Identification of candidate susceptibility genes for colorectal cancer through eQTL analysis.
In this study, we aim to identify the genes responsible for colorectal cancer risk behind the loci identified in genome-wide association studies (GWAS). These genes may be candidate targets for developing new strategies for prevention or therapy. We analyzed the association of genotypes for 26 GWAS single nucleotide polymorphisms (SNPs) with the expression of genes within a 2 Mb region (cis-eQTLs). Affymetrix Human Genome U219 expression arrays were used to assess gene expression in two series of samples, one of healthy colonic mucosa (n = 47) and other of normal mucosa adjacent to colon cancer (n = 97, total 144). Paired tumor tissues (n = 97) were also analyzed but did not provide additional findings. Partial Pearson correlation (r), adjusted for sample type, was used for the analysis. We have found Bonferroni-significant cis-eQTLs in three loci: rs3802842 in 11q23.1 associated to C11orf53, COLCA1 (C11orf92) and COLCA2 (C11orf93; r = 0.60); rs7136702 in 12q13.12 associated to DIP2B (r = 0.63) and rs5934683 in Xp22.3 associated to SHROOM2 and GPR143 (r = 0.47). For loci in chromosomes 11 and 12, we have found other SNPs in linkage disequilibrium that are more strongly associated with the expression of the identified genes and are better functional candidates: rs7130173 for 11q23.1 (r = 0.66) and rs61927768 for 12q13.12 (r = 0.86). These SNPs are located in DNA regions that may harbor enhancers or transcription factor binding sites. The analysis of trans-eQTLs has identified additional genes in these loci that may have common regulatory mechanisms as shown by the analysis of protein-protein interaction networks.


Cross-species comparisons and in vitro models to study tempo in development and homeostasis.
Time is inherent to biological processes. It determines the order of events and the speed at which they take place. However, we still need to refine approaches to measure the course of time in biological systems and understand what controls the pace of development. Here, we argue that the comparison of biological processes across species provides molecular insight into the timekeeping mechanisms in biology. We discuss recent findings and the open questions in the field and highlight the use of in vitro systems as tools to investigate cell-autonomous control as well as the coordination of temporal mechanisms within tissues. Further, we discuss the relevance of studying tempo for tissue transplantation, homeostasis and lifespan.


Thermophilic versus Mesophilic Anaerobic Digestion of Sewage Sludge: A Comparative Review.
During advanced biological wastewater treatment, a huge amount of sludge is produced as a by-product of the treatment process. Hence, reuse and recovery of resources and energy from the sludge is a big technological challenge. The processing of sludge produced by Wastewater Treatment Plants (WWTPs) is massive, which takes up a big part of the overall operational costs. In this regard, anaerobic digestion (AD) of sewage sludge continues to be an attractive option to produce biogas that could contribute to the wastewater management cost reduction and foster the sustainability of those WWTPs. At the same time, AD reduces sludge amounts and that again contributes to the reduction of the sludge disposal costs. However, sludge volume minimization remains, a challenge thus improvement of dewatering efficiency is an inevitable part of WWTP operation. As a result, AD parameters could have significant impact on sludge properties. One of the most important operational parameters influencing the AD process is temperature. Consequently, the thermophilic and the mesophilic modes of sludge AD are compared for their pros and cons by many researchers. However, most comparisons are more focused on biogas yield, process speed and stability. Regarding the biogas yield, thermophilic sludge AD is preferred over the mesophilic one because of its faster biochemical reaction rate. Equally important but not studied sufficiently until now was the influence of temperature on the digestate quality, which is expressed mainly by the sludge dewateringability, and the reject water quality (chemical oxygen demand, ammonia nitrogen, and pH). In the field of comparison of thermophilic and mesophilic digestion process, few and often inconclusive research, unfortunately, has been published so far. Hence, recommendations for optimized technologies have not yet been done. The review presented provides a comparison of existing sludge AD technologies and the gaps that need to be filled so as to optimize the connection between the two systems. In addition, many other relevant AD process parameters, including sludge rheology, which need to be addressed, are also reviewed and presented.


Extraction outcomes of implantable cardioverter-defibrillator leads vary by manufacturer and model family.
Transvenous lead extraction (TLE) of implantable cardioverter-defibrillator (ICD) leads is considered challenging. The structure of each ICD leads is variable between manufacturer and model families. The net impact of lead family on the safety and effectiveness of TLE is poorly characterized. We assessed the safety and efficacy of ICD TLE and the impact of manufacturer ICD model family on the outcomes. The study cohort included all consecutive patients with ICD who underwent TLE between 2013 and 2022 and are enrolled in the Cleveland Clinic Prospective TLE Registry. A total of 885 ICD leads (median implant duration 8 years) in 810 patients were included. Complete ICD TLE success was achieved in 97.2% of the leads (n = 860) and in 98.0% of the patients (n = 794). Major complications occurred in 22 patients (2.7%). Complete procedural success rate varied by manufacturer and lead family; Medtronic 98.9%, Abbott 95.9%, Boston Scientific 95.0%, Biotronik 91.2%, P = 0.03, and Linox family leads had the lowest, 89.7% P = 0.02. Multivariable predictors of incomplete ICD lead removal included ICD lead age > 10 years and Linox family lead. Multivariable predictors of major complications included ICD lead age > 15 years and longer lead extraction time, and predictors of all-cause mortality within 30 days included lead extraction for infection, end-stage renal disease, and higher New York Heart Association functional class. Complete and safe ICD lead removal rate by TLE is extremely high but varied by manufacturer and lead family. Linox family lead and >10 years lead age were independent predictors of incomplete lead removal.


[Relation doctor-patient in oncology: fears, anguishes and communication abilities among doctors in Fortaleza, Ceará State, Brazil].
In oncology the doctor-patient relationship has a particular importance due to the gravity of the illness and to the stigma that is followed many times by the experience of the patient. This research was designed to analyze perceptions and difficulties that doctors face when they are dealing with oncology patient. It is a qualitative study, based mainly on open and in-depth interviews, involving 20 doctors from the Cancer Institute of Ceará. From the relationship of Dr. Sheila with her patients, Cássio and Elisa, fictitious personages of a chronicle larded in the quarrel of the article, the main facts are illustrated. We tried to approach four main subjects: the construction of the bond, the communication abilities performance, the therapeutic approach and the family interaction. The suffering and the emotional implications of patients and familiars, the differences in communication between the interviewed doctors, mainly in reference to the transmission of the diagnosis and the therapy, become important factors that influence the relation and the establishment or not of the therapeutic bond. Because of this, it seems to be necessary studies and debates concerning this subject, aiming at an incorporation of this thematic in the medical training.


The endosomal concentration of a mannose 6-phosphate receptor is unchanged in the absence of ligand synthesis.
The cation-independent mannose-6-phosphate (Man-6-P) receptor is involved in the targeting of newly synthesized lysosomal hydrolases. To investigate the intracellular distribution of this receptor, a conjugate of lactoperoxidase coupled to asialoorosomucoid was used to catalyze its iodination within the endosomes of human hepatoma (HepG2) cells. The 215-kD, cation-independent Man-6-P receptor was iodinated by this procedure as shown by pentamannosyl-6-phosphate-Sepharose affinity chromatography and by immunoprecipitation of labeled cell extracts. The amount of this receptor detected in endosomes was found to be unchanged after inhibition of protein synthesis with cycloheximide. If the Man-6-P receptor accumulates in the Golgi apparatus in the absence of lysosomal hydrolase synthesis, it should have been correspondingly depleted from endosomes after a period of cycloheximide treatment, because these pools of receptor are in rapid equilibrium. Therefore, these data suggest that newly synthesized ligands are not required for the transport of the cation-independent Man-6-P receptor from the Golgi apparatus to endosomes.


Endogenous p21-Dependent Transgene Control for CHO Cell Engineering.
Numerous engineering efforts have been made in Chinese hamster ovary (CHO) cells for high level production of therapeutic proteins. However, the dynamic regulation of transgene expression is limited in current systems. Here, we investigated the effective regulation of transgene expression in CHO cells via targeted integration-based endogenous gene tagging with engineering target genes. Targeted integration of EGFP-human Bcl-2 into the p21 locus effectively reduced the apoptosis, compared with random populations in which Bcl-2 expression was driven by cytomegalovirus (CMV) promoter. Endogenous p21 and EGFP-human Bcl-2 displayed similar expression dynamics in batch cultures, and the antiapoptotic effect altered the expression pattern of endogenous p21 showing the mutual influences between expression of p21 and Bcl-2. We further demonstrated the inducible transgene expression by adding low concentrations of hydroxyurea. The present engineering strategy will provide a valuable CHO cell engineering tool that can be used to control dynamic transgene expression in accordance with cellular states.


Recombineering in Streptococcus mutans Using Direct Repeat-Mediated Cloning-Independent Markerless Mutagenesis (DR-CIMM).
Studies of the dental caries pathogen Streptococcus mutans have benefitted tremendously from its sophisticated genetic system. As part of our own efforts to further improve upon the S. mutans genetic toolbox, we previously reported the development of the first cloning-independent markerless mutagenesis (CIMM) system for S. mutans and illustrated how this approach could be adapted for use in many other organisms. The CIMM approach only requires overlap extension PCR (OE-PCR) protocols to assemble counterselectable allelic replacement mutagenesis constructs, and thus greatly increased the speed and efficiency with which markerless mutations could be introduced into S. mutans. Despite its utility, the system is still subject to a couple limitations. Firstly, CIMM requires negative selection with the conditionally toxic phenylalanine analog p-chlorophenylalanine (4-CP), which is efficient, but never perfect. Typically, 4-CP negative selection results in a small percentage of naturally resistant background colonies. Secondly, CIMM requires two transformation steps to create markerless mutants. This can be inherently problematic if the transformability of the strain is negatively impacted after the first transformation step, which is used to insert the counterselection cassette at the mutation site on the chromosome. In the current study, we develop a next-generation counterselection cassette that eliminates 4-CP background resistance and combine this with a new direct repeat-mediated cloning-independent markerless mutagenesis (DR-CIMM) system to specifically address the limitations of the prior approach. DR-CIMM is even faster and more efficient than CIMM for the creation of all types of deletions, insertions, and point mutations and is similarly adaptable for use in a wide range of genetically tractable bacteria.


