AB0 blood group and risk of venous or arterial thrombosis in carriers of factor V Leiden or prothrombin G20210A polymorphisms.
Routine analyses for thrombophilia include determination of the presence of factor V Leiden and prothrombin 20210A polymorphisms. However, the usefulness of these determinations is controversial and the clinical benefit remains questioned because of the moderate risk of associated thrombosis in carriers. In the search for clusters of thrombotic risk factors to estimate individual risk better, we studied the effect of AB0 blood group, a highly prevalent factor with mild prothrombotic features, on the risk and severity of venous and arterial thromboses in carriers of these polymorphisms. We genotyped the AB0 blood group in 981 carriers of factor V Leiden or prothrombin 20210A polymorphisms. In order to avoid the over-representation of a particular genotype and to suppress confounding factors, we included only non-related heterozygous carriers without additional genetic risk factors. We studied 609 patients with venous thromboembolism (287 with factor V Leiden, and 322 with prothrombin 20210A), 174 patients with myocardial infarction (78 with factor V Leiden, and 96 with prothrombin 20210A), and 198 controls (96 with factor V Leiden, and 102 with prothrombin 20210A). Non-OO blood group did not increase the risk of myocardial infarction in carriers of factor V Leiden or prothrombin 20210A. However, non-OO blood group contributed significantly to the expression of venous thrombosis associated with both factor V Leiden (OR: 1.76; 95%CI: 1.06-2.91) and prothrombin 20210A (OR: 2.17; 95%CI: 1.33-3.53). Exclusion of A(2)A(2) and A(2)O from the non-00 blood group (because factor VIII-von Willebrand factor levels are similar in these and the 00 blood group) increased the thrombotic risk. Finally, non-OO blood group was associated with an earlier onset in symptomatic carriers of these polymorphisms. Our study suggests that non-OO blood group increases the risk and severity of venous thrombosis in carriers of prothrombotic polymorphisms. Thus, AB0 phenotyping or genotyping analyses may be valuable components in assessing future thrombophilic risk profiles and might have implications for the policy of thrombosis prophylaxis and treatment.


A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain.
The Food and Drug Administration (FDA), Substance Abuse and Mental Health Services Administration (SAMHSA), and the National Institute for Drug Abuse (NIDA) report that no sound scientific studies support the medicinal use of cannabis. Despite this lack of scientific validation, many patients routinely use "medical marijuana," and in many cases this use is for pain related to nerve injury. We conducted a double-blinded, placebo-controlled, crossover study evaluating the analgesic efficacy of smoking cannabis for neuropathic pain. Thirty-eight patients with central and peripheral neuropathic pain underwent a standardized procedure for smoking either high-dose (7%), low-dose (3.5%), or placebo cannabis. In addition to the primary outcome of pain intensity, secondary outcome measures included evoked pain using heat-pain threshold, sensitivity to light touch, psychoactive side effects, and neuropsychological performance. A mixed linear model demonstrated an analgesic response to smoking cannabis. No effect on evoked pain was seen. Psychoactive effects were minimal and well-tolerated, with some acute cognitive effects, particularly with memory, at higher doses. This study adds to a growing body of evidence that cannabis may be effective at ameliorating neuropathic pain, and may be an alternative for patients who do not respond to, or cannot tolerate, other drugs. However, the use of marijuana as medicine may be limited by its method of administration (smoking) and modest acute cognitive effects, particularly at higher doses.


A scoping review of competencies for scientific editors of biomedical journals.
Biomedical journals are the main route for disseminating the results of health-related research. Despite this, their editors operate largely without formal training or certification. To our knowledge, no body of literature systematically identifying core competencies for scientific editors of biomedical journals exists. Therefore, we aimed to conduct a scoping review to determine what is known on the competency requirements for scientific editors of biomedical journals. We searched the MEDLINE®, Cochrane Library, Embase®, CINAHL, PsycINFO, and ERIC databases (from inception to November 2014) and conducted a grey literature search for research and non-research articles with competency-related statements (i.e. competencies, knowledge, skills, behaviors, and tasks) pertaining to the role of scientific editors of peer-reviewed health-related journals. We also conducted an environmental scan, searched the results of a previous environmental scan, and searched the websites of existing networks, major biomedical journal publishers, and organizations that offer resources for editors. A total of 225 full-text publications were included, 25 of which were research articles. We extracted a total of 1,566 statements possibly related to core competencies for scientific editors of biomedical journals from these publications. We then collated overlapping or duplicate statements which produced a list of 203 unique statements. Finally, we grouped these statements into seven emergent themes: (1) dealing with authors, (2) dealing with peer reviewers, (3) journal publishing, (4) journal promotion, (5) editing, (6) ethics and integrity, and (7) qualities and characteristics of editors. To our knowledge, this scoping review is the first attempt to systematically identify possible competencies of editors. Limitations are that (1) we may not have captured all aspects of a biomedical editor's work in our searches, (2) removing redundant and overlapping items may have led to the elimination of some nuances between items, (3) restricting to certain databases, and only French and English publications, may have excluded relevant publications, and (4) some statements may not necessarily be competencies. This scoping review is the first step of a program to develop a minimum set of core competencies for scientific editors of biomedical journals which will be followed by a training needs assessment, a Delphi exercise, and a consensus meeting.


Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control.
Understanding how transcriptional enhancers control over 20,000 protein-coding genes to maintain cell-type-specific gene expression programs in all human cells is a fundamental challenge in regulatory biology. Recent studies suggest that gene regulatory elements and their target genes generally occur within insulated neighborhoods, which are chromosomal loop structures formed by the interaction of two DNA sites bound by the CTCF protein and occupied by the cohesin complex. Here, we review evidence that insulated neighborhoods provide for specific enhancer-gene interactions, are essential for both normal gene activation and repression, form a chromosome scaffold that is largely preserved throughout development, and are perturbed by genetic and epigenetic factors in disease. Insulated neighborhoods are a powerful paradigm for gene control that provides new insights into development and disease.


Major obstetric haemorrhage of 2000 ml or greater: a clinical audit.
Haemorrhage remains a leading cause of maternal death. We conducted an audit to identify strategies to improve the management at our local NHS Trust. A data collection form was based on our local guideline. A coded database search was conducted for all deliveries where the estimated blood loss was ≥2000 ml (from June 1 2015 to December 31 2015), returning 68 search results (13.7/1000 births). Fifty-six records were included. Poor compliance (<75%) was seen in some key areas including the major obstetric haemorrhage (MOH) call activation (52%), the presence of an anaesthetic consultant (63%) and tranexamic acid administration (46%). Thirty out of 56 cases (54%) were acutely transfused. Women, who were not transfused acutely, appeared to be more likely to need a secondary transfusion if no MOH call had been activated (9/27 (33%) versus 3/29 (10%), p = .052). A key area for improvement was the activation of MOH calls. Following this audit, we adjusted our guideline to make it more clinically useful and staff training sessions were held, including simulation training. Impact statement What is already known on this subject? A postpartum haemorrhage (PPH) is an obstetric emergency. A structured approach is important to optimise the care of the mothers during this dangerous time, and has been shown to reduce the transfusion requirements. However, clinical practice may not adhere to the guideline recommendations. What the results of this study add? With the objective evidence of increased rates of PPH ≥2000 ml at our institution, our work identifying the flaws in management was a critical component of the work to improve the outcomes. This study gives impetus to find innovative ways to improve adherence to guidelines, and inspired an update of our local guideline to improve the applicability and utility. This project suggests a new marker for the adequacy of an acute management (a requirement for secondary blood transfusion without having received an acute transfusion), and raises questions about what constitutes optimum PPH management. What the implications are of these findings for clinical practice and/or further research? The primary and secondary transfusion data raised new questions to investigate in the future: does the involvement of consultants and the escalation of care via the instigation of major haemorrhage protocols improve decision-making and patient outcomes? Does the necessity for a secondary transfusion indicate a suboptimal acute care?


Cytokine effects on gap junction communication and connexin expression in human bladder smooth muscle cells and suburothelial myofibroblasts.
The last decade identified cytokines as one group of major local cell signaling molecules related to bladder dysfunction like interstitial cystitis (IC) and overactive bladder syndrome (OAB). Gap junctional intercellular communication (GJIC) is essential for the coordination of normal bladder function and has been found to be altered in bladder dysfunction. Connexin (Cx) 43 and Cx45 are the most important gap junction proteins in bladder smooth muscle cells (hBSMC) and suburothelial myofibroblasts (hsMF). Modulation of connexin expression by cytokines has been demonstrated in various tissues. Therefore, we investigate the effect of interleukin (IL) 4, IL6, IL10, tumor necrosis factor-alpha (TNFα) and transforming growth factor-beta1 (TGFβ1) on GJIC, and Cx43 and Cx45 expression in cultured human bladder smooth muscle cells (hBSMC) and human suburothelial myofibroblasts (hsMF). HBSMC and hsMF cultures were set up from bladder tissue of patients undergoing cystectomy. In cytokine stimulated cultured hBSMC and hsMF GJIC was analyzed via Fluorescence Recovery after Photo-bleaching (FRAP). Cx43 and Cx45 expression was assessed by quantitative PCR and confocal immunofluorescence. Membrane protein fraction of Cx43 and Cx45 was quantified by Dot Blot. Upregulation of cell-cell-communication was found after IL6 stimulation in both cell types. In hBSMC IL4 and TGFβ1 decreased both, GJIC and Cx43 protein expression, while TNFα did not alter communication in FRAP-experiments but increased Cx43 expression. GJ plaques size correlated with coupling efficacy measured, while Cx45 expression did not correlate with modulation of GJIC. Our finding of specific cytokine effects on GJIC support the notion that cytokines play a pivotal role for pathophysiology of OAB and IC. Interestingly, the effects were independent from the classical definition of pro- and antiinflammatory cytokines. We conclude, that connexin regulation involves genomic and/or post-translational events, and that GJIC in hBSMC and hsMF depend of Cx43 rather than on Cx45.


