research in the assessment of exercise trait response.


Activity of oxaliplatin against human tumor colony-forming units.
This study was conducted to identify tumor types warranting Phase II clinical trials of oxaliplatin using the human tumor cloning assay. Oxaliplatin was tested at concentrations ranging from 0.5 to 50.0 microg/ml in 1-h and 14-day continuous exposures along with 1.4 microg/ml carboplatin and 0.2 microg/ml cisplatin for comparison. We defined in vitro response as tumor growth inhibition >50% of control. In the 1-h exposure schedule, in vitro responses were observed in 9 of 116 (8%), 18 of 115 (16%), 38 of 103 (37%), and 7 of 13 (54%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. In the 14-day exposure schedule, in vitro responses were observed in 10 of 121 (8%), 37 of 121 (31%), 57 of 106 (54%), and 15 of 15 (100%) tumor specimens at concentrations of 0.5, 5.0, 10.0, and 50.0 microg/ml oxaliplatin, respectively. Activity was observed against colon cancer, non-small cell lung cancer, gastric cancer, and melanoma colony-forming units. In both cisplatin-resistant and cisplatin-sensitive tumors, the activity of oxaliplatin was concentration and time dependent. A 1-h exposure to 5.0 and 10.0 microg/ml oxaliplatin led to 7.4 and 23.4% in vitro responses, respectively, in specimens resistant to 1-h exposure of 0.2 microg/ml cisplatin. Moreover, 1-h exposures to 5.0 microg/ml and 10.0 microg/ml oxaliplatin showed in vitro antitumor responses in 10.2 and 24.3%, 17.2 and 34.5%, 10.0 and 20.0%, 6.7 and 16.7%, and 11.4 and 34.3% of specimens resistant to 1.4 microg/ml carboplatin, 6.0 microg/ml 5-fluorouracil, 3.0 microg/ml irinotecan, 10.0 microg/ml paclitaxel, and 0.04 microg/ml doxorubicin, respectively. The effect in those drug-resistant specimens was improved when oxaliplatin was used on the protracted exposure regimen. Our data indicate that oxaliplatin is an active drug in vitro against a large variety of human tumors. Both concentration and duration of exposure are important factors for oxaliplatin cytotoxicity. The broad spectrum of activity and the in vitro activity against some tumors primarily resistant to conventional anticancer drugs encourage further clinical investigations of oxaliplatin in patients with advanced cancer refractory to conventional chemotherapy.


Assessment of personal qualities in relation to admission to medical school.
Recently there has been much scrutiny of the medical school admissions process by universities, the General Medical Council and the public. Improved objectivity, fairness and effectiveness of selection procedures are desirable. The ultimate outcome sought is the graduation of competent doctors who reflect the values of and are in tune with the communities they serve. Applicants to the Scottish medical schools sat a battery of psychometric tests to measure cognitive ability, personality traits and moral/ethical reasoning (Personal Qualities Assessment, PQA). Analysis determined the potential impact of the latter variables, and those of educational background and socioeconomic class (assessed by residential 'deprivation category'), upon success in gaining a place to study medicine. Cognitive ability did not vary significantly as a function of gender or educational background, although there was a trend for it to be lower in individuals from more deprived backgrounds. Women as a group were more empathic, with a greater communitarian orientation, than men. There was no significant difference between individuals attending independent and state-funded schools in respect of any of the qualities measured by the PQA. Applicants from deprived backgrounds and those attending state-funded schools would not be disadvantaged by an admissions process based on the PQA. The incorporation of an assessment tool such as the PQA may have positive implications for widening access and the objective selection of suitable medical students, resulting in the training of doctors who are more representative of the community at large. A longterm follow-up of the professional careers of those medical students who completed the PQA will be undertaken.