A complex systems science perspective for whole systems of complementary and alternative medicine research.
Whole systems complementary and alternative medicine (WS-CAM) approaches share a basic worldview that embraces interconnectedness; emergent, non-linear outcomes to treatment that include both local and global changes in the human condition; a contextual view of human beings that are inseparable from and responsive to their environments; and interventions that are complex, synergistic, and interdependent. These fundamental beliefs and principles run counter to the assumptions of reductionism and conventional biomedical research methods that presuppose unidimensional simple causes and thus dismantle and individually test various interventions that comprise only single aspects of the WSCAM system. This paper will demonstrate the superior fit and practical advantages of using complex adaptive systems (CAS) and related modeling approaches to develop the scientific basis for WS-CAM. Furthermore, the details of these CAS models will be used to provide working hypotheses to explain clinical phenomena such as (a) persistence of changes for weeks to months between treatments and/or after cessation of treatment, (b) nonlocal and whole systems changes resulting from therapy, (c) Hering's law, and (d) healing crises. Finally, complex systems science will be used to offer an alternative perspective on cause, beyond the simple reductionism of mainstream mechanistic ontology and more parsimonious than the historical vitalism of WS-CAM. Rather, complex systems science provides a scientifically rigorous, yet essentially holistic ontological perspective with which to conceptualize and empirically explore the development of disease and illness experiences, as well as experiences of healing and wellness.


Improved Outcomes Following a Single Session Web-Based Intervention for Problem Gambling.
Research suggests online interventions can have instant impact, however this is yet to be tested with help-seeking adults and in particular those with problem gambling. This study seeks to determine the immediate impact of a single session web-based intervention for problem gambling, and to examine whether sessions evaluated positively by clients are associated with greater improvement. The current study involved 229 participants classified as problem gamblers who agreed to participate after accessing Gambling Help Online between November 2010 and February 2012. Almost half were aged under 35 years of age (45 %), male (57 %) as well as first time treatment seekers (62 %). Participants completed measures of readiness to change and distress both prior to and post-counselling. Following the provision of a single-session of counselling, participants completed ratings of the character of the session (i.e., degree of depth and smoothness) post-counselling. A significant increase in confidence to resist and urge to gamble and a significant decrease in distress (moderate effect size; d = .56 and .63 respectively) was observed after receiving online counselling. A hierarchical regression indicated the character of the session was a significant predictor of change in confidence, however only the sub-scale smoothness was a significant predictor of change in distress. This was the case even after controlling for pre-session distress, session word count and client characteristics (gender, age, preferred gambling activity, preferred mode of gambling, gambling severity, and preferred mode of help-seeking). These findings suggest that single session web-based counselling for problem gambling can have immediate benefits, although further research is required to examine the impact on longer-term outcomes.


Tract-based spatial statistics of diffusion tensor imaging in hereditary spastic paraplegia with thin corpus callosum reveals widespread white matter changes.
We aimed to investigate white matter diffusivity abnormalities in hereditary spastic paraplegia with thin corpus callosum (HSP-TCC) patients in relation with electrophysiological findings. Brain magnetic resonance imaging (MRI) and diffusion tensor imaging were performed on four HSP-TCC patients and 15 age-matched healthy subjects. Voxel-wise statistical analysis of fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity maps were carried out using tract-based spatial statistics, and significantly affected voxels were labeled using a human white matter atlas. Conventional nerve conduction studies, cortical and spinal-root motor evoked potentials, and somatosensory evoked potentials were examined in three patients. On MRI, all patients had a thin corpus callosum with mild T2 hyperintensity in the periventricular white matter. Compared to control subjects, we detected widespread significant decreases in fractional anisotropy, and increases in axial diffusivity, radial diffusivity, and mean diffusivity in structures including in the corpus callosum, motor, and non-motor white matter tracts in HSP-TCC patients. Several different regions showed significant reduction in axial diffusivity. Electrophysiological studies revealed prolonged central motor conduction times and reduced cortical motor evoked potentials and somatosensory evoked potentials amplitudes in all patients. One patient had low sural sensory nerve action potential suggestive of axonal neuropathy. Tract-based spatial statistics of diffusion tensor imaging revealed a more widespread involvement of white matter in HSP-TCC patients than has previously been detected by conventional MRI. This may explain the broad spectrum of electrophysiological and neurological abnormalities that complicate hereditary spastic paraplegia in these patients.


A comparative analysis of immunohistochemistry and fluorescent in situ hybridization assay to detect anaplastic lymphoma kinase status in lung adenocarcinoma cases: A search for a testing algorithm.
Testing for echinoderm microtubule-associated protein-like 4 (EML4) anaplastic lymphoma kinase (ALK) translocation by fluorescence in situ hybridization (FISH) is well established whereas the Food and Drug Administration (FDA) ALK immunohistochemical (IHC) test is relatively new. The aim of this study is to compare FDA-approved ALK IHC test (D5F3 clone) with the standard ALK FISH test. A validation and a test arm with 100 and 200 cases of Formalin-Fixed, Paraffin-embedded blocks of lung adenocarcinoma, respectively, comprised the material. All cases had ALK IHC test on automated Ventana Benchmark XT IHC slide stainer using anti-ALK D5F3 rabbit monoclonal primary antibody; when positive tumor cells (any percentage) showed strong granular cytoplasmic staining. For the FISH test, Vysis ALK Dual Color Break Apart Rearrangement Probe (Abbott Molecular Inc.,) was used to detect ALK gene 2p23 rearrangements; when positive the red and green signals were split two signal diameter apart and/or isolated 3'red signal were detected in more than 15% tumor cells. The ALK FISH results were available in all 100 validation cases and 64-test arm cases which formed the basis of this analysis. The ALK IHC test was positive in 16% cases; four discordant cases were ALK IHC positive but ALK FISH negative, but no case was ALK IHC negative and ALK FISH positive. There was 100% sensitivity, 90.5% specificity, and 93.75% accuracy. A negative ALK IHC result obviates the need for a FISH test barring those with a strong clinical profile, and a positive ALK IHC result is sufficient basis for the initiation of treatment.


Toxic and essential metal interactions.
Cadmium, lead, mercury, and aluminum are toxic metals that may interact metabolically with nutritionally essential metals. Iron deficiency increases absorption of cadmium, lead, and aluminum. Lead interacts with calcium in the nervous system to impair cognitive development. Cadmium and aluminum interact with calcium in the skeletal system to produce osteodystrophies. Lead replaces zinc on heme enzymes and cadmium replaces zinc on metallothionein. Selenium protects from mercury and methylmercury toxicity. Aluminum interacts with calcium in bone and kidneys, resulting in aluminum osteodystrophy. Calcium deficiency along with low dietary magnesium may contribute to aluminum-induced degenerative nervous disease.


[Acupuncture in the combined treatment of pyelonephritis].
In the treatment of pyelonephritis which continues to cause problems in practical uronephrology, the main efforts of the clinicians are now directed at enhancement of the patients resistance, improvement of renal blood flow and urodynamics. Acupuncture (AP) is thought capable to meet the above requirements. It was used in combined treatment of 102 pyelonephritis cases (51 with acute and 51 with chronic manifestations) showing intact renal function. According to radionuclide renography, a positive trend in the secretion and urodynamics of the upper urinary tract was demonstrable in 50% of the patients. Dynamic nephroscintigraphy reported a positive response in 60% of cases versus 25% in those treated without AP. AP promotion of earlier recovery or remission, reduction of the scope of chemotherapy, good short- and long-term response permit this modality to be recommended for application in urological and nephrological practice.


["FlowSecure" artificial urinary sphincter: a new adjustable artificial urinary sphincter concept with conditional occlusion for stress urinary incontinence].
We have implanted the FlowSecure artificial sphincter for the first time in October 2006. The prototype was originally conceived and designed by Professor Craggs M. D. and Professor Mundy A.R. Preliminary clinical results were reported in nine patients early this year. Our objective is to spread technique for surgical implantation. Combined perineal and abdominal incisions are required for exposure of bulbar urethra, creation of a cavity in the para-vesical space and dissection of a pocket under de scrotal wall. A trocar with a stylet is routed from the abdominal incision to the perineal incision to pass the deflated cuff to the perineal site. The cuff is placed around the urethra and secured with Prolene sutures. After refilling the cuff, fluid is removed from the system until the stress relief balloon becomes just indented (atmospheric pressure 0). The pump is placed in the scrotum and the balloons in the paravesical space. We have implanted our first FlowSecure artificial sphincter in a patient with severe stress incontinence following a T.U.R.P. The surgical technique is simple and associated with little handling. He was discharged from hospital 4 days after the procedure and it was decided that pressurisation was unnecessary. Surgical implantation of the new FlowSecure artificial urinary sphincter is an easy procedure in males with stress urinary incontinence. Knigth et al. reported 30 to 40 minutes operating time, 4 days mean hospital stay and unnecessary pressurisation procedure in 3 out of their 9 patients. It seems that their results are reproducible.