Modeling the prevalence of immunodeficiency-associated long-term vaccine-derived poliovirus excretors and the potential benefits of antiviral drugs.
A small number of individuals with B-cell-related primary immunodeficiency diseases (PIDs) may exhibit long-term (prolonged or chronic) excretion of immunodeficiency-associated vaccine-derived polioviruses (iVDPVs) following infection with oral poliovirus vaccine (OPV). These individuals pose a risk of live poliovirus reintroduction into the population after global wild poliovirus eradication and subsequent OPV cessation. Treatment with polio antiviral drugs may potentially stop excretion in some of these individuals and thus may reduce the future population risk. We developed a discrete event simulation model to characterize the global prevalence of long-term iVDPV excretors based on the best available evidence. We explored the impact of different assumptions about the effectiveness of polio antiviral drugs and the fraction of long-term excretors identified and treated. Due to the rarity of long-term iVDPV excretion and limited data on the survival of PID patients in developing countries, uncertainty remains about the current and future prevalence of long-term iVDPV excretors. While the model suggests only approximately 30 current excretors globally and a rapid decrease after OPV cessation, most of these excrete asymptomatically and remain undetected. The possibility that one or more PID patients may continue to excrete iVDPVs for several years after OPV cessation represents a risk for reintroduction of live polioviruses after OPV cessation, particularly for middle-income countries. With the effectiveness of a single polio antiviral drug possibly as low as 40% and no system in place to identify and treat asymptomatic excretors, the impact of passive use of a single polio antiviral drug to treat identified excretors appears limited. Higher drug effectiveness and active efforts to identify long-term excretors will dramatically increase the benefits of polio antiviral drugs. Efforts to develop a second polio antiviral compound to increase polio antiviral effectiveness and/or to maximize the identification and treatment of affected individuals represent important risk management opportunities for the polio endgame. Better data on the survival of PID patients in developing countries and more longitudinal data on their exposure to and recovery from OPV infections would improve our understanding of the risks associated with iVDPV excretors and the benefits of further investments in polio antiviral drugs.


Factors predicting outcome for advanced gastroesophageal cancer in elderly patients receiving palliative chemotherapy.
Most patients with advanced gastroesophageal cancer are elderly, but current standard regimens have emerged from trials predominantly involving patients with a median age <65 years. The aim of this study was to assess the factors influencing survival outcome for an elderly gastroesophageal cancer non-trial population. We reviewed the case notes of all patients in our centre over the age of 65 years who received palliative chemotherapy for gastroesophageal cancer over a period of 3.5 years. Patients were classified as having received standard, non-standard combination or single-agent chemotherapy. After an initial univariate analysis, a multivariate analysis of the most significant prognostic factors was carried out. In total, 120 patients were suitable for analysis. The median overall survival for patients receiving standard chemotherapy was 8.1 months, non-standard combination 8.3 months and single-agent fluoropyrimidines 3.9 months. Poor prognosis was predicted by two independent factors: poor performance status (hazard ratio 2.402; 95% confidence interval 1.53-3.77, P<0.001) and the presence of cancer symptoms (hazard ratio 2.235; 95% confidence interval 1.32-3.79, P=0.003). An assessment of the performance status and the level of symptoms is vital in this vulnerable group of patients. Prospective randomised trials to assess the benefit of chemotherapy in elderly patients with gastroesophageal cancer are required.


Alterations in Connectivity on Functional Magnetic Resonance Imaging with Provocation of Lower Urinary Tract Symptoms: A MAPP Research Network Feasibility Study of Urological Chronic Pelvic Pain Syndromes.
Urological chronic pelvic pain syndromes have refractory bladder or pelvic pain as the dominant symptom. This has been attributed to changes in the central nervous system caused by a chronic barrage of noxious stimuli. We developed what is to our knowledge a novel challenge protocol that induced bladder distention in study participants to reproduce pain and urinary symptoms. We tested to see whether it could discriminate between persons with urological chronic pelvic pain syndrome-like symptoms and asymptomatic controls. We recruited 10 female twin pairs who were discordant for urological chronic pelvic pain syndrome-like symptoms. Before scanning each twin urinated to completion and then consumed 500 cc water. Each twin was scanned with our resting state functional magnetic resonance imaging protocol immediately and approximately 50 minutes after consumption. Time series were extracted from the right and left periaqueductal gray, and the right and left amygdala subregions. We performed the repeated measures 2-sample t-test to assess differences in connectivity between symptomatic and asymptomatic twins before and after bladder distention. Group by condition interaction effects were found from the periaqueductal gray to the right cerebellum VIIIa, the amygdala, the right premotor cortex/supplementary motor area and the insular cortex, and between the amygdala and the frontal pole/medial orbital frontal cortex, the hypothalamus, the insular cortex, the thalamus and the anterior cingulate cortex. These findings demonstrate that our noninvasive bladder distention protocol can detect differences in the processing of urinary sensation between twins discordant for lower urinary tract pain.


The Fab-8 boundary defines the distal limit of the bithorax complex iab-7 domain and insulates iab-7 from initiation elements and a PRE in the adjacent iab-8 domain.
The Drosophila bithorax complex Abdominal-B (Abd-B) gene specifies parasegmental identity at the posterior end of the fly. The specific pattern of Abd-B expression in each parasegment (PS) determines its identity and, in PS10-13, Abd-B expression is controlled by four parasegment-specific cis-regulatory domains, iab-5 to iab-8, respectively. In order to properly determine parasegmental identity, these four cis-regulatory domains must function autonomously during both the initiation and maintenance phases of BX-C regulation. The studies reported here demonstrate that the (centromere) distal end of iab-7 domain is delimited by the Fab-8 boundary. Initiators that specify PS12 identity are located on the proximal iab-7 side of Fab-8, while initiators that specify PS13 identity are located on the distal side of Fab-8, in iab-8. We use transgene assays to demonstrate that Fab-8 has enhancer blocking activity and that it can insulate reporter constructs from the regulatory action of the iab-7 and iab-8 initiators. We also show that the Fab-8 boundary defines the realm of action of a nearby iab-8 Polycomb Response Element, preventing this element from ectopically silencing the adjacent domain. Finally, we demonstrate that the insulating activity of the Fab-8 boundary in BX-C is absolutely essential for the proper specification of parasegmental identity by the iab-7 and iab-8 cis-regulatory domains. Fab-8 together with the previously identified Fab-7 boundary delimit the first genetically defined higher order domain in a multicellular eukaryote.


Predicting discordance between self-reports of sexual behavior and incident sexually transmitted infections with African American female adolescents: results from a 4-city study.
This study examined correlates of the discordance between sexual behavior self-reports and Incident Sexually Transmitted Infections. African American adolescent females (N = 964) from four U.S. cities were recruited for an HIV/STI prevention trial. Self-reported sexual behaviors, demographics, and hypothesized psychosocial antecedents of sexual risk behavior were collected at baseline, 6-, 12-, and 18-month follow-up assessments. Urine specimens were collected and tested for three prevalent STIs (chlamydia, gonorrhea, trichomonas) at each assessment. Seventeen percent of participants with a laboratory-confirmed STI reported either lifetime abstinence or recent abstinence from vaginal sex (discordant self-report). Lower STI knowledge, belief that fewer peers were engaging in sex, and belief that more peers will wait until marriage to have sex were associated with discordant reports. Discordance between self-reported abstinence and incident STIs was marked among African American female adolescents. Lack of STI knowledge and sexual behavior peer norms may result in underreporting of sexual behaviors.


[Influential variables on intention and action to quit smoking between adolescent smokers and adult smokers-based on the transtheoretical model].
This study identified and compared influential variables on intention and action to quit smoking between adolescent smokers and adult smokers. For the selection of variables, the transtheoretical theory was used. A survey was conducted with 376 adolescent smokers in 4 high schools and 451 adult smokers in community settings in South Korea. Discriminant analysis was used for data analysis. The variables of adolescent smokers that predicted an intention to quit smoking were: smoking temptation, self re-evaluation, counter conditioning and stimulus control. The variables that predicted an action to quit smoking were: self-efficacy for smoking abstinence, pros for smoking, self reevaluation, and self liberation. The variables of adult smokers that predicted an intention to quit were: smoking temptation, pros for smoking, cons for smoking, self reevaluation. The variables that self liberation and predicted an action to quit smoking were: self efficacy for smoking abstinence, smoking temptation, and counter conditioning. Developing stage specific smoking intervention methods based on different ways of how individuals make a decision to quit smoking within their contexts needs to be done.


Primaquine radical cure in patients with Plasmodium falciparum malaria in areas co-endemic for P falciparum and Plasmodium vivax (PRIMA): a multicentre, open-label, superiority randomised controlled trial.
In areas co-endemic for Plasmodium vivax and Plasmodium falciparum there is an increased risk of P vivax parasitaemia following P falciparum malaria. Radical cure is currently only recommended for patients presenting with P vivax malaria. Expanding the indication for radical cure to patients presenting with P falciparum malaria could reduce their risk of subsequent P vivax parasitaemia. We did a multicentre, open-label, superiority randomised controlled trial in five health clinics in Bangladesh, Indonesia, and Ethiopia. In Bangladesh and Indonesia, patients were excluded if they were younger than 1 year, whereas in Ethiopia patients were excluded if they were younger than 18 years. Patients with uncomplicated P falciparum monoinfection who had fever or a history of fever in the 48 h preceding clinic visit were eligible for enrolment and were required to have a glucose-6-dehydrogenase (G6PD) activity of 70% or greater. Patients received blood schizontocidal treatment (artemether-lumefantrine in Ethiopia and Bangladesh and dihydroartemisinin-piperaquine in Indonesia) and were randomly assigned (1:1) to receive either high-dose short-course oral primaquine (intervention arm; total dose 7 mg/kg over 7 days) or standard care (standard care arm; single dose oral primaquine of 0·25 mg/kg). Random assignment was done by an independent statistician in blocks of eight by use of sealed envelopes. All randomly assigned and eligible patients were included in the primary and safety analyses. The per-protocol analysis excluded those who did not complete treatment or had substantial protocol violations. The primary endpoint was the incidence risk of P vivax parasitaemia on day 63. This trial is registered at ClinicalTrials.gov, NCT03916003. Between Aug 18, 2019, and March 14, 2022, a total of 500 patients were enrolled and randomly assigned, and 495 eligible patients were included in the intention-to-treat analysis (246 intervention and 249 control). The incidence risk of P vivax parasitaemia at day 63 was 11·0% (95% CI 7·5-15·9) in the standard care arm compared with 2·5% (1·0-5·9) in the intervention arm (hazard ratio 0·20, 95% CI 0·08-0·51; p=0·0009). The effect size differed with blood schizontocidal treatment and site. Routine symptom reporting on day 2 and day 7 were similar between groups. In the first 42 days, there were a total of four primaquine-related adverse events reported in the standard care arm and 26 in the intervention arm; 132 (92%) of all 143 adverse events were mild. There were two serious adverse events in the intervention arm, which were considered unrelated to the study drug. None of the patients developed severe anaemia (defined as haemoglobin <5 g/dL). In patients with a G6PD activity of 70% or greater, high-dose short-course primaquine was safe and relatively well tolerated and reduced the risk of subsequent P vivax parasitaemia within 63 days by five fold. Universal radical cure therefore potentially offers substantial clinical, public health, and operational benefits, but these benefits will vary with endemic setting. Australian Academy of Science Regional Collaborations Program, Bill & Melinda Gates Foundation, and National Health and Medical Research Council.