Risk factors for recurrence after surgery in non-metastatic RCC with thrombus: a contemporary multicentre analysis.
To determine the predictors of post-surgical recurrence for patients with non-metastatic renal cell carcinoma (RCC) and venous thrombus. Records from consecutive patients with non-metastatic RCC with tumour thrombus, treated surgically between 2000 and 2012 at one of three centres, were reviewed. Univariable and multivariable analysis were used to evaluate the association of risk factors for post-surgical recurrence. A total of 465 patients with non-metastatic RCC were identified, including patients with thrombus present in the renal vein (257 patients, 55.3%), infrahepatic inferior vena cava (IVC; 144 patients, 31.0%) and suprahepatic IVC (64 patients, 13.8%). The median (interquartile range) follow-up was 28.3 (12.2-56.4) months, with metastatic RCC developing in 188 patients (40.5%). Independent predictors of recurrence included: body mass index ≤20 kg/m(2) (hazard ratio [HR] 2.66; 95% confidence interval [CI] 1.29-5.49), low preoperative haemoglobin (HR 1.54; 95% CI 1.07-2.20), perinephric fat invasion (HR 1.51; 95% CI 1.09-2.10), IVC thrombus height (HR 2.64; 95% CI 1.47-4.74), tumour diameter (HR 1.04 95% CI 1.00-1.09), nuclear grade (HR 1.56 95% CI 1.12-2.15) and non-clear-cell histology (HR 2.13; 95% CI 1.30-3.50). Independently predictive variables were used to create a recurrence model for three risk groups based on 0, 1-2, or >2 risk factors, respectively. The 5-year recurrence-free survival rate was significantly different in patients with favourable-risk (79.1%) compared with intermediate- (55.1%) or high-risk (22.1%) disease (P < 0.001). Seven risk factors for recurrence were identified for patients with non-metastatic RCC with thrombus, which can be used to select patients who may benefit from increased surveillance or adjuvant therapy clinical trials.


Molecular epidemiology and genotype distribution of Human Papillomavirus (HPV) among Arab women in the State of Qatar.
Human Papilloma Virus (HPV) infection is the major cause of cervical cancer worldwide. With limited data available on HPV prevalence in the Arab countries, this study aimed to identify the prevalence and genotypic distribution of HPV in the State of Qatar. 3008 cervical samples, exclusively of women with Arabic origin residing in Qatar were collected from the Women's Hospital and Primary Health Care Corporation in Doha, State of Qatar. HPV DNA detection was done using GP5+/6+ primers based real time-polymerase chain reaction (RT-PCR) assay followed by the usage of HPV type specific primers based RT- PCR reactions and Sanger sequencing for genotype identification. Similar prevalence rates of HPV infection was identified in both Qatari and non-Qatari women at 6.2% and 5.9% respectively. HPV prevalence rate of 5.8% and 18.4% was identified in women with normal cytology and in women with abnormal cytology respectively. HPV 81, 11 and 16, in decreasing order were the most commonly identified genotypes. HPV 81 was the most frequent low-risk genotype among women with both normal (74.0%) and abnormal (33.3%) cytology. HPV 16 (4.6%) was identified as the predominant high-risk HPV genotype among women with normal cytology and HPV 16, HPV 18, and HPV 56 (22.2% each) were the most common identified high-risk genotypes in women with abnormal cytology. The overall HPV prevalence in Arab women in Qatar was identified as 6.1% with an increased HPV prevalence seen in women with abnormal cytology results and no significant trends seen with age. In contrast to Western countries, we report a varied genotypic profile of HPV with a high prevalence of low-risk HPV genotype 81 among the Arab women residing in Qatar.


A case-sibling assessment of the association between skin pigmentation and other vitamin D-related factors and type 1 diabetes mellitus.
Fair skin pigmentation has been associated with a higher risk of type 1 diabetes mellitus (T1DM). The aim is to compare children with T1DM directly to a sibling in relation to their skin pigmentation in sun-exposed and unexposed sites, past sun exposure and methylation of the VDR gene promoter. The sample consisted of children with T1DM attending a diabetes outpatient clinic and siblings (total n=42). Cutaneous melanin density was estimated using a spectrophotometer. Parental report on past sun exposure was obtained. DNA methylation analysis of the VDR gene promoter was conducted. Matched data analysis was performed comparing each case directly to their sibling. Cases were significantly more likely to have lighter skin pigmentation at the upper arm (AOR 0.69 [95% CI: 0.52, 0.90]; P=0.01). Low infant sun exposure was imprecisely associated with a two-fold increase in T1DM risk (AOR 2.43 [95% CI: 0.91, 6.51]; P=0.08 for under 1 h of winter sun exposure per leisure day). The VDR gene promoter was completely unmethylated in both cases and siblings. The previously demonstrated association between light skin pigmentation and T1DM risk was evident even in this comparison across sibling pairs. Further work on past UVR exposure and related factors such as skin pigmentation is required.


Genetic approaches to metabolic bone diseases.
Metabolic bone diseases comprise a diverse group of disorders characterized by alterations in skeletal homeostasis, and are often associated with abnormal circulating concentrations of calcium, phosphate or vitamin D metabolites. These diseases commonly have a genetic basis and represent either a monogenic disorder due to a germline or somatic single gene mutation, or an oligogenic or polygenic disorder that involves variants in more than one gene. Germline single gene mutations causing Mendelian diseases typically have a high penetrance, whereas the genetic variations causing oligogenic or polygenic disorders are each associated with smaller effects with additional contributions from environmental factors. Recognition of familial monogenic disorders is of clinical importance to facilitate timely investigations and management of the patient and any affected relatives. The diagnosis of monogenic metabolic bone disease requires careful clinical evaluation of the large diversity of symptoms and signs associated with these disorders. Thus, the clinician must pursue a systematic approach beginning with a detailed history and physical examination, followed by appropriate laboratory and skeletal imaging evaluations. Finally, the clinician must understand the increasing number and complexity of molecular genetic tests available to ensure their appropriate use and interpretation.