A pleiotropic nonadditive model of variation in quantitative traits.
A model of mutation-selection-drift balance incorporating pleiotropic and dominance effects of new mutations on quantitative traits and fitness is investigated and used to predict the amount and nature of genetic variation maintained in segregating populations. The model is based on recent information on the joint distribution of mutant effects on bristle traits and fitness in Drosophila melanogaster from experiments on the accumulation of spontaneous and P element-induced mutations. These experiments suggest a leptokurtic distribution of effects with an intermediate correlation between effects on the trait and fitness. Mutants of large effect tend to be partially recessive while those with smaller effect are on average additive, but apparently with very variable gene action. The model is parameterized with two different sets of information derived from P element insertion and spontaneous mutation data, though the latter are not fully known. They differ in the number of mutations per generation which is assumed to affect the trait. Predictions of the variance maintained for bristle number assuming parameters derived from effects of P element insertions, in which the proportion of mutations with an effect on the trait is small, fit reasonably well with experimental observations. The equilibrium genetic variance is nearly independent of the degree of dominance of new mutations. Heritabilities of between 0.4 and 0.6 are predicted with population sizes from 10(4) to 10(6), and most of the variance for the metric trait in segregating population is due to a small proportion of mutations (about 1% of the total number) with neutral or nearly neutral effects on fitness and intermediate effects on the trait (0.1-0.5 sigma P).(ABSTRACT TRUNCATED AT 250 WORDS)


Short-term pacemaker dependency after transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) is a less invasive technique for the treatment of severe aortic stenosis in high-risk patients. Occurrence of conduction disturbances requiring permanent pacemaker (PPM) implantation after TAVI is frequently observed. The retrospective analysis comprised 153 patients (96 women, aged from 65 to 97 years) who underwent TAVI due to high-grade aortic stenosis. The aim was to evaluate the incidence of high-grade atrioventricular (AV) block after TAVI and the percentage of ventricular pacing and pacemaker (PM)-dependency at the first follow-up 6-8 weeks after implantation. Out of the 153 patients (age 81 ± 6 years) who underwent TAVI, 144 (94 %) had a transfemoral and 9 (6 %) patients a transapical approach. A PPM was implanted in 31 (20 %) patients, 24 (16 %) were implanted with the Medtronic CoreValve® and 7 (5 %) with the Edwards Sapien® valve (p = n.s.). Complete AV block was the indication in 21 patients (68 %), second-degree AV block in 1 patient (3 %), slow atrial fibrillation in 3 patients (10 %), new left bundle branch block (LBBB) plus sustained ventricular tachycardia (VT) in 1 patient (3 %), sick sinus syndrome in 2 patients (7 %), whereas in 3 patients (10 %) a PPM was inserted for safety reasons because of new LBBB and first-grade AV block. All of the nine patients (6 %) with a preexisting bundle branch block developed total AV block after TAVI. At follow-up PM-dependency (intrinsic rhythm < 30 bpm) occurred in 11/30 patients (37 %), whereas an intrinsic rhythm > 50 bpm was seen in 17 patients (57 %). At nominal device programming the percentage of ventricular stimulation (VP) during the short-term observation period was 60 ± 44 % in dual-chamber devices (N = 18), and 70 ± 36 % in single-chamber PPM (N = 5). The PPM implantation rate of about 20 % after TAVI is comparable to previously published data. The need for permanent pacing is linked to the valve type and preexistence of a right bundle branch block. At short-term more than half of the patients implanted with a device were not strictly PM-dependent, but presented an underlying intrinsic rhythm, indicating that temporary AV conduction disturbances may recover over time. This might justify a more conservative approach in some patients under watchful waiting. From another point of view, ventricular pacing at a regular or sensor-modulated rate may provide rhythm stability and chronotropy during the short-term period post-TAVI.


Potato virus Y: Contact Transmission, Stability, Inactivation, and Infection Sources.
In glasshouse experiments, two isolates of Potato virus Y 'O' strain (PVYO) were transmitted from infected to healthy potato plants by direct contact when leaves were rubbed against each other, when cut surfaces of infected tubers were rubbed onto leaves, and to a limited extent, when blades contaminated with infective sap were used to cut healthy potato tubers. However, no tuber-to-tuber transmission occurred when blades were used to cut healthy tubers after cutting infected tubers. When leaf sap from potato plants infected with two PVYO isolates was kept at room temperature, it was highly infective for 6 to 7 h and remained infectious for up to 28 h. Also, when sap from infected leaves with one isolate was applied to five surfaces (cotton, hessian, metal, rubber vehicle tire, and wood) and left to dry for up to 24 h before each surface was rubbed onto healthy tobacco plants, PVYO remained infective for 24 h on tire and metal, 6 h on cotton and hessian, and 3 h on wood. The effectiveness of disinfectants at inactivating this isolate was evaluated by adding them to sap from infected leaves which was then rubbed onto healthy tobacco plants. None of the plants became infected when bleach (42 g/liter sodium hypochlorite, diluted 1:4) or Virkon-S (potassium peroxymonosulfate 50% wt/wt, diluted to 1%) was used. A trace of infection remained after using nonfat milk powder (20% wt/vol). PVY infection sources were studied in 2011-2012 in the main potato growing regions of southwest Australia. In tests on >17,000 potato leaf samples, PVY was detected at low levels in seed (4/155) and ware (6/51) crops. It was also detected in volunteer potatoes from a site with a previous history of PVY infection in a seed crop. None of the 15 weed species tested were PVY infected. Plants of Solanum nigrum were symptomlessly infected with PVYO after sap inoculation, and no seed transmission was detected (>2,500 seeds). This study demonstrates PVYO can be transmitted by contact and highlights the need to include removal of volunteer potatoes and other on-farm hygiene practices (decontaminating tools, machinery, clothing, etc.) in integrated disease management strategies for PVY in potato crops.


Internal medicine residents' perceptions of cross-cultural training. Barriers, needs, and educational recommendations.
Physicians increasingly face the challenge of managing clinical encounters with patients from a range of cultural backgrounds. Despite widespread interest in cross-cultural care, little is known about resident physicians' perceptions of what will best enable them to provide quality care to diverse patient populations. To assess medicine residents' (1) perceptions of cross-cultural care, (2) barriers to care, and (3) training experiences and recommendations. Qualitative individual interviews were conducted with 26 third-year medicine residents at Massachusetts General Hospital in Boston (response rate=87%). Interviews were recorded, transcribed, and analyzed. Despite significant interest in cross-cultural care, almost all of the residents reported very little training during residency. Most had gained cross-cultural skills through informal learning. A few were skeptical about formal training, and some expressed concern that it is impossible to understand every culture. Challenges to the delivery of cross-cultural care included managing patients with limited English proficiency, who involve family in critical decision making, and who have beliefs about disease that vary from the biomedical model. Residents cited many implications to these barriers, ranging from negatively impacting the patient-physician relationship to compromised care. Training recommendations included making changes to the educational climate and informal and formal training mechanisms. If cross-cultural education is to be successful, it must take into account residents' perspectives and be focused on overcoming residents' cited barriers. It is important to convey that cross-cultural education is a set of skills that can be taught and applied, in a time-efficient manner, rather than requiring an insurmountable knowledge base.


H5-based DNA constructs derived from selected highly pathogenic H5N1 avian influenza virus induce high levels of humoral antibodies in Muscovy ducks against low pathogenic viruses.
H5 low pathogenic avian influenza virus (LPAIV) infection in domestic ducks is a major problem in duck producing countries. Their silent circulation is an ongoing source of potential highly pathogenic or zoonotic emerging strains. To prevent such events, vaccination of domestic ducks might be attempted but remains challenging. Currently licensed vector vaccines derived from H5N1 HPAIV possess clade 0, clade 2.2 or clade 2.3.4 HA sequences: selection of the best HA candidate inducing the largest cross protection is a key issue. For this purpose, DNA immunization of specific pathogen free Muscovy ducks was performed using different synthetic codon optimized (opt) or native HA genes from H5N2 LPAIV and several H5N1 HPAIV clade 2.1, 2.2.1 and 2.3.4. Humoral cross-immunity was assessed 3 weeks after boost by hemagglutination inhibition (HI) and virus neutralization (VN) against three French H5 LPAIV antigens. Vaccination with LP H5N2 HA induced the highest VN antibody titre against the homologous antigen; however, the corresponding HI titre was lower and comparable to HI titres obtained after immunization with opt HA derived from clades 2.3.4 or 2.1. Compared to the other HPAIV-derived constructs, vaccination with clade 2.3.4 opt HA consistently induced the highest antibody titres in HI and VN, when tested against all three H5 LPAIV antigens and H5N2 LPAIV, respectively: differences in titres against this last strain were statistically significant. The present study provides a standardized method to assess cross-immunity based on HA immunogenicity alone, and suggests that clade 2.3.4-derived recombinant vaccines might be the optimal candidates for further challenge testing to vaccinate domestic Muscovy ducks against H5 LPAIV.


Adhesion of Active Cytoskeletal Vesicles.
Regulation of adhesion is a ubiquitous feature of living cells, observed during processes such as motility, antigen recognition, or rigidity sensing. At the molecular scale, a myriad of mechanisms are necessary to recruit and activate the essential proteins, whereas at the cellular scale, efficient regulation of adhesion relies on the cell's ability to adapt its global shape. To understand the role of shape remodeling during adhesion, we use a synthetic biology approach to design a minimal experimental model, starting with a limited number of building blocks. We assemble cytoskeletal vesicles whose size, reduced volume, and cytoskeletal contractility can be independently tuned. We show that these cytoskeletal vesicles can sustain strong adhesion to solid substrates only if the actin cortex is actively remodeled significantly. When the cytoskeletal vesicles are deformed under hypertonic osmotic pressure, they develop a crumpled geometry with deformations. In the presence of molecular motors, these deformations are dynamic in nature, and the excess membrane area generated thereby can be used to gain adhesion energy. The cytoskeletal vesicles are able to attach to the rigid glass surfaces even under strong adhesive forces just like the cortex-free vesicles. The balance of deformability and adhesion strength is identified to be key to enable cytoskeletal vesicles to adhere to solid substrates.


Divergent Long-Term Detection Rates of Proximal and Distal Advanced Neoplasia in Fecal Immunochemical Test Screening Programs: A Retrospective Cohort Study.
Short-term studies have reported that the fecal immunochemical test (FIT) is less accurate in detecting proximal than distal colorectal neoplasia. To assess the long-term detection rates for advanced adenoma and colorectal cancer (CRC), according to anatomical location. Retrospective study. Population-based, organized screening program in the Veneto region of Italy. Persons aged 50 to 69 years who completed 6 rounds of FIT screening. At each screening round, the detection rates for advanced adenoma and cancer, as well as the proportional interval cancer rate (PICR), were calculated by anatomical location (proximal colon, distal colon, or rectum). Between 2002 and 2014, a total of 123 347 participants had 441 647 FITs. The numbers of advanced adenomas and cancer cases detected, respectively, were 1704 and 200 in the proximal colon, 3703 and 324 in the distal colon, and 1220 and 209 in the rectum. Although the detection rate for proximal colon cancer declined only from the first to the second screening round (0.63 to 0.36 per 1000 screenees), the rate for both distal colon and rectal cancer steadily decreased across 6 rounds (distal colon, 1.65 in the first round to 0.17 in the sixth; rectum, 0.82 in the first round to 0.17 in the sixth). Similar trends were found for advanced adenoma (proximal colon, 5.32 in the first round to 4.22 in the sixth; distal colon, 15.2 in the first round to 5.02 in the sixth). Overall, 150 cases of interval cancer were diagnosed. The PICR was higher in the proximal colon (25.2% [95% CI, 19.9% to 31.5%]) than the distal colon (6.0% [CI, 3.9% to 8.9%]) or rectum (9.9% [CI, 6.9% to 13.7%]). Participants with irregular attendance were censored. Those who had a false-positive result on a previous FIT but negative colonoscopy results were included in subsequent rounds. This FIT-based, multiple-round, long-term screening program had a negligible reduction in detection rates for neoplastic lesions in the proximal versus the distal colon after the first round. This was related to a higher PICR in the proximal colon and suboptimal efficacy in preventing the age-related proximal shifting of CRC. None.