Biomechanical signals and the C-type natriuretic peptide counteract catabolic activities induced by IL-1β in chondrocyte/agarose constructs.
The present study examined the effect of C-type natriuretic peptide (CNP) on the anabolic and catabolic activities in chondrocyte/agarose constructs subjected to dynamic compression. Constructs were cultured under free-swelling conditions or subjected to dynamic compression with low (0.1 to 100 pM) or high concentrations (1 to 1,000 nM) of CNP, interleukin-1β (IL-1β), and/or KT-5823 (inhibits cyclic GMP-dependent protein kinase II (PKGII)). Anabolic and catabolic activities were assessed as follows: nitric oxide (NO) and prostaglandin E2 (PGE2) release, and [3H]-thymidine and 35SO4 incorporation were quantified by using biochemical assays. Gene expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aggrecan, and collagen type II were assessed with real-time quantitative PCR (qPCR). Two-way ANOVA and the post hoc Bonferroni-corrected t tests were used to examine data. CNP reduced NO and PGE2 release and partially restored [3H]-thymidine and 35SO4 incorporation in constructs cultured with IL-1β. The response was dependent on the concentration of CNP, such that 100 pM increased [3H]-thymidine incorporation (P < 0.001). This is in contrast to 35SO4 incorporation, which was enhanced with 100 or 1000 nM CNP in the presence and absence of IL-1β (P < 0.001). Stimulation by both dynamic compression and CNP and/or the PKGII inhibitor further reduced NO and PGE2 release and restored [3H]-thymidine and 35SO4 incorporation. In the presence and absence of IL-1β, the magnitude of stimulation for [3H]-thymidine and 35SO4 incorporation by dynamic compression was dependent on the concentration of CNP and the response was inhibited with the PKGII inhibitor. In addition, stimulation by CNP and/or dynamic compression reduced IL-1β-induced iNOS and COX-2 expression and restored aggrecan and collagen type II expression. The catabolic response was not further influenced with the PKGII inhibitor in IL-1β-treated constructs. Treatment with CNP and dynamic compression increased anabolic activities and blocked catabolic effects induced by IL-1β. The anabolic response was PKGII mediated and raises important questions about the molecular mechanisms of CNP with mechanical signals in cartilage. Therapeutic agents like CNP could be administered in conjunction with controlled exercise therapy to slow the OA disease progression and to repair damaged cartilage. The findings from this research provide the potential for developing novel agents to slow the pathophysiologic mechanisms and to treat OA in the young and old.


Mediterranean dietary pattern and cancer risk in the EPIC cohort.
Although several studies have investigated the association of the Mediterranean diet with overall mortality or risk of specific cancers, data on overall cancer risk are sparse. We examined the association between adherence to Mediterranean dietary pattern and overall cancer risk using data from the European Prospective Investigation Into Cancer and nutrition, a multi-centre prospective cohort study including 142,605 men and 335,873. Adherence to Mediterranean diet was examined using a score (range: 0-9) considering the combined intake of fruits and nuts, vegetables, legumes, cereals, lipids, fish, dairy products, meat products, and alcohol. Association with cancer incidence was assessed through Cox regression modelling, controlling for potential confounders. In all, 9669 incident cancers in men and 21,062 in women were identified. A lower overall cancer risk was found among individuals with greater adherence to Mediterranean diet (hazard ratio=0.96, 95% CI 0.95-0.98) for a two-point increment of the Mediterranean diet score. The apparent inverse association was stronger for smoking-related cancers than for cancers not known to be related to tobacco (P (heterogeneity)=0.008). In all, 4.7% of cancers among men and 2.4% in women would be avoided in this population if study subjects had a greater adherence to Mediterranean dietary pattern. Greater adherence to a Mediterranean dietary pattern could reduce overall cancer risk.


Converting acute inpatient take to outpatient take with fast-track assessment in internal medicine wards - a before-after study.
With an extensive rise in the number of acute patients and increases in both admissions and readmissions, hospitals are at times overcrowded and under immense pressure and this may challenge patient safety. This study evaluated an innovative strategy converting acute internal medicine inpatient take to an outpatient take. Here, acute patients, following referral, underwent fast-track assessment to the needed level of medical care as outpatients, directly in internal medicine wards. The two internal medicine wards at Diagnostic Centre, Silkeborg, Denmark, changed their take of acute patients 1st of March 2017. The intervention consisted of acute medical patients being received in medical examination chairs, going through accelerated evaluation as outpatients with assessment within one hour for either admission or another form of treatment. A before-and-after study design was used to evaluate changes in activity. All referred patients for 10 months following implementation of the intervention were compared with patients referred in corresponding months the previous year. A total of 5339 contacts (3632 patients) who underwent acute medical assessment (2633 contacts before and 2706 after) were included. Median hospital length-of-stay decreased from 32.6 h to 22.3 h, and the proportion of referred acute patients admitted decreased with 36.3% points from 94.5 to 58.2%. The median length-of-admission time for the admitted patients increased as expected after the intervention. The risk of being admitted, being readmitted as well as having a hospital length-of-time longer than 24 h, 72 h or 7 days, respectively, were significantly lower during the after-period in comparison to the before-period. Adverse effects, unplanned re-contacts, total contacts to general practice and mortality did not change after the intervention. Assessing referred acute patients in medical examination chairs as outpatients directly in internal medicine wards and promoting an accelerated trajectory, reduced inpatient admissions and total length-of-stay considerably. This strategy seems effective in everyday acute medical patients and has the potential to ease the increasing pressure on the acute take for wards receiving acute medical patients.


Chronic pancreatitis: early results of pancreatoduodenectomy and analysis of risk factors.
Although mortality after pancreatoduodenectomy for chronic pancreatitis has declined, the complication rate remains high. Today, there is an increasing need to base clinical decisions on the available scientific evidence to provide the best available treatment for the patients. Therefore, we retrospectively analyzed comprehensive preoperative and postoperative characteristics of patients undergoing pancreatic head resection for chronic pancreatitis and performed an outcome analysis to provide prospective selection or managing criteria that could improve the early surgical results. Data from 168 patients who underwent pancreatic head resection for chronic pancreatitis between October 1993 and November 2008 in our center were retrospectively analyzed. Risk factors for surgical complications were evaluated by multivariate analysis. Perioperative mortality was 0.6%, and surgical morbidity was 14.3%. Multivariate analysis identified hypertension as significant independent risk factor for surgical complications with an odds ratio (OR) of 3.24. We also found protective factors, namely, preoperative exocrine insufficiency (OR, 0.33) and preoperative diabetes (OR, 0.18). Both protective factors might indicate an advanced chronic pancreatitis. As patients undergoing pancreatic head resection are highly selected, the identified risk factors should only individually be considered in the decision to operate.


The cAMP response element binding protein (CREB) as an integrative HUB selector in metazoans: clues from the hydra model system.
In eukaryotic cells, a multiplicity of extra-cellular signals can activate a unique signal transduction system that at the nuclear level will turn on a variety of target genes, eliciting thus diverse responses adapted to the initial signal. How distinct signals can converge on a unique signalling pathway that will nevertheless produce signal-specific responses provides a theoretical paradox that can be traced back early in evolution. In bilaterians, the CREB pathway connects diverse extra-cellular signals via cytoplasmic kinases to the CREB transcription factor and the CBP co-activator, regulating according to the context, cell survival, cell proliferation, cell differentiation, pro-apoptosis, long-term memory, hence achieving a "hub" function for cellular and developmental processes. In hydra, the CREB pathway is highly conserved and activated during early head regeneration through RSK-dependent CREB phosphorylation. We show here that the CREB transcription factor and the RSK kinase are co-expressed in all three hydra cell lineages including dividing interstitial stem cells, proliferating nematoblasts, proliferating spermatogonia and spermatocytes, differentiating and mature neurons as well as ectodermal and endodermal myoepithelial cells. In addition, CREB gene expression is specifically up-regulated during early regeneration and early budding. When the CREB function was chemically prevented, the early post-amputation induction of the HyBraI gene was no longer observed and head regeneration was stacked. Thus, in hydra, the CREB pathway appears already involved in multiple tasks, such as reactivation of developmental programs in an adult context, self-renewal of stem cells, proliferation of progenitors and neurogenesis. Consequently, the hub function played by the CREB pathway was established early in animal evolution and might have contributed to the formation of an efficient oral pole through the integration of the neurogenic and patterning functions.