Role of EEG as biomarker in the early detection and classification of dementia.
The early detection and classification of dementia are important clinical support tasks for medical practitioners in customizing patient treatment programs to better manage the development and progression of these diseases. Efforts are being made to diagnose these neurodegenerative disorders in the early stages. Indeed, early diagnosis helps patients to obtain the maximum treatment benefit before significant mental decline occurs. The use of electroencephalogram as a tool for the detection of changes in brain activities and clinical diagnosis is becoming increasingly popular for its capabilities in quantifying changes in brain degeneration in dementia. This paper reviews the role of electroencephalogram as a biomarker based on signal processing to detect dementia in early stages and classify its severity. The review starts with a discussion of dementia types and cognitive spectrum followed by the presentation of the effective preprocessing denoising to eliminate possible artifacts. It continues with a description of feature extraction by using linear and nonlinear techniques, and it ends with a brief explanation of vast variety of separation techniques to classify EEG signals. This paper also provides an idea from the most popular studies that may help in diagnosing dementia in early stages and classifying through electroencephalogram signal processing and analysis.


Mild Cognitive Impairment and Dementia Involving Multiple Cognitive Domains in Mexican Urbanites.
Exposures to fine particulate matter PM2.5 and ozone O3 are associated with Alzheimer's disease (AD) risk. Mexico City residents have lifetime exposures to PM2.5 and O3 above annual USEPA standards and their brains contain high redox, combustion, and friction-derived magnetite nanoparticles. AD pathological changes with subcortical pre-tangle stages in infancy and cortical tau pre-tangles, NFT Stages I-II, and amyloid phases 1-2 are identified by the 2nd decade. Given their AD continuum, a reliable identification of cognitive impairment is of utmost importance. The Montreal Cognitive Assessment (MoCA) was administered to 517 urbanites, age 21.60±5.88 years, with 13.69±1.28 formal education years, in Mexican PM2.5 polluted cities. MoCA score was 23.92±2.82, and 24.7% and 30.3% scored ≤24 and ≤22, respectively (MCI≤24, AD≤22). Cognitive deficits progressively targeted Visuospatial, Executive, Language, and Memory domains, body mass index (BMI) impacting total scores negatively (p = 0.0008), aging driving down Executive, Visuospatial, and Language index scores (p < 0.0001, 0.0037, and 0.0045), and males performing better in Executive tasks. Average age for AD MoCA scores was 22.38±7.7 years. Residency in polluted cities is associated with progression of multi-domain cognitive impairment affecting 55% of Mexican seemingly healthy youth. Normal BMI ought to be a neuroprotection goal. MoCA provides guidance for further mandatory neuropsychological testing in young populations. Identifying and lowering key neurotoxicants impacting neural risk trajectories in the developing brain and monitoring cognitive performance would greatly facilitate multidisciplinary early diagnosis and prevention of AD in high risk young populations. Cognitive deficits hinder development of those representing the force moving the country in future years.


Increasing value and reducing waste in biomedical research: who's listening?
The biomedical research complex has been estimated to consume almost a quarter of a trillion US dollars every year. Unfortunately, evidence suggests that a high proportion of this sum is avoidably wasted. In 2014, The Lancet published a series of five reviews showing how dividends from the investment in research might be increased from the relevance and priorities of the questions being asked, to how the research is designed, conducted, and reported. 17 recommendations were addressed to five main stakeholders-funders, regulators, journals, academic institutions, and researchers. This Review provides some initial observations on the possible effects of the Series, which seems to have provoked several important discussions and is on the agendas of several key players. Some examples of individual initiatives show ways to reduce waste and increase value in biomedical research. This momentum will probably move strongly across stakeholder groups, if collaborative relationships evolve between key players; further important work is needed to increase research value. A forthcoming meeting in Edinburgh, UK, will provide an initial forum within which to foster the collaboration needed.