Routes to diagnosis of heart failure: observational study using linked data in England.
Timely diagnosis and management of heart failure (HF) is critical, but identification of patients with suspected HF can be challenging, especially in primary care. We describe the journey of people with HF in primary care from presentation through to diagnosis and initial management. We used the Clinical Practice Research Datalink (primary care consultations linked to hospital admissions data and national death registrations for patients registered with participating primary care practices in England) to describe investigation and referral pathways followed by patients from first presentation with relevant symptoms to HF diagnosis, particularly alignment with recommendations of the National Institute for Health and Care Excellence guideline for HF diagnosis. 36 748 patients had a diagnosis of HF recorded that met the inclusion criteria between 1 January 2010 and 31 March 2013. For 29 113 (79.2%) patients, this was first recorded in hospital. In the 5 years prior to diagnosis, 15 057 patients (41.0%) had a primary care consultation with one of three key HF symptoms recorded, 17 724 (48.2%) attended for another reason and 3967 (10.8%) did not see their general practitioner. Only 24% of those with recorded HF symptoms followed a pathway aligned with guidelines (echocardiogram and/or serum natriuretic peptide test and specialist referral), while 44% had no echocardiogram, natriuretic peptide test or referral. Patients follow various pathways to the diagnosis of HF. However, few appear to follow a pathway supported by guidelines for investigation and referral. There are likely to be missed opportunities for earlier HF diagnosis in primary care.


Power of regression and maximum likelihood methods to map QTL from sib-pair and DZ twin data.
A common study design to map quantitative trait loci (QTL) is to compare the phenotypes and marker genotypes of two or more siblings in a sample of unrelated sib groups, and to test for linkage between chromosome location and quantitative trait values. The simplest case is sib pairs only, in particular dizygotic twin pairs, and a simple and elegant regression method was proposed by Haseman & Elston in 1972 to test for linkage. Since then, several other methods have been proposed to test for linkage. In this study, we derived the statistical power of linear regression and maximum likelihood methods to map QTL from sib pair data analytically, and determined which methods are superior under which set of population parameters. In particular, we considered four regression-based and three maximum likelihood-based approaches, and derived asymptotic approximations of the mean test statistic and statistical power for each method. It was found, both analytically and by computer simulation, that the revisited or new Haseman-Elston method (based upon the mean-corrected crossproduct of the observations on sib-pairs) is less powerful than a full maximum likelihood approach and is also inferior to the Haseman-Elston method under a realistic range of values for the population parameters. We found that a simple regression method, based upon both the squared difference and the mean-corrected squared sum of the observations on sib-pairs, is as powerful as a full maximum likelihood approach. Our derivations of statistical power for regression and maximum likelihood methods provide a simple way to compare alternative methods and obviate the need to perform elaborate computer simulations. DZ twin pairs are likely to be more powerful for linkage analysis than ordinary siblings because they may share more common environmental effects, thereby increasing the proportion of within-family variance that is explained by a QTL.


Variations of thiaminase I activity pH dependencies among typical Great Lakes forage fish and Paenibacillus thiaminolyticus.
The source of thiaminase in the Great Lakes food web remains unknown. Biochemical characterization of the thiaminase I activities observed in forage fish was undertaken to provide insights into potential thiaminase sources and to optimize catalytic assay conditions. We measured the thiaminase I activities of crude extracts from five forage fish species and one strain of Paenibacillus thiaminolyticus over a range of pH values. The clupeids, alewife Alosa pseudoharengus and gizzard shad Dorosoma cepedianum, had very similar thiaminase I pH dependencies, with optimal activity ranges (> or = 90% of maximum activity) between pH 4.6 and 5.5. Rainbow smelt Osmerus mordax and spottail shiner Notropis hudsonius had optimal activity ranges between pH 5.5-6.6. The thiaminase I activity pH dependence profile of P. thiaminolyticus had an optimal activity range between pH 5.4 and 6.3, which was similar to the optimal range for rainbow smelt and spottail shiners. Incubation of P. thiaminolyticus extracts with extracts from bloater Coregonus hoyi (normally, bloaters have little or no detectable thiaminase I activity) did not significantly alter the pH dependence profile of P. thiaminolyticus-derived thiaminase I, such that it continued to resemble that of the rainbow smelt and spottail shiner, with an apparent optimal activity range between pH 5.7 and 6.6. These data are consistent with the hypothesis of a bacterial source for thiaminase I in the nonclupeid species of forage fish; however, the data also suggest different sources of thiaminase I enzymes in the clupeid species.


Patient engagement in a Canadian consensus forum for heart donation after circulatory determination of death.
Heart donation and transplantation following circulatory determination of death has yet to be performed in Canada. A consensus forum was held to provide expert guidance to inform policy with a comprehensive patient partner strategy. This paper describes the process used to create fulsome patient partner engagement resulting in mutually beneficial policy development in this complex area. A wide-ranging process for involving patient partners in this area included pre-meeting education, in-meeting expert support, full participation and permission to step back if desired, and post-meeting debriefing. Following the meeting, a questionnaire was used to guide a debrief discussion with patient partners and steering committee members who co-authored this paper. Five key themes arose that echoed the sentiments and contributions made by patient partners, including: 1) a strong desire to improve the system, 2) gratitude and honour, 3) expert support and process, 4) simplification of complex concepts, and 5) mutual benefit expressed by patient partners and healthcare professionals. Despite the complexity of the content and the emotionally sensitive nature of discussions around deceased organ donation, a well-planned strategy to involve patient partners is important, impactful, and central to the process. This suggests a broad interprofessional audience can engage with properly prepared and supported patient partners to strengthen and focus dialogue and outputs in the development of health policy in the donation and transplant sector.


Insight into the evolution of the Solanaceae from the parental genomes of Petunia hybrida.
Petunia hybrida is a popular bedding plant that has a long history as a genetic model system. We report the whole-genome sequencing and assembly of inbred derivatives of its two wild parents, P. axillaris N and P. inflata S6. The assemblies include 91.3% and 90.2% coverage of their diploid genomes (1.4 Gb; 2n = 14) containing 32,928 and 36,697 protein-coding genes, respectively. The genomes reveal that the Petunia lineage has experienced at least two rounds of hexaploidization: the older gamma event, which is shared with most Eudicots, and a more recent Solanaceae event that is shared with tomato and other solanaceous species. Transcription factors involved in the shift from bee to moth pollination reside in particularly dynamic regions of the genome, which may have been key to the remarkable diversity of floral colour patterns and pollination systems. The high-quality genome sequences will enhance the value of Petunia as a model system for research on unique biological phenomena such as small RNAs, symbiosis, self-incompatibility and circadian rhythms.


Structure-Activity Relationship Study of Covalent Pan-phosphatidylinositol 5-Phosphate 4-Kinase Inhibitors.
Phosphatidylinositol 5-phosphate 4-kinases (PI5P4Ks) are important molecular players in a variety of diseases, such as cancer. Currently available PI5P4K inhibitors are reversible small molecules, which may lack selectivity and sufficient cellular on-target activity. In this study, we present a new class of covalent pan-PI5P4K inhibitors with potent biochemical and cellular activity. Our designs are based on THZ-P1-2, a covalent PI5P4K inhibitor previously developed in our lab. Here, we report further structure-guided optimization and structure-activity relationship (SAR) study of this scaffold, resulting in compound 30, which retained biochemical and cellular potency, while demonstrating a significantly improved selectivity profile. Furthermore, we confirm that the inhibitors show efficient binding affinity in the context of HEK 293T cells using isothermal CETSA methods. Taken together, compound 30 represents a highly selective pan-PI5P4K covalent lead molecule.


Nasal saline irrigation in children: a study of compliance and tolerance.
To determine the compliance with and tolerance of nasal saline irrigation in children. Phone survey. Tertiary pediatric hospital. Children diagnosed with nasal congestion and rhinorrhea from sinusitis, chronic rhinitis or allergic rhinitis were identified. Children who were prescribed a therapeutic course of nasal saline, who were instructed how to administer the treatment and who were available for follow up were included. Parents were contacted by phone and asked to complete a questionnaire regarding their child's experience with nasal saline irrigation. 61 Children met inclusion criteria. 73% of parents initially thought that nasal saline irrigation would be helpful, but only 28% thought that their children would tolerate the treatment. 93% of children made an attempt to use nasal saline irrigation and 86% were able to tolerate the treatment. 84% of parents whose children attempted nasal saline irrigation noted an improvement in their child's nasal symptoms. 77% of children that attempted nasal saline irrigation continue to use this treatment for symptom relief. 93% reported an improvement in their child's overall health that they attributed to this treatment. Perhaps the biggest barrier to routine recommendation of nasal saline irrigation in children is the assumption by both parents and physicians that children will not tolerate it. However, this study demonstrates that the majority of children, regardless of age, were judged by their parents to tolerate nasal saline irrigation.


Immunoglobulin G from bovine milk primes intestinal epithelial cells for increased colonization of bifidobacteria.
A bovine colostrum fraction (BCF) was recently shown to enhance the adherence of several commensal organisms to intestinal epithelial cells through modulating the epithelial cell surface. In this study, the main components of the BCF were examined to investigate the active component/s responsible for driving the changes in the intestinal cells. The adherence of various bifidobacteria to HT-29 cells was increased when the intestinal cells were pre-incubated with immunoglobulin G (IgG). Modulation of the intestinal cells by IgG was concentration dependent with 16 mg/mL IgG resulting in a 43-fold increase in the adhesion of Bifidobacterium longum NCIMB 8809 to HT-29 cells. Periodate treatment of colostral IgG prior to performing the colonization studies resulted in a reduction in the adhesion of the strain to the intestinal cells demonstrating that the glycans of IgG may be important in modulating the intestinal cells for enhanced commensal adhesion. IgG isolated from mature milk also resulted in significant increases in adhesion of the Bifidobacterium strains tested albeit at reduced levels (3.9-fold). The impact of IgG on the HT-29 cells was also visualised via scanning electron microscopy. This study builds a strong case for the inclusion of IgG ingredients sourced from cow's milk in functional foods aimed at increasing numbers of health promoting bacteria in the human gut.