From macro- to microplastics - Analysis of EU regulation along the life cycle of plastic bags.
Plastic pollution and its environmental effects has received global attention the recent years. However, limited attention has so far been directed towards how plastics are regulated in a life cycle perspective and how regulatory gaps can be addressed in order to limit and prevent environmental exposure and hazards of macro- and microplastics. In this paper, we map European regulation taking outset in the life cycle perspective of plastic carrier bags: from plastic bag production to when it enters the environment. Relevant regulatory frameworks, directives and authorities along the life cycle are identified and their role in regulation of plastics is discussed. Most important regulations were identified as: the EU chemical Regulation, the Packaging and Packaging Waste Directive including the amending Directive regarding regulation of the consumption of lightweight plastic carrier bags, the Waste Framework Directive and the Directive on the Landfill of Waste. The main gaps identified relate to lack of clear definitions of categories of polymers, unambitious recycling rates and lack of consideration of macro- and microplastics in key pieces of legislation. We recommend that polymers are categorized according to whether they are polymers with the same monomer constituents (homopolymers) or with different monomer constituents (copolymers) and that polymers are no longer exempt from registration and evaluation under REACH. Plastics should furthermore have the same high level of monitoring and reporting requirements as hazardous waste involving stricter requirements to labelling, recordkeeping, monitoring and control over the whole lifecycle. Finally, we recommend that more ambitious recycle and recovery targets are set across the EU. Regulation of the consumption of lightweight plastic carrier bags should also apply to heavyweight plastic carrier bags. Last, the Marine and Water Framework Directives should specifically address plastic waste affecting water quality.


Activity and plasticity in the CA1, the dentate gyrus, and the amygdala following controllable vs. uncontrollable water stress.
The level of controllability has been shown to modulate the effects of stress on physiology and behavior. In the present study, we investigated the effects of controllable vs. uncontrollable stressors on plasticity in hippocampal CA1, the dentate gyrus (DG), and basal amygdala nucleus (B) in the rat, using the electrophysiological procedure of long-term potentiation (LTP). A naive group was left undisturbed until the electrophysiological recording commenced. Rats of the two controllable stress groups were trained in the Morris water maze to locate an invisible underwater platform (the first group), or visible platform (the second group), thus escaping from the water, before the recording. The uncontrollable stress group underwent the same procedure (exposure time to water was adjusted to the averaged exposure time of the first controllable group) without the escape platform. We first assessed the effects of stress and controllability on LTP in CA1. Both controllable stressors and the uncontrollable stress impaired CA1 LTP, with a more robust effect induced by the uncontrollable stress. We further assessed the effects of the same procedures on LTP in DG and B. The uncontrollable stress enhanced LTP in DG and increased baseline responses (suggesting uncontrollable stress-induced plasticity) in the amygdala. All the stressors decreased amygdalar LTP. An assessment of plasma levels of corticosterone (CORT), following the behavioral procedures, revealed an enhancement in CORT release following the uncontrollable, but not controllable stress, indicating the uncontrollable condition as the most stressful. These findings provide insight into the differential effects of stress and stress controllability on different hippocampal subregions and the amygdala.


Middermal wound healing. A comparison between dermatomal excision and pulsed carbon dioxide laser ablation.
Continuous-wave carbon dioxide lasers are not widely used for the surgical removal of most skin lesions because it is difficult to control laser ablation and the extensive laser-induced thermal damage slows healing. Pulsed lasers provide means to reduce thermal damage produced during laser ablation and permit precise control of tissue removed during ablation. Using a swine model, we compared on a gross and microscopic level the healing of middermal wounds of similar depth and area created by a dermatome and a focused pulsed CO2 laser. Pulsed CO2 laser ablation removed skin precisely and bloodlessly with 85 +/- 15 microns (mean +/- SD) of residual thermal damage covering the surface of the wound. Compared with the dermatome, tissue reepithelialization was delayed in the laser wounds at day 3. By day 7, epithelial coverage of the laser-created wounds was not significantly different from the dermatome-created wounds. No significant difference in the appearance of the two wounds was noted at 42 days. We conclude that the focused pulsed CO2 laser is capable of precisely and bloodlessly ablating skin with conservation of residual subjacent adnexal elements, minimal early interference with epibolic epithelial outgrowth, and no pathologic effects on the wound healing process. Pulsed CO2 lasers may be a valuable instrument for the conservative ablation of skin and skin lesions.


Replication Fork Slowing and Reversal upon DNA Damage Require PCNA Polyubiquitination and ZRANB3 DNA Translocase Activity.
DNA damage tolerance during eukaryotic replication is orchestrated by PCNA ubiquitination. While monoubiquitination activates mutagenic translesion synthesis, polyubiquitination activates an error-free pathway, elusive in mammals, enabling damage bypass by template switching. Fork reversal is driven in vitro by multiple enzymes, including the DNA translocase ZRANB3, shown to bind polyubiquitinated PCNA. However, whether this interaction promotes fork remodeling and template switching in vivo was unknown. Here we show that damage-induced fork reversal in mammalian cells requires PCNA ubiquitination, UBC13, and K63-linked polyubiquitin chains, previously involved in error-free damage tolerance. Fork reversal in vivo also requires ZRANB3 translocase activity and its interaction with polyubiquitinated PCNA, pinpointing ZRANB3 as a key effector of error-free DNA damage tolerance. Mutations affecting fork reversal also induced unrestrained fork progression and chromosomal breakage, suggesting fork remodeling as a global fork slowing and protection mechanism. Targeting these fork protection systems represents a promising strategy to potentiate cancer chemotherapy.


What the Baldwin Effect affects depends on the nature of plasticity.
In a process known as the Baldwin Effect, developmental plasticity, such as learning, has been argued to accelerate the biological evolution of high-fitness traits, including language and complex intelligence. Here we investigate the evolutionary consequences of developmental plasticity by asking which aspects of a plastic trait are the focus of genetic change. The aspects we consider are: (i) dependencies between elements of a trait, (ii) the importance of each element to fitness, and (iii) the difficulty of acquiring each element through plasticity. We also explore (iv) how cultural inheritance changes the relationship between plasticity and genetic change. We find that evolution by natural selection preferentially fixes elements that are depended upon by others, important to fitness, or difficult to acquire through plasticity, but that cultural inheritance can suppress and even reverse genetic change. We replicate some of these effects in experimental evolutionary simulations with human learners. We conclude that what the Baldwin Effect affects depends upon the mechanism of plasticity, which for behavior and cognition includes the psychology of learning.


Human papillomavirus genome integration in multifocal vulvar Bowen's disease and squamous cell carcinoma.
Human papillomavirus (HPV) is an important aetiological agent in cervical carcinomas and in malignant skin tumours. Integration of the HPV DNA into host genome is one of the most important risk factors for malignant transformation. We report a patient with multiple black plaques and an erythematous nodule on her vulva. On histological examination, multifocal vulvar Bowen's disease (BD) and invasive squamous cell carcinoma (SCC) were found. An amplification of papillomavirus oncogene transcripts (APOT) assay showed that two locations of BD had only episome-derived HPV16 transcripts, but the other two sites of BD and the nodule of invasive SCC had HPV16 transcripts derived from integration. Sequencing analysis revealed that the invasive SCC had its integration site at 8q24, the Myc locus. Our results suggest that the APOT assay in multiple sites of the same patient may be a valuable tool for evaluation of the clinical degree of malignancy for vulvar BD.


Protein binding site prediction using an empirical scoring function.
Most biological processes are mediated by interactions between proteins and their interacting partners including proteins, nucleic acids and small molecules. This work establishes a method called PINUP for binding site prediction of monomeric proteins. With only two weight parameters to optimize, PINUP produces not only 42.2% coverage of actual interfaces (percentage of correctly predicted interface residues in actual interface residues) but also 44.5% accuracy in predicted interfaces (percentage of correctly predicted interface residues in the predicted interface residues) in a cross validation using a 57-protein dataset. By comparison, the expected accuracy via random prediction (percentage of actual interface residues in surface residues) is only 15%. The binding sites of the 57-protein set are found to be easier to predict than that of an independent test set of 68 proteins. The average coverage and accuracy for this independent test set are 30.5 and 29.4%, respectively. The significant gain of PINUP over expected random prediction is attributed to (i) effective residue-energy score and accessible-surface-area-dependent interface-propensity, (ii) isolation of functional constraints contained in the conservation score from the structural constraints through the combination of residue-energy score (for structural constraints) and conservation score and (iii) a consensus region built on top-ranked initial patches.


Beyond Host Defense: Deregulation of Drosophila Immunity and Age-Dependent Neurodegeneration.
Age-dependent neurodegenerative disorders are a set of diseases that affect millions of individuals worldwide. Apart from a small subset that are the result of well-defined inherited autosomal dominant gene mutations (e.g., those encoding the β-amyloid precursor protein and presenilins), our understanding of the genetic network that underscores their pathology, remains scarce. Genome-wide association studies (GWAS) especially in Alzheimer's disease patients and research in Parkinson's disease have implicated inflammation and the innate immune response as risk factors. However, even if GWAS etiology points toward innate immunity, untangling cause, and consequence is a challenging task. Specifically, it is not clear whether predisposition to de-regulated immunity causes an inadequate response to protein aggregation (such as amyloid or α-synuclein) or is the direct cause of this aggregation. Given the evolutionary conservation of the innate immune response in Drosophila and humans, unraveling whether hyperactive immune response in glia have a protective or pathological role in the brain could be a potential strategy in combating age-related neurological diseases.


Beating the odds: Sustained Chagas disease vector control in remote indigenous communities of the Argentine Chaco over a seven-year period.
Rapid reinfestation of insecticide-treated dwellings hamper the sustained elimination of Triatoma infestans, the main vector of Chagas disease in the Gran Chaco region. We conducted a seven-year longitudinal study including community-wide spraying with pyrethroid insecticides combined with periodic vector surveillance to investigate the house reinfestation process in connection with baseline pyrethroid resistance, housing quality and household mobility in a rural section of Pampa del Indio mainly inhabited by deprived indigenous people (Qom). Despite evidence of moderate pyrethroid resistance in local T. infestans populations, house infestation dropped from 31.9% at baseline to 0.7% at 10 months post-spraying (MPS), with no triatomine found at 59 and 78 MPS. Household-based surveillance corroborated the rare occurrence of T. infestans and the house invasion of other four triatomine species. The annual rates of loss of initially occupied houses and of household mobility were high (4.6-8.0%). Housing improvements did not translate into a significant reduction of mud-walled houses and refuges for triatomines because most households kept the former dwelling or built new ones with mud walls. Our results refute the assumption that vector control actions performed in marginalized communities of the Gran Chaco are doomed to fail. The larger-than-expected impacts of the intervention program were likely associated with the combined effects of high-coverage, professional insecticide spraying followed by systematic vector surveillance-and-response, broad geographic coverage creating a buffer zone, frequent housing replacement and residential mobility. The dynamical interactions among housing quality, mobility and insecticide-based control largely affect the chances of vector elimination.