Ultrafast Photophysics of a Dinitrogen-Bridged Molybdenum Complex.
Among the many metal-dinitrogen complexes synthesized, the end-on bridging (μ2, η1, η1-N2) coordination mode is notoriously unreactive for nitrogen fixation. This is principally due to the large activation energy for ground-state nitrogen-element bond formation and motivates exploration of the photoexcited reactivity of this coordination mode. To provide the foundation for this concept, the photophysics of a dinitrogen-bridged molybdenum complex was explored by ultrafast electronic spectroscopies. The complex absorbs light from the UV to near-IR, and the transitions are predominantly of metal-to-ligand charge transfer (MLCT) character. Five excitation wavelengths (440, 520, 610, 730, and 1150 nm) were employed to access MLCT bands, and the dynamics were probed between 430 and 1600 nm. Despite the large energy space occupied by electronic states (ca. 1.2 eV), the dynamics were independent of the excitation wavelength. In the proposed kinetic model, photoexcitation from a Mo-N═N-Mo centered ground state populates the π*-state delocalized over two terpyridine ligands. Due to a large terpyridine-terpyridine spatial separation, electronic localization occurs within 100 fs, augmented by symmetry breaking. The subsequent interplay of internal conversion and intersystem crossing (ISC) populates the lowest 3MLCT state in 2-3 ps. Decay to the ground state occurs either directly or via a thermally activated metal-centered (3MC) trap state having two time constants (10-15 ps, 23-26 ps [298 K]; 103 ps, 612 ps [77 K]). ISC between 1MLCT and 3MLCT involves migration of energized electron density from the terpyridine π* orbitals to the Mo-N═N-Mo core. Implication of the observed dynamics for the potential N-H bond forming reactivity are discussed.


Image subtraction by solid state electroradiography.
An analog radiographic image subtraction technique is presented. A selenium photoconductor is used as the radiation sensitive medium and image subtraction is achieved by electrostatically adding latent images of opposite polarities to get a latent image of the region of interest. In principle, the technique is simple and a comparison with commercial digital techniques shows a similar image quality, suggesting that the electrostatic subtraction technique could be developed into a clinical tool as an inexpensive alternative to digital radiography.


A Y chromosome census of the British Isles.
The degree of population replacement in the British Isles associated with cultural changes has been extensively debated. Recent work has demonstrated that comparisons of genetic variation in the British Isles and on the European Continent can illuminate specific demographic processes in the history of the British Isles. For example, Wilson et al. used the similarity of Basque and Celtic Y chromosomes to argue for genetic continuity from the Upper Palaeolithic to the present in the paternal history of these populations (see also ). Differences in the Y chromosome composition of these groups also suggested genetic signatures of Norwegian influence in the Orkney Islands north of the Scottish mainland, an important center of Viking activities between 800 and 1300 A.D. More recently, Weale et al. argued for substantial Anglo-Saxon male migration into central England based on the analysis of eight British sample sets collected on an east-west transect across England and Wales. To provide a more complete assessment of the paternal genetic history of the British Isles, we have compared the Y chromosome composition of multiple geographically distant British sample sets with collections from Norway (two sites), Denmark, and Germany and with collections from central Ireland, representing, respectively, the putative invading and the indigenous populations. By analyzing 1772 Y chromosomes from 25 predominantly small urban locations, we found that different parts of the British Isles have sharply different paternal histories; the degree of population replacement and genetic continuity shows systematic variation across the sampled areas.


Forage and rangeland plants from uranium mine soils: long-term hazard to herbivores and livestock?
Metalliferous uranium mine overburden soils integrated into arable land or stabilized by perennial rangeland plants evoke concern about the quality of crops and the exposure of grazing and thereby soil-ingesting (wildlife) herbivores to heavy metals (HM) and radionuclides. In a 2-year trial, thirteen annual and perennial forage and rangeland plants were thus potted on, or taken from, cultivated field soil of a metalliferous hot spot near Ronneburg (Germany). The content of soil and shoot tissues in 20 minerals was determined by ICP-MS to estimate HM (and uranium) toxicities to grazing animals and the plants themselves, and to calculate the long-term persistence of the metal toxicants (soil clean-up times) from the annual uptake rates of the plants. On Ronneburg soil elevated in As, Cd, Cu, Mn, Pb, U, and Zn, the shoot mineral content of all test plants remained preferentially in the range of "normal plant concentrations" but reached up to the fourfold to sixfold in Mn, Ni, and Zn, the 1.45- to 21.5-fold of the forage legislative limit in Cd, and the 10- to 180-fold of common herb concentrations in U. Shoot and the calculated root concentrations in Cd, Cu, Ni, and Zn accounted for phytotoxic effects at least to grasses and cereals. Based on WHO PTWI values for the tolerable weekly human Cd and Pb intake, the expanded Cd and Pb limits for forage, and reported rates of hay, roots, and adhering-soil ingestion, the tolerable daily intake rates of 0.65/11.6 mg in Cd/Pb by a 65 kg herbivore would be surpassed by the 11- to 27/0.7- to 4.7-fold across the year, with drastic consequences for winter-grazing and thereby high rates of roots and soil-ingesting animals. The daily intake of 5.3-31.5 mg of the alpha radiation emitter, U, may be less disastrous to short-lived herbivores. The annual phytoextraction rates of critical HM by the tested excluder crops indicate that hundreds to thousands of years are necessary to halve the HM and (long-lived) radionuclide load of Ronneburg soil, provided the herbage is harvested at all. It is concluded that the content in Cd/As, Cd, and Cu exclude herbage/Ronneburg soil from the commercial use as forage or pasture land soil for incalculable time spans. Caution is required, too, with the consumption of game.