Emerging Updates on the Posterior Cruciate Ligament: A Review of the Current Literature.
The posterior cruciate ligament (PCL) is recognized as an essential stabilizer of the knee. However, the complexity of the ligament has generated controversy about its definitive role and the recommended treatment after injury. A proper understanding of the functional role of the PCL is necessary to minimize residual instability, osteoarthritic progression, and failure of additional concomitant ligament graft reconstructions or meniscal repairs after treatment. Recent anatomic and biomechanical studies have elucidated the surgically relevant quantitative anatomy and confirmed the codominant role of the anterolateral and posteromedial bundles of the PCL. Although nonoperative treatment has historically been the initial treatment of choice for isolated PCL injury, possibly biased by the historically poorer objective outcomes postoperatively compared with anterior cruciate ligament reconstructions, surgical intervention has been increasingly used for isolated and combined PCL injuries. Recent studies have more clearly elucidated the biomechanical and clinical effects after PCL tears and resultant treatments. This article presents a thorough review of updates on the clinically relevant anatomy, epidemiology, biomechanical function, diagnosis, and current treatments for the PCL, with an emphasis on the emerging clinical and biomechanical evidence regarding each of the treatment choices for PCL reconstruction surgery. It is recommended that future outcomes studies use PCL stress radiographs to determine objective outcomes and that evidence level 1 and 2 studies be performed to assess outcomes between transtibial and tibial inlay reconstructions and also between single- and double-bundle PCL reconstructions.


Exploring the utility of Brachypodium distachyon as a model pathosystem for the wheat pathogen Zymoseptoria tritici.
Zymoseptoria tritici, the causative organism of Septoria tritici blotch disease is a prevalent biotic stressor of wheat production, exerting substantial economic constraints on farmers, requiring intensive chemical control to protect yields. A hemibiotrophic pathogen with a long asymptomless phase of up to 11 days post inoculation (dpi) before a rapid switch to necrotrophy; a deficit exists in our understanding of the events occurring within the host during the two phases of infection. Brachypodium distachyon has demonstrated its potential as a model species for the investigation of fungal disease resistance in cereal and grass species. The aim of this study was to assess the physical interaction between Z. tritici (strain IPO323) and B. distachyon and examine its potential as a model pathosystem for Z. tritici. Septoria tritici blotch symptoms developed on the wheat cultivar Riband from 12 dpi with pycnidial formation abundant by 20 dpi. Symptoms on B. distachyon ecotype Bd21-1 were visible from 1 dpi: characteristic pale, water soaked lesions which developed into blotch-like lesions by 4 dpi. These lesions then became necrotic with chlorotic regions expanding up to 7 dpi. Sporulation on B. distachyon tissues was not observed and no evidence of fungal penetration could be obtained, indicating that Z. tritici was unable to complete its life cycle within B. distachyon ecotypes. However, observation of host responses to the Z. tritici strain IPO323 in five B. distachyon ecotypes revealed a variation in resistance responses, ranging from immunity to a chlorotic/necrotic phenotype. The observed interactions suggest that B. distachyon is an incompatible host for Z. tritici infection, with STB symptom development on B. distachyon comparable to that observed during the early infection stages on the natural host, wheat. However first visible symptoms occurred more rapidly on B. distachyon; from 1 dpi in comparison to 12 dpi in wheat. Consequently, we propose that the interaction between B. distachyon and Z. tritici as observed in this study could serve as a suitable model pathosystem with which to investigate mechanisms underpinning an incompatible host response to Z. tritici.


Comparing short versions of the Alcohol Use Disorders Identification Test (AUDIT) in a military cohort.
The Alcohol Use Disorders Identification Test (AUDIT) is widely used for monitoring harmful alcohol consumption among high-risk populations. A number of short versions of AUDIT have been developed for use in time-constrained settings. In military populations, a range of AUDIT variations have been used, but the optimal combination of AUDIT items has not been determined. A total of 952 participants (80% male), recruited as part of a wider study, completed the AUDIT-10. We systematically assessed all possible combinations of three or four AUDIT items and established AUDIT variations using the following statistics: Cronbach's alpha (internal consistency), variance explained (R2) and Pearson's correlation coefficient (concurrent validity). Median AUDIT-10 score was 7 for males and 6 for females, and 380 (40%) participants were classified as having a score indicative of harmful or hazardous alcohol use (≥8) according to WHO classifications.A novel four-item AUDIT variation (3, 4, 8 and 9) performed consistently higher than established variations across statistical measures; it explained 85% of variance in AUDIT-10, had a Pearson's correlation of 0.92 and Cronbach's alpha was 0.63. The FAST, an established shortened AUDIT variant, together with several other four-item novel variants of AUDIT-10 performed similarly. The AUDIT-C performed consistently low on all measures, but with a satisfactory level of internal consistency (75%). Shortened AUDIT variations may be suitable alternatives to the full AUDIT for screening hazardous alcohol consumption in military populations. Four-item AUDIT variations focused on short-term risky drinking and its consequences performed better than three item versions. ACTRN12614001332617.


Monoclonal antibody recognizing N-terminal epitope of hepatitis C virus nonstructural 5B inhibits viral RNA replication.
The nonstructural 5B (NS5B) protein of hepatitis C virus (HCV) is an RNA-dependent RNA polymerase (RdRp) with a key role in HCV replication. To characterize the functional roles of NS5B in HCV replication, we produced a panel of 10 monoclonal antibodies (mAbs) directed against NS5B protein from mice immunized with functionally active RdRp. The epitopes of eight mAbs are localized in the middle region (amino acid 240-263) of NS5B protein. On the other hand, the epitopes of two mAbs are mapped to amino acids 67-88 at the N-terminus of NS5B protein. To examine the effects of mAbs on HCV-RNA replication, we performed in vitro RdRp assay using either the 3'-untranslated region (UTR) or the full-length of HCV-RNA as a template in the presence of each mAb. mAbs specific for the middle region of NS5B had no effect on RdRp activity. Surprisingly, mAb recognizing the N-terminal region of NS5B inhibited RdRp activity in a dose-dependent manner. We have confirmed the same result using the other subclass of mAb, whose epitope is also localized to the same N-terminal region of NS5B. These data show that NS5B contains a B-cell epitope located between amino acid residues 67 and 88. Binding of this epitope with an antibody interferes with the enzymatic function of NS5B.


Inhibition of rat corneal angiogenesis by a nuclease-resistant RNA aptamer specific for angiopoietin-2.
Angiopoietin-2 (Ang2) appears to be a naturally occurring antagonist of the endothelial receptor tyrosine kinase Tie2, an important regulator of vascular stability. Destabilization of the endothelium by Ang2 is believed to potentiate the actions of proangiogenic growth factors. To investigate the specific role of Ang2 in the adult vasculature, we generated a nuclease-resistant RNA aptamer that binds and inhibits Ang2 but not the related Tie2 agonist, angiopoietin-1. Local delivery of this aptamer but not a partially scrambled mutant aptamer inhibited basic fibroblast growth factor-mediated neovascularization in the rat corneal micropocket angiogenesis assay. These in vivo data directly demonstrate that a specific inhibitor of Ang2 can act as an antiangiogenic agent.


Restoration of ovariectomy-induced osteopenia by nitroglycerin.
Nitric oxide (NO) is known to inhibit osteoclastic bone resorption. Previously, we demonstrated that the NO donor nitroglycerin (NG) prevented ovariectomy (OVX)-induced bone loss. The current study shows that NG restores ovariectomy-induced osteopenia. Twenty-four female Sprague-Dawley rats, 36 weeks of age, underwent OVX, and a further six rats were sham-operated. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometric (DXA) scanning prior to OVX, at 6 weeks postsurgery, and at 6 weeks posttreatment. OVX rats were then assigned to four groups and treated with either (1) vehicle, (2) 17-beta-estradiol, (3) NG (0.2 mg/kg/day), or (4) a combination of estrogen and NG (n = 6/group). During the first 6-week post-OVX period, there was a significant decrease in the BMD in all ovariectomized (OVXed) rats (-11.0%, P < 0.001). There were no significant changes in BMD during the entire 12-week period in sham-operated rats. During the second 6-week period (after developing bone loss), there was no further significant loss of BMD in OVXed controls. BMD loss and loss of femur weight produced by OVXed were restored by treatment with estrogen, NG, or the two agents together during the second 6-week period (P < 0.01). The effects of estrogen and NG together, however, were not additive. The BMD of rats treated with NG alone, at 12 weeks, was similar to that of animals treated with estrogen alone or with estrogen and NG, and was comparable to that of sham-operated rats. The increased urinary excretion of deoxypyridinolines caused by OVX was negated by estrogen, NG, and estrogen together with NG (P < 0.01). In contrast to estrogen, NG did not decrease the post-OVX-induced increase of serum osteocalcin levels, suggesting that NG may also have a positive effect on bone formation. In summary, the results suggest that the NO donor, NG, reverses the OVX-induced bone loss in rats, and these effects are likely due to decreased bone resorption and, perhaps, increased bone formation.


Peer rejection in childhood, involvement with antisocial peers in early adolescence, and the development of externalizing behavior problems.
A longitudinal, prospective design was used to examine the roles of peer rejection in middle childhood and antisocial peer involvement in early adolescence in the development of adolescent externalizing behavior problems. Both early starter and late starter pathways were considered. Classroom sociometric interviews from ages 6 through 9 years, adolescent reports of peers' behavior at age 13 years, and parent, teacher, and adolescent self-reports of externalizing behavior problems from age 5 through 14 years were available for 400 adolescents. Results indicate that experiencing peer rejection in elementary school and greater involvement with antisocial peers in early adolescence are correlated but that these peer relationship experiences may represent two different pathways to adolescent externalizing behavior problems. Peer rejection experiences, but not involvement with antisocial peers. predict later externalizing behavior problems when controlling for stability in externalizing behavior. Externalizing problems were most common when rejection was experienced repeatedly. Early externalizing problems did not appear to moderate the relation between peer rejection and later problem behavior. Discussion highlights multiple pathways connecting externalizing behavior problems from early childhood through adolescence with peer relationship experiences in middle childhood and early adolescence.