Full circumpolar migration ensures evolutionary unity in the Emperor penguin.
Defining reliable demographic models is essential to understand the threats of ongoing environmental change. Yet, in the most remote and threatened areas, models are often based on the survey of a single population, assuming stationarity and independence in population responses. This is the case for the Emperor penguin Aptenodytes forsteri, a flagship Antarctic species that may be at high risk continent-wide before 2100. Here, using genome-wide data from the whole Antarctic continent, we reveal that this top-predator is organized as one single global population with a shared demography since the late Quaternary. We refute the view of the local population as a relevant demographic unit, and highlight that (i) robust extinction risk estimations are only possible by including dispersal rates and (ii) colony-scaled population size is rather indicative of local stochastic events, whereas the species' response to global environmental change is likely to follow a shared evolutionary trajectory.


Electrification of Biotechnology: Quo Vadis?
Electrobiotechnology has come a long way and has gained much interest among researchers all over the world. In the previous chapters of this book, an abundance of successful developments of lab-scale electrobiosynthesis and their underlying fundamentals are described. Thereby the individual needs and lines of research are highlighted. In this final chapter we will try to shed light on the overall performance of electrobiosynthetic processes with regard to their technological maturity, as well as the potential ecological and economic incentives for their industrial implementation.The evaluation of technical maturity, in particular, clearly demonstrates that electrobiosynthesis is still in its infancy. Bridging the "valley of death" between promising lab-scale results and first industrial applications as a market opener can only be achieved by the joint efforts of researchers from different disciplines in academia and industry, as well as by public funding and venture capital.Unfortunately, among other factors, the low degree of technical maturity hampers ecological evaluation, which so far has been limited to a small number of complete life cycle assessments. Therefore, we suggest using simplified evaluation tools (e.g., the environmental E-factor) to at least acquire clues about different parameters that influence the ecological impact. Ultimately, money makes the world go round and, hence, economic aspects will determine whether or not electrobiotechnological processes are implemented in industry. The existing examples show that different production routes based on electrobiosynthesis can become economically feasible.


Considerations of Environmentally Relevant Test Conditions for Improved Evaluation of Ecological Hazards of Engineered Nanomaterials.
Engineered nanomaterials (ENMs) are increasingly entering the environment with uncertain consequences including potential ecological effects. Various research communities view differently whether ecotoxicological testing of ENMs should be conducted using environmentally relevant concentrations-where observing outcomes is difficult-versus higher ENM doses, where responses are observable. What exposure conditions are typically used in assessing ENM hazards to populations? What conditions are used to test ecosystem-scale hazards? What is known regarding actual ENMs in the environment, via measurements or modeling simulations? How should exposure conditions, ENM transformation, dose, and body burden be used in interpreting biological and computational findings for assessing risks? These questions were addressed in the context of this critical review. As a result, three main recommendations emerged. First, researchers should improve ecotoxicology of ENMs by choosing test end points, duration, and study conditions-including ENM test concentrations-that align with realistic exposure scenarios. Second, testing should proceed via tiers with iterative feedback that informs experiments at other levels of biological organization. Finally, environmental realism in ENM hazard assessments should involve greater coordination among ENM quantitative analysts, exposure modelers, and ecotoxicologists, across government, industry, and academia.


Human factors studies for injectable combination products: from planning to reporting.
Interest in human factors usability testing has seen a sharp increase from manufacturers bringing new injectable pharmaceutical combination products to market and from regulators reviewing and approving submissions. This paper highlights the special regulatory considerations in the planning, execution, and reporting of human factor usability studies for injectable combination products. The paper describes recent human factors examples that capture and convey important sponsor learning for drug/device combination products. Special emphasis is placed on the recent focus across U.S. Food and Drug Administration centers, offices, and divisions in issuing new draft guidance outlining expectations in the execution and reporting of usability testing. Insight is provided into how the new guidance has been put into practice in the development and review of injectable combination products, and some of the unwritten recommendations/expectations that have been gleaned from these regulatory interactions are identified. The paper also describes future areas of opportunity for regulatory guidance based on reflections from over two dozen recent combination product human factor studies covering from early design development and testing through to the reporting of human factors results in the final submission. Human factors is the study of the interaction of people and technology to ensure the safety and effectiveness of that interaction and to improve human/device compatibility, including the user interface, instructions, and training programs to avoid use error. The enhanced focus on human factors usability assessments for injectable combination products is an acknowledgement by regulators and industry that the device mechanics are typically quite reliable and that device risk hazards are likely due to device usability. Use errors can occur when the device is not being used as intended or the design features are less than optimal. Human factors testing, analysis, and validation helps to identify and eliminate use errors by informing appropriate mitigation strategies to ensure the device design provides the optimum use of injectable drug/device combination products.


Physical fitness in older people with ID-Concept and measuring instruments: a review.
A certain level of physical fitness is a prerequisite for independent functioning and self-care, but the level of physical fitness declines with ageing. This applies to older adult with intellectual disabilities too, but very little is known about their actual level of physical fitness. This lack of knowledge is partly caused by a lack of suitable instruments to measure physical fitness in this group, but the search for and choice of instruments depends on the operationalisation of the concept physical fitness for specific this target population. In this article the advantages of two known definitions of physical fitness are combined, leading to a combination of seven components to describe physical fitness in older adults with intellectual disabilities: coordination, reaction time, balance, muscular strength, muscular endurance, flexibility and cardio-respiratory endurance. A literature search for all instruments to measure any of these components resulted in a large number of available instruments. These instruments were evaluated according criteria of functionality, reliability and feasibility in this target population. The aim of this article was to propose a selection of instruments which complied with these criteria and creates possibilities for widespread use and sharing and/or pooling of data. The proposed selection of tests to measure physical fitness in older adults with intellectual disabilities is: Box and Block test, Reaction time test with an auditive and visual signal, Berg balance scale, Walking speed comfortable and fast, Grip strength with a hand dynamometer, 30s chair stand, modified back saver sit and reach and the 10 m incremental shuttle walking test.


Whole-blood interferon-gamma release assay for diagnosis of tuberculous lymphadenitis.
Tuberculosis remains a major problem for much of the world. Tuberculous lymphadenitis is the most common type of extrapulmonary tuberculosis, although a difficult invasive procedure is required for its diagnosis. We evaluated the usefulness of the whole-blood interferon-gamma release assay (IGRA) for diagnosis of tuberculous lymphadenitis. From January 2008 to October 2010, 108 patients underwent lymph node biopsy and the IGRA concurrently in Wonju Christian Hospital, Yonsei University Wonju College of Medicine. Among the patients, 27 were diagnosed with tuberculous lymphadenitis and 81 were diagnosed with non-tuberculous lymphadenitis. The diagnostic performances of the IGRA were evaluated. The median patient age was 33 years (interquartile range [IQR] 23.5 to 48 years), and 28 (25.9%) patients were male. No patient was administered immunosuppressive agents such as high-dose steroids or underwent chemotherapy within 90 days before the IGRA test. The IGRA was positive in 25 of 27 patients with tuberculous lymphadenitis and in 13 of 81 patients with non-tuberculous lymphadenopathy. Therefore, the sensitivity of IGRA was 92.6% (95% CI, 82.0 to 100), and the specificity was 80.2% (95% CI, 71.4 to 89.1). In the patients with positive IGRA results, the INF-γ concentration was significantly higher in the patients with tuberculous lymphadenitis compared to that in the patients without tuberculous lymphadenitis (15.58 [IQR 6.87 to 45.10] IU/mL versus 0.97 [IQR 0.65 to 2.41] IU/mL, p < 0.001). In conclusion, the IGRA is helpful for the diagnosis of tuberculous lymphadenitis.


Mixed-phase oxide catalyst based on Mn-mullite (Sm, Gd)Mn2O5 for NO oxidation in diesel exhaust.
Oxidation of nitric oxide (NO) for subsequent efficient reduction in selective catalytic reduction or lean NO(x) trap devices continues to be a challenge in diesel engines because of the low efficiency and high cost of the currently used platinum (Pt)-based catalysts. We show that mixed-phase oxide materials based on Mn-mullite (Sm, Gd)Mn(2)O(5) are an efficient substitute for the current commercial Pt-based catalysts. Under laboratory-simulated diesel exhaust conditions, this mixed-phase oxide material was superior to Pt in terms of cost, thermal durability, and catalytic activity for NO oxidation. This oxide material is active at temperatures as low as 120°C with conversion maxima of ~45% higher than that achieved with Pt. Density functional theory and diffuse reflectance infrared Fourier transform spectroscopy provide insights into the NO-to-NO(2) reaction mechanism on catalytically active Mn-Mn sites via the intermediate nitrate species.


When Neuroscience Meets Pharmacology: A Neuropharmacology Literature Analysis.
Background: Considering the enormous progress in the field of neuropharmacology and its global importance, as well as the lack of bibliometric studies examining this field as a whole, it is a high time to assess the prevailing topics and citation performances of its research works. Methods: Web of Science (WoS) was searched to identify relevant neuropharmacology articles, which were analyzed with reference to (1) publication year, (2) journal title, (3) total citation count, (4) authorship, (5) WoS category, and (6) manuscript type. The identified manuscripts were analyzed with VOSviewer for further bibliometric parameters, such as citation analysis of institutions, countries/regions, and journals, and to visualize the citation patterns of the terms appearing in the titles and abstracts. Results: The literature search resulted in 43,354 manuscripts. Nearly 98% of them were published since the 1990s. The majority of the manuscripts were original articles (n = 31,360) and reviews (n = 11,266). The top five WoS categories associated with the analyzed manuscripts were Pharmacology/Pharmacy (n = 14,892, 34.3%), Neurosciences (n = 11,747, 27.1%), Clinical Neurology (n = 4,981, 11.5%), Psychiatry (n = 4,464, 10.3%), and Biochemistry/Molecular Biology (n = 4,337, 10.0%). Seven of the top ten most prolific institutions were located in the USA, and one each in Canada, Italy, and the UK, respectively. Manuscripts mentioning certain molecules or pharmaceuticals had high citations per manuscript, such as those reporting about anandamide, tetrahydrocannabinol (THC), L-glutamate, clozapine, and curcumin. These terms with at least 50 citations per manuscript were mostly related to cannabis and anti-psychotic drugs, with some dealing with anti-epilepsy effects and Alzheimer's disease. Conclusion: We have identified and analyzed all neuropharmacology articles published since the 1990s. Importantly, the area of neuropharmacology research has been growing steadily due to the global trend in population aging and associated with this continuously increasing number of patients with neuropsychiatric disorders worldwide. It is hoped that identification of new pharmaceutically useful molecules or new clinical applications will continue in the future, in order to improve clinical outcomes and to further strengthen the field of neuropharmacology, a research area cross-linking basic and clinical sciences.