A model for intratumoural chemotherapy in the rat brain.
To achieve the best reproducibility in rat brain tumour models several injection techniques have been used. Although stereotactic cell injections have proved to be effective and reliable, they are expensive and time consuming. A new permanently implanted device is presented here. It allows precise cell delivery for best tumour reproducibility, and it can be left in place for future injections at the exact same location, such as intratumoural chemotherapy. A Teflon tube was mounted on a disc, inserted into the rat brain and sealed to the skull. The device was tested in two rat strains (Wistar and New Zealand Nude rats) with two different glioma cell lines (9L and C6). Rats were treated with placebo to determine if repeated treatments had an effect on the device placement, or if device-related morbidity was induced. Analysis of brain sections showed that the device path was always within the tumour. The device never moved or came off the scalp. Both Wistar rats and NZ nude rats tolerated the device well. No morbidity or mortality was observed, regardless of the presence of the device; no infections were seen. Biocompatible, non-irritating and well tolerated, such a device can be used for reproducible tumour cell injections and repeated intralesional delivery of drugs.


Impact of human mobility on the periodicities and mechanisms underlying measles dynamics.
Three main mechanisms determining the dynamics of measles have been described in the literature: invasion in disease-free lands leading to import-dependent outbreaks, switching between annual and biennial attractors driven by seasonality, and amplification of stochastic fluctuations close to the endemic equilibrium. Here, we study the importance of the three mechanisms using a detailed geographical description of human mobility. We perform individual-based simulations of an SIR model using a gridded description of human settlements on top of which we implement human mobility according to the radiation model. Parallel computation permits detailed simulations of large areas. Focusing our research on the British Isles, we show that human mobility has an impact on the periodicity of measles outbreaks. Depending on the level of mobility, we observe at the global level multi-annual, annual or biennial cycles. The periodicity observed globally, however, differs from the local epidemic cycles: different locations show different mechanisms at work depending on both population size and mobility. As a result, the periodicities observed locally depend on the interplay between the local population size and human mobility.


cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions.
Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.


Progress Toward Measles Elimination - Pakistan, 2000-2018.
In 1997, the 21 countries in the World Health Organization (WHO) Eastern Mediterranean Region* (EMR) passed a resolution during the 41st session of the Regional Committee for the Eastern Mediterranean to eliminate measles† (1). In 2015, this goal was included as a priority in the Eastern Mediterranean Vaccine Action Plan 2016-2020 (2), approved at the 62nd session of the Regional Committee (3). To achieve measles elimination, the WHO Regional Office for the Eastern Mediterranean developed the following four-pronged strategy: 1) achieve ≥95% vaccination coverage with the first dose of measles-containing vaccine (MCV) among children in every district of each country through routine immunization services; 2) achieve ≥95% vaccination coverage with a second MCV dose in every district of each country either through implementation of a routine 2-dose vaccination schedule or through supplementary immunization activities (SIAs)§; 3) conduct high-quality, case-based measles surveillance in all countries; and 4) provide optimal measles clinical case management, including dietary supplementation with vitamin A (4). Pakistan, an EMR country with a population of approximately 200 million, accounts for nearly one third of the overall EMR population. This report describes progress and challenges toward measles elimination in Pakistan during 2000-2018. During the study period, estimated coverage with the first MCV dose (MCV1) increased from 57% in 2000 to 76% in 2017. The second MCV dose (MCV2) was introduced nationwide in 2009, and MCV2 coverage increased from 30% in 2009 to 45% in 2017. During 2000-2018, approximately 232.5 million children received doses of MCV during SIAs. Reported confirmed measles incidence increased from an average of 24.6 per 1 million persons during 2000-2009 to an average of 80.4 during 2010-2018, with peaks in 2013 (230.3) and 2018 (153.6). In 2017 and 2018, the rates of suspected cases discarded as nonmeasles after investigation were 2.1 and 1.5 per 100,000 population, reflecting underreporting of cases. To achieve measles elimination, additional efforts are needed to increase MCV1 and MCV2 coverage, develop strategies to identify and reach communities not accessing immunization services, and increase sensitivity of case-based measles surveillance in all districts.