Neurophysiological Correlates of Colour Induction on White Surfaces.
Coloured light surrounding a white surface of about equal luminance makes the white surface appear illuminated with an unsaturated light of the complementary colour. In an attempt to discover the neurophysiological basis of such colour induction, we recorded from spectrally opponent cells of the parvocellular layers of the lateral geniculate nucleus (P-LGN) of anaesthetized macaques. Only cells with wide-band (W) spectral sensitivity in the short (S) or long wavelength (L) part of the spectrum (WS, WL) are excited by white spots of light centred on their receptive field. Cells with narrow-band (N) spectral sensitivity (NS, NL) and light-inhibited (LI) cells are inhibited by white light. Therefore, it is likely that the code for white is contained in a balanced excitation of the W cells. The effects of continuous illumination of remote surrounds with different wavelengths on the responses to achromatic light stimuli were investigated. Responses [on minus maintained discharge rate (MDR) or on-minus-off] were determined for white spots (1 - 3 degrees diameter) flashed on the receptive field centre, presented either alone or in the presence of an annular surround of equal luminance (inner diameter 5 degrees; outer diameter 20 degrees ). During red surround illumination the responses of WL cells to white spots tended to be reduced as were those of WS cells during blue surround illumination. Surround illumination with the opponent colour had more variable effects, neither WS nor WL cells showing a significant alteration of their mean response to white during surround illumination with opponent light. Response alterations were to a large extent due to changes in MDR, which increased in WS cells during blue surround illumination and in WL cells during red surround illumination. It is argued that the surround effects on centre responses are due to intraocular stray light rather than lateral connections in the retina. The surround effects also depended to some extent on the size of the test spot. LI cells and the very rare parvocellular panchromatic on-cells showed no chromatic response changes during coloured surround illumination. Inasmuch as the excitation of WS cells, either alone or in combination with NS cell activation, is involved in coding for green and blue, and that of WL cells, in combination with NL cell activation, is involved in coding for red and yellow in perception, the shift of excitation towards one or the other W cell group indicates relatively more red or green signals in the white response, consistent with and in the same direction as colour induction. In addition, the summed population response of WS and WL cells is decreased during surround illumination with any colour including white. This is related to brightness decrease during surround illumination in perception.


Phloretin ameliorates hepatic steatosis through regulation of lipogenesis and Sirt1/AMPK signaling in obese mice.
Phloretin is isolated from apple trees and could increase lipolysis in 3T3-L1 adipocytes. Previous studies have found that phloretin could prevent obesity in mice. In this study, we investigated whether phloretin ameliorates non-alcoholic fatty liver disease (NAFLD) in high-fat diet (HFD)-induced obese mice, and evaluated the regulation of lipid metabolism in hepatocytes. HepG2 cells were treated with 0.5 mM oleic acid to induce lipid accumulation, and then treated with phloretin to evaluate the molecular mechanism of lipogenesis. In another experiment, male C57BL/6 mice were fed normal diet or HFD (60% fat, w/w) for 16 weeks. After the fourth week, mice were treated with or without phloretin by intraperitoneal injection for 12 weeks. Phloretin significantly reduced excessive lipid accumulation and decreased sterol regulatory element-binding protein 1c, blocking the expression of fatty acid synthase in oleic acid-induced HepG2 cells. Phloretin increased Sirt1, and phosphorylation of AMP activated protein kinase to suppress acetyl-CoA carboxylase expression, reducing fatty acid synthesis in hepatocytes. Phloretin also reduced body weight and fat weight compared to untreated HFD-fed mice. Phloretin also reduced liver weight and liver lipid accumulation and improved hepatocyte steatosis in obese mice. In liver tissue from obese mice, phloretin suppressed transcription factors of lipogenesis and fatty acid synthase, and increased lipolysis and fatty acid β-oxidation. Furthermore, phloretin regulated serum leptin, adiponectin, triglyceride, low-density lipoprotein, and free fatty acid levels in obese mice. These findings suggest that phloretin improves hepatic steatosis by regulating lipogenesis and the Sirt-1/AMPK pathway in the liver.


Powerful gene-based testing by integrating long-range chromatin interactions and knockoff genotypes.
Gene-based tests are valuable techniques for identifying genetic factors in complex traits. Here, we propose a gene-based testing framework that incorporates data on long-range chromatin interactions, several recent technical advances for region-based tests, and leverages the knockoff framework for synthetic genotype generation for improved gene discovery. Through simulations and applications to genome-wide association studies (GWAS) and whole-genome sequencing data for multiple diseases and traits, we show that the proposed test increases the power over state-of-the-art gene-based tests in the literature, identifies genes that replicate in larger studies, and can provide a more narrow focus on the possible causal genes at a locus by reducing the confounding effect of linkage disequilibrium. Furthermore, our results show that incorporating genetic variation in distal regulatory elements tends to improve power over conventional tests. Results for UK Biobank and BioBank Japan traits are also available in a publicly accessible database that allows researchers to query gene-based results in an easy fashion.


A comparison between characterization and biological properties of Brazilian fresh and aged propolis.
As propolis is a highly valued bee product, we aimed to verify the quality of aged propolis, investigating their phenolic and flavonoid composition, levels of toxic metals, radical scavenging and antimicrobial activities. Samples of fresh and aged propolis of six different beekeepers, from the same geographical location, were investigated in terms of their phenolic and flavonoid composition and levels of Pb, Cd, and Cr, as well as radical scavenging and antimicrobial activities. The two groups of propolis had similar qualitative composition by HPLC-PDA and ESI(-)-MS. Fresh propolis and aged propolis show no differences when average values of extraction yield, flavonoids, EC50, or MIC were compared and both types of propolis showed good antimicrobial activity at low concentrations. Only levels of phenolic compounds were higher in fresh propolis. The propolis samples considered in this study, aged or fresh, had similar qualitative composition, although they were collected in different periods. Samples only differed in their levels of total phenolic content. Moreover, aged propolis conserves significant radical scavenging and antimicrobial properties. We suggest that aged propolis should not be discarded but explored for alternative applications.


The Efficacy and Safety of Simple-Needling Therapy for Treating Ankylosing Spondylitis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Clinical investigators have found that the use of needling in the treatment of ankylosing spondylitis (AS) has a good clinical application prospect in recent years. However, these studies were insufficient to provide evidence for the efficacy and safety of simple-needling for AS. So, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of simple-needling for treating AS. We searched the PubMed, Cochrane Library, Embase, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), Wangfang database (Wanfang), Chinese Science and Technology Periodical Database (VIP), and any other gray literature sources for randomized controlled trials (RCTs) that used simple-needling to treat AS before June 2019 with the language restriction of Chinese and English. Researchers evaluated the retrieved literature studies and extracted valid data according to relevant requirements and used RevMan5.3 software for meta-analysis. A total of 10 studies were included, all of which were Chinese literature studies, involving 729 patients. Compared with the control groups, simple-needling groups had a better effect on the clinical effective rate (RR = 1.20, 95% CI (1.11, 1.29), P < 0.00001), TCM syndrome score (MD = -5.26, 95% CI (-5.99, -4.53), P < 0.00001), symptom score (MD = -8.08, 95% CI (-10.18, -5.97), P < 0.00001), and Schober test outcome (MD = 0.39, 95% CI (0.15, 0.64), P=0.002). Sensibility analysis was based on the leave-one-out cross-validation procedure, and the results showed no significant changes. Most studies did not describe adverse reactions. The funnel plot suggested publication bias on clinical effectiveness. This systematic review and meta-analysis demonstrated that simple-needling was effective as an intervention for AS. However, due to the low quality of the methodology of included studies, the designs of clinical trials were not rigorously standardized. Therefore, it is necessary to carry out multiquality RCTs for verification.


Research priorities during infectious disease emergencies in West Africa.
This paper presents the results of the consultations conducted with various stakeholders in Africa and other experts to document community perspectives on the types of research to be prioritised in outbreak conditions. The Delphi method was used to distill consensus. Our consultations highlighted as key, the notion that in an infectious disease outbreak situation, the need to establish an evidence base on how to reduce morbidity and mortality in real time takes precedence over the production of generalizable knowledge. Research studies that foster understanding of how disease transmission could be prevented in the future remain important, implementation research that explores how to mitigate the impact of outbreaks in the present should be prioritized. Clinical trials aiming to establish the safety profile of therapeutic interventions should be limited during the acute phase of an epidemic with high fatality-and should preferably use adaptive designs. We concluded that community members have valuable perspectives to share about research priorities during infectious disease emergencies. Well designed consultative processes could help identify these opinions.


Arrhythmia Classification Based on Multi-Domain Feature Extraction for an ECG Recognition System.
Automatic recognition of arrhythmias is particularly important in the diagnosis of heart diseases. This study presents an electrocardiogram (ECG) recognition system based on multi-domain feature extraction to classify ECG beats. An improved wavelet threshold method for ECG signal pre-processing is applied to remove noise interference. A novel multi-domain feature extraction method is proposed; this method employs kernel-independent component analysis in nonlinear feature extraction and uses discrete wavelet transform to extract frequency domain features. The proposed system utilises a support vector machine classifier optimized with a genetic algorithm to recognize different types of heartbeats. An ECG acquisition experimental platform, in which ECG beats are collected as ECG data for classification, is constructed to demonstrate the effectiveness of the system in ECG beat classification. The presented system, when applied to the MIT-BIH arrhythmia database, achieves a high classification accuracy of 98.8%. Experimental results based on the ECG acquisition experimental platform show that the system obtains a satisfactory classification accuracy of 97.3% and is able to classify ECG beats efficiently for the automatic identification of cardiac arrhythmias.


Singleton search is guided by knowledge of the target, but maybe it shouldn't be.
Among studies of visual search for a singleton, some studies show evidence of top-down attentional guidance driven by goals, while others do not, leading to uncertainty as to how goal-driven guidance should be included in attentional theories. Six experiments tested this guidance when a target shape is found by locating a singleton feature (color or shape) and an orientation within the target is then reported. Experiments 1 and 2 use the dimensional priming paradigm underlying the most effective arguments against goal-driven guidance, and show evidence for guidance in many circumstances. Experiment 3 extends the results to feature priming, and demonstrates a complex interaction between attentional goals and memory for previous targets. In Experiment 4, symbolic (word) cues were just as effective as image cues, further strengthening the case for goal-driven guidance. In Experiments 5 and 6, as in the previous experiments, valid cues again produced faster responses than invalid cues, showing the advantage of goal-driven guidance. Surprisingly, however, responses were even faster when the cues were uninformative. Furthermore, participants who began the experiment with neutral cues seemed to ignore informative cues later in the experiment. The results show that attention can be guided by goals even in easy searches, but that searchers have much flexibility in the use of this guidance, and may choose not to use it. Furthermore, their decisions about using this guidance are not always well informed, because they are not aware of the relative costs and benefits.