Primary Outcome Measures in Pediatric Septic Shock Trials: A Systematic Review.
To evaluate all published pediatric randomized controlled trials of patients with septic shock from any cause to examine the outcome measures used, the strengths and limitations of these measurements and whether the trial outcomes met feasibility criteria. We used a previously published database of pediatric critical care randomized controlled trials (PICUtrials.net) derived from searches of MEDLINE, EMBASE, LILACS, and CENTRAL. We included randomized controlled trials of interventions to children admitted to a PICU with septic or dengue hemorrhagic shock which were published in English. Study characteristics and outcomes were retrieved by two independent reviewers with disagreement being resolved by a third reviewer. We defined feasibility as 1) recruitment of at least 90% of the targeted sample size and agreement of the observed outcome rate in the control group with the rate used for the sample size calculation to within 10% or 2) finding of a statistically significant difference in an interim or final analysis. Nineteen of 321 identified articles were selected for review. Fourteen of 19 studies (74%) provided an a priori definition of their primary outcome measure in their "Methods section." Mortality rate was the most commonly reported primary outcome (8/14; 57%), followed by duration of shock (4/14; 29%) followed by organ failure (1/14; 7%). Only three of 19 included trials met feasibility criteria. Our review found that use of mortality alone as a primary outcome in pediatric septic shock trials was associated with significant limitations and that long-term patient-centered outcomes were not used in this setting. Composite outcomes incorporating mortality and long-term outcomes should be explored for use in future pediatric septic shock trials.


Zinc-dependent multi-conductance channel activity in mitochondria isolated from ischemic brain.
Transient global ischemia is a neuronal insult that induces delayed cell death. A hallmark event in the early post-ischemic period is enhanced permeability of mitochondrial membranes. The precise mechanisms by which mitochondrial function is disrupted are, as yet, unclear. Here we show that global ischemia promotes alterations in mitochondrial membrane contact points, a rise in intramitochondrial Zn2+, and activation of large, multi-conductance channels in mitochondrial outer membranes by 1 h after insult. Mitochondrial channel activity was associated with enhanced protease activity and proteolytic cleavage of BCL-xL to generate its pro-death counterpart, deltaN-BCL-xL. The findings implicate deltaN-BCL-xL in large, multi-conductance channel activity. Consistent with this, large channel activity was mimicked by introduction of recombinant deltaN-BCL-xL to control mitochondria and blocked by introduction of a functional BCL-xL antibody to post-ischemic mitochondria via the patch pipette. Channel activity was also inhibited by nicotinamide adenine dinucleotide, indicative of a role for the voltage-dependent anion channel (VDAC) of the outer mitochondrial membrane. In vivo administration of the membrane-impermeant Zn2+ chelator CaEDTA before ischemia or in vitro application of the membrane-permeant Zn2+ chelator tetrakis-(2-pyridylmethyl) ethylenediamine attenuated channel activity, suggesting a requirement for Zn2+. These findings reveal a novel mechanism by which ischemic insults disrupt the functional integrity of the outer mitochondrial membrane and implicate deltaN-BCL-xL and VDAC in the large, Zn2+-dependent mitochondrial channels observed in post-ischemic hippocampal mitochondria.


Visual disruption using the thermal lensing effect in the human eye: pilot study.
At select wavelengths, near infrared (IR) light is absorbed in the preretinal media of the eye. This produces small transient increases in temperature that temporarily alter the local index of refraction. If the IR exposure is sufficiently high, a momentary reduction in the focusing power of the eye can be induced through an effect known as thermal lensing. Fundamental optical interaction and safety aspects of this phenomenon have been demonstrated previously in animal and artificial eye models. However, whether the effect will induce an observable visual change in human subjects has not been explored. Here, results of a pilot study are shown where eight human subjects were exposed to an IR laser at levels that were below the safe exposure limit. The exposures did induce a transient visual distortion if sufficiently high levels were used. While the description of the visual change varied between subjects, this experiment was able to determine a general guideline for power needed to induce significant effects in human subjects.


Minimal incisions vertical endoscopic lifting and fat grafting as a systematic approach to the rejuvenation of the periocular esthetic unit.
The forehead/brow complex, the temporal region, the upper eyelid, the zygomatic area, the lower eyelid, and the cheek comprise the periocular esthetic unit. The combination of variable degrees of tissue descent and fat deflation of the component parts of the unit determine its appearance with age. The authors report the results of tissue repositioning through a minimal incisions vertical endoscopic lift and volume restoration used in combination to restore the natural youthful appearance of the periocular esthetic unit. The authors retrospectively reviewed the charts of patients who underwent minimal incisions vertical endoscopic lift and fat grafting over a 12-year period in 3 different centers. Patients results were evaluated with standardized pre- and postoperative pictures graded by masked observers in a scale from poor, fair, satisfactory, to very satisfactory results. Patient satisfaction was self-graded in the same manner. The study consists of 400 patients, of whom 337 (85%) were women and 63 (14.8%) were men, with a mean age of 46 years (range 38-67) for women and mean age of 53 years (range 48-65) for men. Mean follow up was 16 months (range 6 months-8 years); in 180 patients follow up was 2 years or longer. Additional procedures included lower blepharoplasty in 205 patients (51%), neck lift in 102 patients (26%), upper blepharoplasty in 63 patients (15.7%), lateral canthoplasty in 9 patients (2.3%), and upper eyelid ptosis in 6 patients (1.5%). The results were graded as satisfactory or very satisfactory by 95% of patients and by 91% of observers. On the basis of the anatomical changes that occur in the periocular esthetic unit, tissue repositioning is indicated to address the descent of the superior complex and in minor part of the inferior complex, while volume restoration is indicated to address the volume depletion of the inferior and the lateral complexes and for refinements of the superior complex. The authors propose a systematic combination of lifting and filling to naturally restore the youthful appearance of the periocular esthetic unit. Conservative blepharoplasty can be associated in selected cases for result optimization.


Defective autophagy is a key feature of cerebral cavernous malformations.
Cerebral cavernous malformation (CCM) is a major cerebrovascular disease affecting approximately 0.3-0.5% of the population and is characterized by enlarged and leaky capillaries that predispose to seizures, focal neurological deficits, and fatal intracerebral hemorrhages. Cerebral cavernous malformation is a genetic disease that may arise sporadically or be inherited as an autosomal dominant condition with incomplete penetrance and variable expressivity. Causative loss-of-function mutations have been identified in three genes, KRIT1 (CCM1), CCM2 (MGC4607), and PDCD10 (CCM3), which occur in both sporadic and familial forms. Autophagy is a bulk degradation process that maintains intracellular homeostasis and that plays essential quality control functions within the cell. Indeed, several studies have identified the association between dysregulated autophagy and different human diseases. Here, we show that the ablation of the KRIT1 gene strongly suppresses autophagy, leading to the aberrant accumulation of the autophagy adaptor p62/SQSTM1, defective quality control systems, and increased intracellular stress. KRIT1 loss-of-function activates the mTOR-ULK1 pathway, which is a master regulator of autophagy, and treatment with mTOR inhibitors rescues some of the mole-cular and cellular phenotypes associated with CCM. Insufficient autophagy is also evident in CCM2-silenced human endothelial cells and in both cells and tissues from an endothelial-specific CCM3-knockout mouse model, as well as in human CCM lesions. Furthermore, defective autophagy is highly correlated to endothelial-to-mesenchymal transition, a crucial event that contributes to CCM progression. Taken together, our data point to a key role for defective autophagy in CCM disease pathogenesis, thus providing a novel framework for the development of new pharmacological strategies to prevent or reverse adverse clinical outcomes of CCM lesions.


Some features of Cannabis plants grown in the United Kingdom from seeds of known origin.
The cannabinoid content of UK-grown plants (up to the 6th generation) from Moroccan, Sri Lankan and Zambian seedstock was determined by TLC, GLC and HPLC. All plants from the 5th and 6th series resembled their parents, and UK-grown plants were always much greener than those grown overseas. Cannabinoid content remained broadly typical of the source countries. However, tetrahydrocannabinolic acid (THCA) consistently predominated over tetrahydrocannabinol (THC) to a far greater extent than in the original plants; the THCA/THC ratio was 17 in UK-grown plants compared with 2.0 in the plants from the original areas. Two types of plant emerged from the Moroccan seedstock, one tending to increased cannabidiol (CBD), the other tending to zero levels of this component. The first generation Sri Lankan plants revealed one type of plant with an increased CBD/THC ratio (1.7 compared with 0.11) but this returned to the original value in the succeeding generations. Other Sri Lankan plants had low or undetectable levels of CBD. Moroccan and Sri Lankan CBD-rich plants did not contain cannabichromene, although this cannabinoid was found in THC-rich plants. Zambian plants did not appear to show such a pattern. Zambian seedstock plants had total tetrahydrocannabivarin (diol and acid) levels greater than THC but the ratio was progressively reversed in succeeding generations. The study concludes that the ratios of particular cannabinoids is greatly influenced by the environment.