Surgical management and genetic analysis of a Chinese family with the S171P mutation in the UBIAD1 gene, the gene for Schnyder corneal dystrophy.
To describe the underlying molecular genetic basis, surgical management and phenotypic variation of Schnyder corneal dystrophy (SCD) identified in a four-generation Chinese family. This is an interventional case series of 13 members from a non-consanguineous Chinese family. All patients underwent complete ophthalmological examination and slit-lamp photography. Subsequent corneal transplantations were performed (n = 3). Blood samples were taken for DNA extraction and subsequent genetic analysis. Genotyping indicated linkage to the locus at chromosome 1p36. Screening of the UBIAD1 gene identified a highly conserved mutation, Ser171Pro. Phenotypic variation in this large pedigree is similar to that seen in Caucasian patients. Surgical management of patients with anterior lamellar keratoplasty and deep anterior lamellar keratoplasty showed good visual outcomes. The S171P mutation is described for the first time in a Chinese family. This is the largest non-Caucasian pedigree described with SCD. Visual rehabilitation may be performed successfully with lamellar surgical procedures as opposed to full-thickness corneal grafts.


Diagnosing and managing patients with dementia.
As the number of older Americans grows, the prevalence of dementia is increasing. Older patients who present to primary care offices often have some form of dementia, but various factors can cause the diagnosis to be missed or delayed. Physicians can work to proactively assess dementia in their patients and provide a timely diagnosis. The diagnostic process for dementia includes screening for pathology and, when indicated, conducting a cognitive evaluation and performing a differential diagnosis. Several brief but reliable tools are available to aid in screening and evaluating patients for dementia.


Exome Sequencing in a Family with Luminal-Type Breast Cancer Underpinned by Variation in the Methylation Pathway.
Panel-based next generation sequencing (NGS) is currently preferred over whole exome sequencing (WES) for diagnosis of familial breast cancer, due to interpretation challenges caused by variants of uncertain clinical significance (VUS). There is also no consensus on the selection criteria for WES. In this study, a pathology-supported genetic testing (PSGT) approach was used to select two BRCA1/2 mutation-negative breast cancer patients from the same family for WES. Homozygosity for the MTHFR 677 C>T mutation detected during this PSGT pre-screen step was considered insufficient to cause bilateral breast cancer in the index case and her daughter diagnosed with early-onset breast cancer (<30 years). Extended genetic testing using WES identified the RAD50 R385C missense mutation in both cases. This rare variant with a minor allele frequency (MAF) of <0.001 was classified as a VUS after exclusion in an affected cousin and extended genotyping in 164 unrelated breast cancer patients and 160 controls. Detection of functional polymorphisms (MAF > 5%) in the folate pathway in all three affected family members is consistent with inheritance of the luminal-type breast cancer in the family. PSGT assisted with the decision to pursue extended genetic testing and facilitated clinical interpretation of WES aimed at reduction of recurrence risk.


Systematic derivation of partition functions for ligand binding to two-dimensional lattices.
The Ising problem consists in finding the analytical solution of the partition function of a lattice once the interaction geometry among its elements is specified. No general analytical solution is available for this problem, except for the one-dimensional case. Using site-specific thermodynamics, it is shown that the partition function for ligand binding to a two-dimensional lattice can be obtained from those of one-dimensional lattices with known solution. The complexity of the lattice is reduced recursively by application of a contact transformation that involves a relatively small number of steps. The transformation implemented in a computer code solves the partition function of the lattice by operating on the connectivity matrix of the graph associated with it. This provides a powerful new approach to the Ising problem, and enables a systematic analysis of two-dimensional lattices that model many biologically relevant phenomena. Application of this approach to finite two-dimensional lattices with positive cooperativity indicates that the binding capacity per site diverges as Na (N = number of sites in the lattice) and experiences a phase-transition-like discontinuity in the thermodynamic limit N-->infinity. The zeroes of the partition function tend to distribute on a slightly distorted unit circle in complex plane and approach the positive real axis already for a 5 x 5 square lattice. When the lattice has negative cooperativity, its properties mimic those of a system composed of two classes of independent sites with the apparent population of low-affinity binding sites increasing with the size of the lattice, thereby accounting for a phenomenon encountered in many ligand-receptor interactions.