Missense glucokinase mutation in maturity-onset diabetes of the young and mutation screening in late-onset diabetes.
We describe a codon 299 mutation in the glucokinase gene in a British pedigree with maturity-onset diabetes of the young (MODY) resulting in a substitution of glycine to arginine. One out of fifty patients diagnosed with classical late-onset type 2 diabetes mellitus was also found to have this mutation. All nine relatives of this patient who have inherited the mutation have type 2 diabetes, although six others without the mutation are also present with diabetes. The discovery that glucokinase mutations can cause MODY and was also found in ten affected members of a pedigree with type 2 diabetes in which MODY had not previously been considered indicates that diagnosis based on molecular pathology will be helpful in understanding the aetiology of type 2 diabetes.


Pulse-stream VLSI neural networks mixing analog and digital techniques.
The pulse-stream technique, which represents neural states as sequences of pulses, is reviewed. Several general issues are raised, and generic methods appraised, for pulsed encoding, arithmetic, and intercommunication schemes. Two contrasting synapse designs are presented and compared. The first is based on a fully analog computational form in which the only digital component is the signaling mechanism itself-asynchronous, pulse-rate encoded digital voltage pulses. In this circuit, multiplication occurs in the voltage/current domain. The second design uses more conventional digital memory for weight storage, with synapse circuits based on pulse stretching. Integrated circuits implementing up to 15000 analog, fully programmable synaptic connections are described. A demonstrator project is described in which a small robot localization network is implemented using asynchronous, analog, pulse-stream devices.


Neuropsychiatric studies in a family with presenile dementia different from Alzheimer and Pick disease.
We have studied a family in which 14 persons among 73 are or have been suffering from presenile dementia. Post mortem examination showed atrophy but no sign of any known demential syndrome. Cerebral blood flow measured in the late stage of disease was low, but with no characteristic pattern in flow distribution. In one patient in the initial stage of disease, the cerebral blood flow was unexpectedly increased. The patients with presenile dementia in this family did not reveal pathological signs of any known demential syndrome and showed CBF-changes not earlier reported. Moreover, contrary to widely held views we have evidence that dementia may be connected to a high blood flow at least in the initial state. An increased blood flow was also seen in seven of ten well functioning first degree relatives, in some cases along with cerebral atrophy and/or psychological tests with signs of dementia. Are these people going to develop manifest dementia later in life?


SLAP lesions: a treatment algorithm.
Tears of the superior labrum involving the biceps anchor are a common entity, especially in athletes, and may highly impair shoulder function. If conservative treatment fails, successful arthroscopic repair of symptomatic SLAP lesions has been described in the literature particularly for young athletes. However, the results in throwing athletes are less successful with a significant amount of patients who will not regain their pre-injury level of performance. The clinical results of SLAP repairs in middle-aged and older patients are mixed, with worse results and higher revision rates as compared to younger patients. In this population, tenotomy or tenodesis of the biceps tendon is a viable alternative to SLAP repairs in order to improve clinical outcomes. The present article introduces a treatment algorithm for SLAP lesions based upon the recent literature as well as the authors' clinical experience. The type of lesion, age of patient, concomitant lesions, and functional requirements, as well as sport activity level of the patient, need to be considered. Moreover, normal variations and degenerative changes in the SLAP complex have to be distinguished from "true" SLAP lesions in order to improve results and avoid overtreatment. The suggestion for a treatment algorithm includes: type I: conservative treatment or arthroscopic debridement, type II: SLAP repair or biceps tenotomy/tenodesis, type III: resection of the instable bucket-handle tear, type IV: SLAP repair (biceps tenotomy/tenodesis if >50 % of biceps tendon is affected), type V: Bankart repair and SLAP repair, type VI: resection of the flap and SLAP repair, and type VII: refixation of the anterosuperior labrum and SLAP repair.


Novel low-kVp beamlet system for choroidal melanoma.
Treatment of choroidal melanoma with radiation often involves placement of customized brachytherapy eye-plaques. However, the dosimetric properties inherent in source-based radiotherapy preclude facile dose optimization to critical ocular structures. Consequently, we have constructed a novel system for utilizing small beam low-energy radiation delivery, the Beamlet Low-kVp X-ray, or "BLOKX" system. This technique relies on an isocentric rotational approach to deliver dose to target volumes within the eye, while potentially sparing normal structures. Monte Carlo N-Particle (MCNP) transport code version 5.0(14) was used to simulate photon interaction with normal and tumor tissues within modeled right eye phantoms. Five modeled dome-shaped tumors with a diameter and apical height of 8 mm and 6 mm, respectively, were simulated distinct positions with respect to the macula iteratively. A single fixed 9 x 9 mm2 beamlet, and a comparison COMS protocol plaque containing eight I-125 seeds (apparent activity of 8 mCi) placed on the scleral surface of the eye adjacent to the tumor, were utilized to determine dosimetric parameters at tumor and adjacent tissues. After MCNP simulation, comparison of dose distribution at each of the 5 tumor positions for each modality (BLOKX vs. eye-plaque) was performed. Tumor-base doses ranged from 87.1-102.8 Gy for the BLOKX procedure, and from 335.3-338.6 Gy for the eye-plaque procedure. A reduction of dose of at least 69% to tumor base was noted when using the BLOKX. The BLOKX technique showed a significant reduction of dose, 89.8%, to the macula compared to the episcleral plaque. A minimum 71.0 % decrease in dose to the optic nerve occurred when the BLOKX was used. The BLOKX technique allows more favorable dose distribution in comparison to standard COMS brachytherapy, as simulated using a Monte Carlo iterative mathematical modeling. Future series to determine clinical utility of such an approach are warranted.


Early postoperative serum cystatin C predicts severe acute kidney injury following pediatric cardiac surgery.
In this multicenter, prospective study of 288 children (half under 2 years of age) undergoing cardiac surgery, we evaluated whether the measurement of pre- and postoperative serum cystatin C (CysC) improves the prediction of acute kidney injury (AKI) over that obtained by serum creatinine (SCr). Higher preoperative SCr-based estimated glomerular filtration rates predicted higher risk of the postoperative primary outcomes of stage 1 and 2 AKI (adjusted odds ratios (ORs) 1.5 and 1.9, respectively). Preoperative CysC was not associated with AKI. The highest quintile of postoperative (within 6 h) CysC predicted stage 1 and 2 AKI (adjusted ORs of 6 and 17.2, respectively). The highest tertile of percent change in CysC independently predicted AKI, whereas the highest tertile of SCr predicted stage 1 but not stage 2 AKI. Postoperative CysC levels independently predicted longer duration of ventilation and intensive care unit length of stay, whereas the postoperative SCr change only predicted longer intensive care unit stay. Thus, postoperative serum CysC is useful to risk-stratify patients for AKI treatment trials. More research, however, is needed to understand the relation between preoperative renal function and the risk of AKI.


A periodic charge-dipole electrostatic model: parametrization for silver slabs.
We present an extension of the charge-dipole model for the description of periodic systems. This periodic charge-dipole electrostatic model (PCDEM) allows one to describe the linear response of periodic structures in terms of charge- and dipole-type gaussian basis functions. The long-range electrostatic interaction is efficiently described by means of the continuous fast multipole method. As a first application, the PCDEM method is applied to describe the polarizability of silver slabs. We find that for a correct description of the polarizability of the slabs both charges and dipoles are required. However a continuum set of parametrizations, i.e., different values of the width of charge- and dipole-type gaussians, leads to an equivalent and accurate description of the slabs polarizability but a completely unphysical description of induced charge-density inside the slab. We introduced the integral squared density measure which allows one to obtain a unique parametrization which accurately describes both the polarizability and the induced density profile inside the slab. Finally the limits of the electrostatic approximations are also pointed out.


Long-term effects of a binary mixture of perfluorooctane sulfonate (PFOS) and bisphenol A (BPA) in zebrafish (Danio rerio).
Previous in vitro studies have reported the potential of perfluorooctane sulfonate (PFOS) to increase the toxicity of other compounds. Given the complex nature of mixtures of environmental pollutants in aquatic systems together with the persistent and bioaccumulative properties of PFOS, this study aimed at evaluating the long-term effects and toxicity-increasing behavior of PFOS in vivo using the zebrafish (Danio rerio). Fish were maintained in flow-through conditions and exposed to single and binary mixtures of PFOS and the endocrine disruptor bisphenol A (BPA) at nominal concentrations of 0.6, 100 and 300 μg/L and 10, 200 and 400 μg/L, respectively. F1 and F2 generations were evaluated from 0 to 180 days post-fertilization (dpf) and F3 generation was evaluated from 0 to 14 dpf. Survival was documented in all generations, whereas growth, fecundity, fertilization rate, histological alterations (in liver, thyroid and gonads) and vitellogenin (Vtg) induction in males were evaluated for F1 and F2 generations. Data for growth were collected at 30, 90 and 180 dpf and data for histological evaluations and Vtg induction were analyzed at 90 and 180 dpf. No significant effects on survival were seen in the F1 generation in any treatment following 180 d exposure; however, in the F2 generation, 300 μg/L PFOS both alone and in combination with BPA (10, 200 and 400 μg/L) induced 100% mortality within 14 dpf. PFOS (0.6 and 300 μg/L) did not increase the Vtg-inducing potential of BPA (10, 200 and 400 μg/L) in a binary mixture. In contrast, binary mixtures with 300 μg/L PFOS suppressed the Vtg levels in F1 males at 90 dpf when compared to single BPA exposures. Whereas the lowest tested PFOS concentration (0.6 μg/L) showed an estrogenic potential in terms of significant Vtg induction, Vtg levels were generally found to decrease with increasing PFOS-exposure in both F1 and F2 generations. In F1 generation, BPA-exposure was found to increase Vtg levels in a concentration-dependent manner. Histological analyses of F1 and F2 fish revealed hepatocellular vacuolization, predominantly in males, following PFOS-exposure both alone and in combination with BPA. Hepatotoxicity by PFOS might explain the suppressed Vtg response seen in PFOS-exposed F1 and F2 males. PFOS-exposed fish also showed granulomas, mainly in the liver. Given previous reports of the immunosuppressive potential of PFOS, the granulomas could be a consequence of a PFOS-induced reduction of the immune response potential. In conclusion, the hypothesis that the presence of PFOS increases the endocrine potential of BPA could not be confirmed in zebrafish. Adverse effects on liver structure and survival were only seen at concentrations well above ecologically relevant concentrations; however, the decline in survival rates following PFOS-exposure seen over generations again documents the importance of long-term studies for the investigation of persistent environmental pollutants.