Prevalence of reduced renal function among diabetic hypertensive patients.
Patients with diabetes mellitus and hypertension are at high risk of vascular complications, particularly, renal deterioration. This study aimed to evaluate the prevalence and the risk factors of reduced renal function corresponding to chronic kidney disease (CKD) stages 3 - 5 among diabetic hypertensive patients. This is a retrospective cohort study of diabetic hypertensive patients attending A-Watani governmental medical center from August 2006 until August 2007. Creatinine clearance (CrCl) was estimated using the Cockcroft-Gault equation. Those with CrCl< 60 ml/ min, corresponding to CDK stages 3 - 5, were considered to have reduced renal function. The prevalence of reduced renal function was calculated, and the risk factors associated with it were evaluated using multiple logistic regression. The following were the results found in this study: (a) the prevalence of reduced renal function among the study patients was 35.5% distributed as follows: (63.5%) had stage 3 CKD, 21.7% had stage 4 and 13% had stage 5 CKD. (b) Patients with reduced renal function were elderly, had a higher number of chronic diseases and had a longer duration of diabetes and hypertension than those with CrCl≥ 60ml/ min. (c) Men had a higher prevalence of reduced renal function than women. (d) Significant predictors of reduced renal function were older age, duration of diabetes and the number of chronic diseases based on logistic regression analysis. Early and continuous screening of renal function among diabetic hypertensive patients is required to implement preventable strategies of end stage renal disease (ESRD). Better control of blood pressure and diabetes mellitus are important.


Costs of promoting cancer screening: Evidence from CDC's Colorectal Cancer Control Program (CRCCP).
The Colorectal Cancer Control Program (CRCCP) provided funding to 29 grantees to increase colorectal cancer screening. We describe the screening promotion costs of CRCCP grantees to evaluate the extent to which the program model resulted in the use of funding to support interventions recommended by the Guide to Community Preventive Services (Community Guide). We analyzed expenditures for screening promotion for the first three years of the CRCCP to assess cost per promotion strategy, and estimated the cost per person screened at the state level based on various projected increases in screening rates. All grantees engaged in small media activities and more than 90% used either client reminders, provider assessment and feedback, or patient navigation. Based on all expenditures, projected cost per eligible person screened for a 1%, 5%, and 10% increase in state-level screening proportions are $172, $34, and $17, respectively. CRCCP grantees expended the majority of their funding on Community Guide recommended screening promotion strategies but about a third was spent on other interventions. Based on this finding, future CRC programs should be provided with targeted education and information on evidence-based strategies, rather than broad based recommendations, to ensure that program funds are expended mainly on evidence-based interventions.


Hypoxia promotes glycogen synthesis and accumulation in human ovarian clear cell carcinoma.
Ovarian clear cell carcinoma (OCCC) has several significant characteristics based on molecular features that are distinct from those of ovarian high-grade serous carcinoma. Cellular glycogen accumulation is the most conspicuous feature of OCCC and in the present study its metabolic mechanism was investigated. The amount of glycogen in cells cultured under hypoxia increased significantly and approximately doubled after 48 h (P<0.01) compared to that under normoxic conditions. Periodic acid-Schiff positive staining also demonstrated intracellular glycogen storage. Western blot analysis revealed that HIF1α, which was overexpressed and stabilized under hypoxic conditions, led to an increase in the levels of cellular glycogen synthase 1, muscle type (GYS1), and conversely to a decrease in inactive phosphorylated GYS1 at serine (Ser) 641. Additional increases were observed in both protein phosphatase 1, which dephosphorylates and thereby induces GYS1 enzyme activity, and glycogen synthase kinase 3 beta (GSK3β) phosphorylated at Ser9, which is inactive on phosphorylation of GYS1 and subsequently induces its enzyme activity. By contrast, the level of PYGM-b decreased. These results indicated that the glycogen accumulation under a hypoxic environment resulted in the promotion of glycogen synthesis, but did not lead to inhibition of glycogen degradation and/or consumption. Under hypoxic conditions, HAC2 cells showed activation of the PI3K/AKT pathway caused by a mutation in exon 20 of PIK3CA, encoding the catalytic subunit p110α of PI3K. The resulting activation of AKT (phosphoSer473) also plays a role as a central enhancer in glycogen synthesis through suppression of GSK3β via phosphorylation at Ser9. Hypoxia decreased the cytocidal activity of cisplatin and doxorubicin to various degrees. In conclusion, the hypoxic conditions together with HIF1 expression and stabilization increased the intracellular glycogen contents and resistance to the anticancer drugs.


A single point mutation of Ala-25 to Asp in the 14,000-Mr envelope protein of vaccinia virus induces a size change that leads to the small plaque size phenotype of the virus.
The molecular defect responsible for a structural and functional abnormality of the 14,000-molecular-weight (14K) envelope protein of vaccinia virus has been identified. Through DNA sequence analysis of the entire 14K gene from wild-type vaccinia virus and three vaccinia virus mutants, a single base change of C to A was found that resulted in the substitution of Asp for Ala-25. This mutation is responsible for protein size abnormality, as documented by cell-free translation in a rabbit reticulocyte lysate of in vitro mRNA transcripts. In addition, through marker rescue experiments we show that this mutation is responsible for the small plaque size phenotype of vaccinia virus mutants. The structural consequence of the point mutation is a possible turn in an alpha-helix domain with destabilization of a hydrophobic interaction at the N terminus, resulting in monomers and trimers of vaccinia virus 14K protein with decreased electrophoretic mobilities. The functional consequence of the point mutation is a reduction in virulence of the virus.


Radiation response of cancer stem-like cells from established human cell lines after sorting for surface markers.
A subpopulation of cancer stem-like cells (CSLC) is hypothesized to exist in different cancer cell lines and to mediate radioresistance in solid tumors. Cells were stained for CSLC markers and sorted (fluorescence-activated cell sorter/magnetic beads) to compare foci and radiosensitivity of phosphorylated histone H2AX at Ser 139 (gamma-H2AX) in sorted vs. unsorted populations in eight cell lines from different organs. CSLC properties were examined using anchorage-independent growth and levels of activated Notch1. Validation consisted of testing tumorigenicity and postirradiation enrichment of CSLC in xenograft tumors. The quantity of CSLC was generally in good agreement with primary tumors. CSLC from MDA-MB-231 (breast) and Panc-1 and PSN-1 (both pancreatic) cells had fewer residual gamma-H2AX foci than unsorted cells, pointing to radioresistance of CSLC. However, only MDA-MB-231 CSLC were more radioresistant than unsorted cells. Furthermore, MDA-MB-231 CSLC showed enhanced anchorage-independent growth and overexpression of activated Notch1 protein. The expression of cancer stem cell surface markers in the MDA-MB-231 xenograft model was increased after exposure to fractionated radiation. In contrast to PSN-1 cells, a growth advantage for MDA-MB-231 CSLC xenograft tumors was found compared to tumors arising from unsorted cells. CSLC subpopulations showed no general radioresistant phenotype, despite the quantities of CSLC subpopulations shown to correspond relatively well in other reports. Likewise, CSLC characteristics were found in some but not all of the tested cell lines. The reported problems in testing for CSLC in cell lines may be overcome by additional techniques, beyond sorting for markers.


Fine-Scale Doppler Radar Observations of Tornadoes
Observations obtained with a mobile pencil-beam Doppler radar revealed many previously unresolved structures within tornadic storms and tornadoes and helped verify various aspects of conceptual models. Radar data from the parent circulations indicate the existence of spiral reflectivity bands, intense radial wind shear zones, and multiple larger-scale velocity maxima. Tornado structures observed include debris shields, clear axial (eye) regions, multiple reflectivity bands surrounding the center of the eye, and occasional reflectivity protrusions into the eye. Velocity and reflectivity data from tornado-scale circulations show evidence of axial downdrafts.


KCNQ/M-channels regulate mouse vagal bronchopulmonary C-fiber excitability and cough sensitivity.
Increased airway vagal sensory C-fiber activity contributes to the symptoms of inflammatory airway diseases. The KCNQ/Kv7/M-channel is a well-known determinant of neuronal excitability, yet whether it regulates the activity of vagal bronchopulmonary C-fibers and airway reflex sensitivity remains unknown. Here we addressed this issue using single-cell RT-PCR, patch clamp technique, extracellular recording of single vagal nerve fibers innervating the mouse lungs, and telemetric recording of cough in free-moving mice. Single-cell mRNA analysis and biophysical properties of M-current (IM) suggest that KCNQ3/Kv7.3 is the major M-channel subunit in mouse nodose neurons. The M-channel opener retigabine negatively shifted the voltage-dependent activation of IM, leading to membrane hyperpolarization, increased rheobase, and suppression of both evoked and spontaneous action potential (AP) firing in nodose neurons in an M-channel inhibitor XE991-sensitive manner. Retigabine also markedly suppressed the α,β-methylene ATP-induced AP firing in nodose C-fiber terminals innervating the mouse lungs, and coughing evoked by irritant gases in awake mice. In conclusion, KCNQ/M-channels play a role in regulating the excitability of vagal airway C-fibers at both the cell soma and nerve terminals. Drugs that open M-channels in airway sensory afferents may relieve the sufferings associated with pulmonary inflammatory diseases such as chronic coughing.


Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial.
Angiotensin receptor blockers (ARB) and angiotensin converting enzyme (ACE) inhibitors are known to reduce proteinuria. Their combination might be more effective than either treatment alone, but long-term data for comparative changes in renal function are not available. We investigated the renal effects of ramipril (an ACE inhibitor), telmisartan (an ARB), and their combination in patients aged 55 years or older with established atherosclerotic vascular disease or with diabetes with end-organ damage. The trial ran from 2001 to 2007. After a 3-week run-in period, 25 620 participants were randomly assigned to ramipril 10 mg a day (n=8576), telmisartan 80 mg a day (n=8542), or to a combination of both drugs (n=8502; median follow-up was 56 months), and renal function and proteinuria were measured. The primary renal outcome was a composite of dialysis, doubling of serum creatinine, and death. Analysis was by intention to treat. This study is registered with ClinicalTrials.gov, number NCT00153101. 784 patients permanently discontinued randomised therapy during the trial because of hypotensive symptoms (406 on combination therapy, 149 on ramipril, and 229 on telmisartan). The number of events for the composite primary outcome was similar for telmisartan (n=1147 [13.4%]) and ramipril (1150 [13.5%]; hazard ratio [HR] 1.00, 95% CI 0.92-1.09), but was increased with combination therapy (1233 [14.5%]; HR 1.09, 1.01-1.18, p=0.037). The secondary renal outcome, dialysis or doubling of serum creatinine, was similar with telmisartan (189 [2.21%]) and ramipril (174 [2.03%]; HR 1.09, 0.89-1.34) and more frequent with combination therapy (212 [2.49%]: HR 1.24, 1.01-1.51, p=0.038). Estimated glomerular filtration rate (eGFR) declined least with ramipril compared with telmisartan (-2.82 [SD 17.2] mL/min/1.73 m(2)vs -4.12 [17.4], p<0.0001) or combination therapy (-6.11 [17.9], p<0.0001). The increase in urinary albumin excretion was less with telmisartan (p=0.004) or with combination therapy (p=0.001) than with ramipril. In people at high vascular risk, telmisartan's effects on major renal outcomes are similar to ramipril. Although combination therapy reduces proteinuria to a greater extent than monotherapy, overall it worsens major renal outcomes.