The efficacy of combined therapy of arsenic trioxide and alpha interferon in human T-cell leukemia virus type-1-infected squirrel monkeys (Saimiri sciureus).
Human T-cell lymphotropic virus type 1 (HTLV-1)-associated adult T-cell leukemia/lymphoma (ATLL) has a poor prognosis owing to its intrinsic resistance to chemotherapy. Although zidovudine (AZT) and alpha interferon (IFN-alpha) give rise to some response and improve the prognosis of ATLL, alternative therapies are needed. Arsenic trioxide (As(2)O(3)) has been shown to synergize with IFN-alpha in arresting cell growth and inducing apoptosis of ATLL cells in vitro. In this study, we evaluated the toxicity and the efficacy of this combined treatment in HTLV-1-infected squirrel monkeys (Saimiri sciureus) and HTLV-1 infected cell lines derived therefrom. We first show that treatment with As(2)O(3) and IFN-alpha can induce growth arrest in HTLV-1-transformed monkey T-cell lines in vitro. We then show that treatment of squirrel monkeys with As(2)O(3) in vivo is highly toxic at 0.9 or 0.3mg/day but not at 0.14mg/day for up to 2 weeks. Although the combination of As(2)O(3) and IFN-alpha did not affect significantly the HTLV-1 proviral load in infected monkeys, it reduced the absolute numbers of CD3(+), CD4(+) and CD8(+) cells during treatment, with a significant reduction in the total number of circulating HTLV-1 flower cells in the infected monkeys with chronic ATLL-like disease.


NADPH Oxidase 2 Mediates Myocardial Oxygen Wasting in Obesity.
Obesity and diabetes are independent risk factors for cardiovascular diseases, and they are associated with the development of a specific cardiomyopathy with elevated myocardial oxygen consumption (MVO2) and impaired cardiac efficiency. Although the pathophysiology of this cardiomyopathy is multifactorial and complex, reactive oxygen species (ROS) may play an important role. One of the major ROS-generating enzymes in the cardiomyocytes is nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (NOX2), and many potential systemic activators of NOX2 are elevated in obesity and diabetes. We hypothesized that NOX2 activity would influence cardiac energetics and/or the progression of ventricular dysfunction following obesity. Myocardial ROS content and mechanoenergetics were measured in the hearts from diet-induced-obese wild type (DIOWT) and global NOK2 knock-out mice (DIOKO) and in diet-induced obese C57BL/6J mice given normal water (DIO) or water supplemented with the NOX2-inhibitor apocynin (DIOAPO). Mitochondrial function and ROS production were also assessed in DIO and DIOAPO mice. This study demonstrated that ablation and pharmacological inhibition of NOX2 both improved mechanical efficiency and reduced MVO2 for non-mechanical cardiac work. Mitochondrial ROS production was also reduced following NOX2 inhibition, while cardiac mitochondrial function was not markedly altered by apocynin-treatment. Therefore, these results indicate a link between obesity-induced myocardial oxygen wasting, NOX2 activation, and mitochondrial ROS.


Multiple abiotic stimuli are integrated in the regulation of rice gene expression under field conditions.
Plants rely on transcriptional dynamics to respond to multiple climatic fluctuations and contexts in nature. We analyzed the genome-wide gene expression patterns of rice (Oryza sativa) growing in rainfed and irrigated fields during two distinct tropical seasons and determined simple linear models that relate transcriptomic variation to climatic fluctuations. These models combine multiple environmental parameters to account for patterns of expression in the field of co-expressed gene clusters. We examined the similarities of our environmental models between tropical and temperate field conditions, using previously published data. We found that field type and macroclimate had broad impacts on transcriptional responses to environmental fluctuations, especially for genes involved in photosynthesis and development. Nevertheless, variation in solar radiation and temperature at the timescale of hours had reproducible effects across environmental contexts. These results provide a basis for broad-based predictive modeling of plant gene expression in the field.


Generation of an adenovirus-parvovirus chimera with enhanced oncolytic potential.
In this study, our goal was to generate a chimeric adenovirus-parvovirus (Ad-PV) vector that combines the high-titer and efficient gene transfer of adenovirus with the anticancer potential of rodent parvovirus. To this end, the entire oncolytic PV genome was inserted into a replication-defective E1- and E3-deleted Ad5 vector genome. As we found that parvoviral NS expression inhibited Ad-PV chimera production, we engineered the parvoviral P4 early promoter, which governs NS expression, by inserting into its sequence tetracycline operator elements. As a result of these modifications, P4-driven expression was blocked in the packaging T-REx-293 cells, which constitutively express the tetracycline repressor, allowing high-yield chimera production. The chimera effectively delivered the PV genome into cancer cells, from which fully infectious replication-competent parvovirus particles were generated. Remarkably, the Ad-PV chimera exerted stronger cytotoxic activities against various cancer cell lines, compared with the PV and Ad parental viruses, while being still innocuous to a panel of tested healthy primary human cells. This Ad-PV chimera represents a novel versatile anticancer agent which can be subjected to further genetic manipulations in order to reinforce its enhanced oncolytic capacity through arming with transgenes or retargeting into tumor cells.