Successful immunization of humans with irradiated malaria sporozoites: humoral and cellular responses of the protected individuals.
Two groups of volunteers were vaccinated by repeated exposure to the bites of Plasmodium falciparum-infected, x-irradiated mosquitoes in order to characterize the humoral and cellular immune responses of sporozoite-immunized, protected individuals. One of the two volunteers in the first immunization trial, when challenged by the bite of P. falciparum-infected mosquitoes, developed an infection only after a prolonged prepatent period. A second group of three volunteers who were exposed more frequently to larger numbers of infected mosquitoes irradiated with a lower x-ray dose was completely protected against sporozoite challenge. These individuals and the volunteer with delayed infection had high levels of antibodies to sporozoites and to the repeat region of the circumsporozoite (CS) protein. The CS-specific cellular immune responses of these volunteers were also stimulated by sporozoite immunization, as determined by proliferation of peripheral blood mononuclear cells (PBMC) and mitogen or antigen-expanded PBMC, in response to in vitro challenge with a recombinant P. falciparum CS protein. Based upon the assays used in this study, it is not possible to reach conclusions regarding specific immunologic responses and protection from sporozoite challenge.


Is children's choice in health care rhetoric or reality? A scoping review.
This paper is a report of a scoping review examining children and young people's health services with respect to choice in order to inform future development of choice initiatives. The importance of including children and young people in the choice agenda reflects the increasing acknowledgement that, individually and collectively, they are important consumers of health care in their own right. Data sources. A scoping review of all major health and medical research databases was undertaken using current guidelines to identify original relevant research papers and grey literature sources from 1990 to 2006. Reference Manager software was used to collate, summarize, categorize, store and retrieve the search results. Papers meeting the inclusion criteria were read in full and descriptively summarized using a data extraction sheet. Each paper was repeatedly selected using a snowballing approach until saturation was reached. Results. Children and young people want more say in the planning and development of appropriate hospital and community health services. However, little evaluative research was found about whether these choices are acted upon and lead to more responsive services. Choice for children and young people is viewed as a positive development in health care and many innovative examples of their involvement in decision-making were found. These illustrated that, given the opportunity, children and young people are willing and able to make decisions about their healthcare services. However, there is a long way to go before the rhetoric of the choice agenda is realized.


Prevalence and Associated Factors of Alcoholism among Tuberculosis Patients in Udupi Taluk, Karnataka, India: A Cross Sectional Study.
Tuberculosis (TB) is a major public health problem in India. Several studies carried out in India have shown alcoholism as a risk factor for tuberculosis mortality, factor for default in TB and reason for non-compliance under the Revised National Tuberculosis Control Program (RNTCP). The aim of this study was to assess the prevalence, pattern and associated factors of alcohol use among tuberculosis patients in Udupi taluk, Karnataka, India. A cross-sectional study was conducted with the complete enumeration of all the cases undergoing Directly Observed Treatment Short-course (DOTS) treatment in Primary Health Centre and Community Health Centre of Udupi taluk from March to April 2013. Interview was conducted to obtain the socio-demographic and health information and participants were screened using WHO developed Alcohol Use Disorders Identification Test (AUDIT) for alcohol use. Out of 123 participants, 78% were males, 86.2% were Hindu, 79.7% were married and 88.6% were from low socio-economic status. About 20.3% (n=25) participants were alcoholic. Among them, 44% were low risk drinkers, 32% were hazardous drinkers, 4% were harmful drinkers and 20% were alcohol dependent. Age, sex, occupation, tobacco use, perceived health status and discrimination due to tuberculosis positive status were significantly associated with alcohol use. On logistic regression sex, tobacco use, perceived health status and facing discrimination due infection with tuberculosis were found to be factors associated with alcohol use. This study found a high prevalence of alcoholism among tuberculosis patients which is of concern and has to be addressed.


Cause-specific infant mortality in a population-based Swedish study of term and post-term births: the contribution of gestational age and birth weight.
To investigate infant mortality and causes of infant death in relation to gestational age (GA) and birth weight for GA in non-malformed term and post-term infants. Observational, retrospective nationwide cohort study. Sweden 1983-2006. 2 152 738 singleton non-malformed infants born at 37 gestational weeks or later. Infant, neonatal and postneonatal mortality and causes of infant death. Infant mortality rate was 0.12% (n=2687). Compared with infants born at 40 weeks, risk of infant mortality was increased among early term infants (37 weeks, adjusted OR 1.70, 95% CI 1.43 to 2.02). Compared with infants with normal birth weight for GA, very small for gestational age (SGA; <3rd percentile) infants faced a doubled risk of infant mortality (adjusted OR 2.13, 95% CI 1.80 to 2.53), and corresponding risk was also increased among moderately SGA infants (3rd to <10th percentile; adjusted OR 1.46, 95% CI 1.26 to 1.68). Sudden infant death syndrome (SIDS) was the most common cause of death, accounting for 39% of all infant mortality. Compared with birth at 40 weeks, birth at 37 weeks was associated with increased risks of death by infections, cardiovascular disorders, SIDS and malignant neoplasms. Very and moderately SGA were associated with increased risks of death by neonatal respiratory disorders, infections, cardiovascular disorders, SIDS and neuromuscular disorders. High birth weight for GA was associated with increased risks of death by asphyxia and malignant neoplasms. Early term birth and very to moderately low birth weight for GA are independent risk factors for infant mortality among non-malformed term infants.


Regulation of factor IXa in vitro in human and mouse plasma and in vivo in the mouse. Role of the endothelium and the plasma proteinase inhibitors.
The regulation of human Factor IXa was studied in vitro in human and mouse plasma and in vivo in the mouse. In human plasma, approximately 60% of the 125I-Factor IXa was bound to antithrombin III (ATIII) by 2 h, with no binding to alpha 2-macroglobulin or alpha 1-proteinase inhibitor, as assessed by gel electrophoresis and IgG- antiproteinase inhibitor-Sepharose beads. In the presence of heparin, virtually 100% of the 125I-Factor IXa was bound to ATIII by 1 min. The distribution of 125I-Factor IXa in mouse plasma was similar. The clearance of 125I-Factor IXa was rapid (50% clearance in 2 min) and biphasic and was inhibited by large molar excesses of ATIII-thrombin and alpha 1-proteinase inhibitor-trypsin, but not alpha 2-macro-globulin-trypsin; it was also inhibited by large molar excesses of diisopropylphosphoryl - (DIP-) Factor Xa, DIP-thrombin, and Factor IX, but not by prothrombin or Factor X. The clearance of Factor IX was also rapid (50% clearance in 2.5 min) and was inhibited by a large molar excess of Factor IX, but not by large molar excesses of Factor X, prothrombin, DIP-Factor Xa, or DIP-thrombin. Electrophoresis and IgG- antiproteinase inhibitor-Sepharose bead studies confirmed that by 2 min after injection into the murine circulation, 60% of the 125I-Factor IXa was bound to ATIII. Organ distribution studies with 125I-Factor IXa demonstrated that most of the radioactivity was in the liver. These studies suggest that Factor IXa binds to at least two classes of binding sites on endothelial cells. One site apparently recognizes both Factors IX and IXa, but not Factor X, Factor Xa, prothrombin, or thrombin. The other site recognizes thrombin, Factor Xa, and Factor IXa, but not the zymogen forms of these clotting factors. After this binding, Factor IXa is bound to ATIII and the complex is cleared from the circulation by hepatocytes.


Pathogen analysis and genetic predisposition testing using microelectronic arrays and isothermal amplification.
A simple yet powerful tool for providing for rapid gene identification in the clinic would be the combination of isothermal gene amplification with electronic microchip analysis. This is a first report of such a union of these technologies. The first assay demonstrates discrimination between four bacterial pathogens. For this, one portion of the bacterial 16S rRNA gene encompassing a microheterogeneous region was isothermally amplified using Strand Displacement Amplification (SDA). Type identification was then made by "sandwich" assay format either using selective electronic hybridization of amplicons to sequence-specific capture oligonucleotides and a universal, fluorescently labeled reporter oligonucleotide, or, alternatively, sequence-specific reporters and a universal capture oligonucleotide. The second assay tested for the presence or absence of the Factor V Leiden point mutation using DNA obtained from 18 patients in a blind assay. For this, allele-specific SDA was developed. Following amplification using a sense-biotinylated primer and either the corresponding antisense wild type or mutant primer, multiple patient amplicons were targeted to specified locations on the microarray and visualized using a fluorescently labeled reporter oligonucleotide. Positive signals were scored as greater than or equal to two times the background. Bacterial type-specific signals were between 3- to 10-fold greater than nonspecific in both assay formats. Using allele-specific SDA, 100% agreement was observed between PAGE analysis, microarray results, and clinical diagnosis in Factor V mutation analysis. We demonstrated two model clinical assays combining amplified materials and microelectronic arrays, one potentially suitable for pathogen screening and the other for a deleterious genetic mutation.


Left ventricular apical diseases.
There are many disorders that may involve the left ventricular (LV) apex; however, they are sometimes difficult to differentiate. In this setting cardiac imaging methods can provide the clue to obtaining the diagnosis. The purpose of this review is to illustrate the spectrum of diseases that most frequently affect the apex of the LV including Tako-Tsubo cardiomyopathy, LV aneurysms and pseudoaneurysms, apical diverticula, apical ventricular remodelling, apical hypertrophic cardiomyopathy, LV non-compaction, arrhythmogenic right ventricular dysplasia with LV involvement and LV false tendons, with an emphasis on the diagnostic criteria and imaging features. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13244-011-0091-6) contains supplementary material, which is available to authorized users.