Caregiving intensity and change in physical functioning over a 2-year period: results of the caregiver-study of osteoporotic fractures.
It is unknown whether caregivers who perform more caregiving tasks have a greater decline in health from higher stress or less decline because of better health, staying active, or psychological factors. This 1999-2004 US study examined caregiving intensity and 2-year change in performance-based functioning among 901 elderly women from the Caregiver-Study of Osteoporotic Fractures sample. Caregivers were categorized as high (n = 167) or low (n = 166) intensity based on how many activities of daily living they performed for the care recipient. Caregiving intensity status and physical performance score (sum of quartiles of walking pace, grip strength, and chair-stand speed; range, 0-9) were assessed at baseline and at 2 annual follow-up interviews. At baseline, high-intensity caregivers reported the most stress but had the best physical functioning; noncaregivers (n = 568) had the poorest physical functioning (adjusted scores = 5.09 vs. 4.54, P = 0.03). Low-intensity caregivers declined more than noncaregivers over 2 years, but high-intensity caregivers did not (adjusted difference = -0.33, P = 0.07 vs. 0.03, P = 0.89). Among respondents with the same caregiving status at baseline and 1-year interviews, high-intensity caregivers maintained the highest physical performance throughout follow-up. Higher levels of physical performance persisted over 2 years among high-intensity caregivers, which did not support the traditional stress hypothesis.


Achievement of the National Kidney Foundation Kidney Disease Outcomes Quality Initiative: recommended serum calcium, phosphate and parathyroid hormone values with parathyroidectomy in patients with secondary hyperparathyroidism.
The National Kidney Foundation Kidney Disease Outcomes Quality Initiative (NKF-K/DOQI) 2003 has established guidelines for the treatment of secondary hyperparathyroidism (SHPT) in patients with chronic kidney disease - minerals and bone disorder (CKD-MBD). This study evaluated parathyroidectomy in SHPT patients for the achievement of the NKF-K/DOQI-recommended values of serum calcium, phosphate, and parathyroid hormone (PTH). Between January 2005 and December 2010, parathyroidectomy was performed as recommended by the NKF-K/DOQI guidelines in 81 patients with SHPT and CKD-MBD. Serum PTH, calcium, and phosphate levels were measured prior to and 6, 12, 36, and 60 months after parathyroidectomy. Calcium, phosphate, and PTH levels dropped shortly after parathyroidectomy; however, a slight increase showed in the long term. Calcium levels increased for up to 60 months. Phosphate and PTH levels increased for up to 36 months but tended to decrease slightly at 60 months. The mean values were within the target ranges, except for PTH at 36 months. The target parameters of serum phosphate (42.9-61.1% of patients) and serum calcium (a peak of 61.1% of patients at 36 months, but only 28.6% at 60 months) were achieved the most. Less than 34% of patients achieved the recommended range for PTH. Parathyroidectomy was not an optimal procedure for achieving all the biochemical parameters recommended by the NKF-K/DOQI. Although it was helpful in attaining the recommended values for serum calcium and phosphate in SHPT patients resistant to medical therapy, the PTH levels did not fall within the recommended range.


Quantification of cardiac fiber orientation using optical coherence tomography.
Heterogeneity in cardiac tissue microstructure is a potential mechanism for the generation and maintenance of arrhythmias. Abnormal changes in fiber orientation increase the likelihood of arrhythmia. We present optical coherence tomography (OCT) as a method to image myofibers in excised intact heart preparations. Three-dimensional (3-D) image sets were gathered from the rabbit right ventricular free wall (RVFW) using a microscope-integrated OCT system. An automated algorithm for fiber orientation quantification in the plane parallel to the wall surface was developed. The algorithm was validated by comparison with manual measurements. Quantifying fiber orientation in the plane parallel to the wall surface from OCT images can be used to help understand the conduction system of the specific sample being imaged.


Equitoxic doses of 5-azacytidine and 5-aza-2'deoxycytidine induce diverse immediate and overlapping heritable changes in the transcriptome.
The hypomethylating agent 5-Azacytidine (5-Aza-CR) is the first drug to prolong overall survival in patients with myelodysplastic syndrome (MDS). Surprisingly, the deoxyribonucleoside analog 5-Aza-2'deoxycytidine (5-Aza-CdR) did not have a similar effect on survival in a large clinical trial. Both drugs are thought to exert their effects after incorporation into DNA by covalent binding of DNA methyltransferase (DNMT). While 5-Aza-CdR is incorporated into only DNA, 5-Aza-CR is also incorporated into RNA. Here, we have analyzed whether this difference in nucleic acid incorporation may influence the capacities of these drugs to regulate the expression of mRNA and microRNAs (miRNA), which may potentially affect the activities of the drugs in patients. A hematopoietic (HL-60; acute myeloid leukemia) and a solid (T24; transitional cell carcinoma) cancer cell line were treated with equitoxic doses of 5-Aza-CR and 5-Aza-CdR for 24 hrs, and the immediate (day 2) and lasting (day 8) effects on RNA expression examined. There was considerable overlap between the RNAs heritably upregulated by both drugs on day 8 but more RNAs were stably induced by the deoxy analog. Both drugs strongly induced expression of cancer testis antigens. On day 2 more RNAs were downregulated by 5-Aza-CR, particularly at higher doses. A remarkable downregulation of miRNAs and a significant upregulation of tRNA synthetases and other genes involved in amino acid metabolism was observed in T24 cells. Overall, this suggests that significant differences exist in the immediate action of the two drugs, however the dominant pattern of the lasting, and possible heritable changes, is overlapping.


Accuracy of physician reporting in routine public health surveillance for hepatitis C virus infection.
From January 2007 to December 2008, the Montréal Public Health Department sent postal questionnaires to physicians and conducted patient interviews for all those newly diagnosed with hepatitis C virus (HCV) infection. We evaluated physician responses to risk factor questions for non-acute HCV cases. We compared physician and patient responses with each of nine risk factor questions, determined the sensitivity and specificity of physician responses compared with patient responses, and evaluated agreement using Gwet's agreement coefficient (AC1). We ranked risk factors and compared the distributions by principal exposure category according to physician reporting vs. patient interview using the Chi-square test. The completeness of physicians' responses (yes, no, or unknown) varied by risk factor question from 90.8% to 96.7%. For risk factors present among more than 5% of cases, sensitivity of physician responses ranged from 26.9% to 87.7% and specificity ranged from 93.0% to 98.6%. The AC1 coefficients for agreement between physician and patient responses to lifetime risk factors considered most important in HCV acquisition were 0.80 for injection drug use, 0.95 for blood transfusion before 1990, and 0.86 for birth in a country with high HCV prevalence. Risk distributions by principal exposure category according to physician reporting vs. patient interview were not statistically different (χ(2)[4] = 2.17, p=0.704). Postal questionnaires completed by physicians appear valid for determining the principal exposure category among non-acute HCV cases. Physician reporting can be a useful and low-cost component of routine HCV surveillance.


Prevalence and characteristics of primary angle-closure diseases in a rural adult Chinese population: the Handan Eye Study.
To investigate the prevalence and characteristics of primary angle-closure suspect (PACS), primary angle closure (PAC), and primary angle-closure glaucoma (PACG) in a rural population in China. In all, 6716 Han Chinese 30 years of age and older (5480 subjects 40 years of age and older) from 13 villages in Handan were randomly selected and completed an ophthalmologic examination, including visual acuity, intraocular pressure (IOP), slit-lamp examination, gonioscopy and stereoscopic photography, and visual field. PACS was defined as present if either eye had the posterior trabecular meshwork not visible for 180° or more on gonioscopy. PAC was present in an eye with PACS and peripheral anterior synechiae (PAS) and/or IOP ≥ 21 mm Hg, but without glaucomatous neuropathy (GON). PACG was defined as PAC with evidence of GON. The standardized prevalences of PACG, PAC, and PACS were 0.5% (95% confidence interval [CI]: 0.3-0.7%), 1.5% (95% CI: 1.2-1.8%), and 10.4% (95% CI: 9.6-11.2%) in those 40 years of age and older. The prevalence of all three conditions increased with age (P < 0.001). Females had much higher rates of PACS, PAC, and PACG (P < 0.05); 21 persons with PACG (65%) were blind in at least one eye: 13 were due to glaucoma and the other 8 likely had other causes. The prevalence of PACS, PAC, and PACG in this rural population is similar to what was previously reported in urban Chinese residents. Two thirds of those with PACG were blind in at least one eye. Strategies to detect and treat this preventable disease in rural China are needed.


γH2AX expression in cytological specimens as a biomarker of response to radiotherapy in solid malignancies.
Many anticancer treatments, including radiotherapy, act by damaging DNA and hindering cell function and proliferation. H2AX is a histone protein directly associated with DNA that is phosphorylated to produce γH2AX that accumulates in foci in an early response to DNA double-strand breaks, the most deleterious lesion caused by anticancer therapy. This study reports a γH2AX detection assay that has the potential to be used as a biomarker of response to guide cancer treatment. γH2AX immunostaining was applied to tumour cell specimens obtained using fine needle aspiration (FNA). Liquid-based cytology and direct smear cytology methods were evaluated and immunostaining protocols established using FNA samples from five cancer patients. The assay was then applied to three patients before and after radiotherapy. Results demonstrate induction of γH2AX foci following treatment, persisting for as long as one week after therapy. Immunostaining for γH2AX has been successfully applied to FNA samples, providing an opportunity to evaluate γH2AX as a treatment response marker in cancer.