Immediate effect and predictors of effectiveness of taping for patellofemoral pain syndrome: a prospective cohort study.
Taping has been used to treat patellofemoral pain syndrome for more than 20 years, but its effectiveness is still controversial. This study was undertaken to investigate the effect and predictors of effectiveness of taping in the treatment of patellofemoral pain syndrome. Cohort study; Level of evidence, 3. A total of 118 consecutive patients with patellofemoral pain syndrome were recruited; 100 of them completed this study. Patient sex, age, body mass index, Q angle, lateral patellar displacement, and lateral patellofemoral angle were recorded/measured. One therapist applied adhesive tape to each patient by the McConnell method. Patients scored their pain level on a 100-mm visual analog scale during stepping down from an 8-in platform, before and after taping. The change of score was evaluated by paired t test. Patients with a visual analog scale score decrease of 20 mm or more after taping were considered responsive, and the others were considered nonresponsive. The influences of the aforementioned factors, plus pretaping visual analog scale score, on the effectiveness of taping were analyzed by multivariate logistic regression. The overall mean visual analog scale score decreased significantly after taping (from 49.0 to 29.3 mm; P < .001). There were 66 patients in the responsive group and 34 in nonresponsive group. Among the factors, body mass index, lateral patellofemoral angle, and Q angle were significant predictors of effectiveness. The responsive group had significantly smaller mean lateral patellofemoral angle, larger mean Q angle, and larger mean pretaping visual analog scale score than the nonresponsive group. Taping was an effective treatment for patellofemoral pain syndrome, but was less effective in patients with higher body mass index, larger lateral patellofemoral angle, and smaller Q angle.


Relationship between e-cigarette point of sale recall and e-cigarette use in secondary school children: a cross-sectional study.
There has been a rapid increase in the retail availability of e-cigarettes in the UK and elsewhere. It is known that exposure to cigarette point-of-sale (POS) displays influences smoking behaviour and intentions in young people. However, there is as yet no evidence regarding the relationship between e-cigarette POS display exposure and e-cigarette use in young people. This cross sectional survey was conducted in four high schools in Scotland. A response rate of 87 % and a total sample of 3808 was achieved. Analysis was by logistic regression on e-cigarette outcomes with standard errors adjusted for clustering within schools. The logistic regression models were adjusted for recall of other e-cigarette adverts, smoking status, and demographic variables. Multiple chained imputation was employed to assess the consistency of the findings across different methods of handling missing data. Adolescents who recalled seeing e-cigarettes in small shops were more likely to have tried an e-cigarette (OR 1.92 99 % CI 1.61 to 2.29). Adolescents who recalled seeing e-cigarettes for sale in small shops (OR 1.80 99 % CI 1.08 to 2.99) or supermarkets (OR 1.70 99 % CI 1.22 to 2.36) were more likely to intend to try them in the next 6 months. This study has found a cross-sectional association between self-reported recall of e-cigarette POS displays and use of, and intention to use, e-cigarettes. The magnitude of this association is comparable to that between tobacco point of sale recall and intention to use traditional cigarettes in the same sample. Further longitudinal data is required to confirm a causal relationship between e-cigarette point of sale exposure and their use and future use by young people.


First detection of canine norovirus in dogs and a complete GVI.2 genome in mainland China.
Canine norovirus (CNV) is a diarrhea-causing pathogen in canines. In this study, 268 canine diarrheic fecal samples were collected from 13 pet hospitals across three provinces in China between March 2017 and May 2019, and 7.8% (21/268) samples were detected as CNV-positive by RT-PCR. Phylogenetic analysis of twenty-one CNV RdRp fragments showed that eighteen of the strains clustered in GVI.2, two clustered in GVI.1 and one clustered in GIV.2. The complete RdRp, VP1, and VP2 genes of four GVI.2 strains obtained from three provinces were successfully sequenced. Phylogenetic analyses based on the RdRp, VP1, and VP2 genes showed that the GVI.2 strains from this study were closely related to USA GVI.2 strains. The complete genome of GVI.2 strain Dog/M9/18/CH was successfully sequenced, it was 7905 nucleotides (nt) in length and shared 95.9% nt identity with the sole available, nearly full-length genome of GVI.2 strain genome. To our knowledge, this is first description of the molecular prevalence of CNV in mainland China, and the first report of a complete GVI.2 genome. These findings will extend our understanding of epidemics and the genetic evolution of CNV.