[Transient elastography (FibroScan) for the non-invasive assessment of liver fibrosis: current status and perspectives].
A precise staging of the degree of liver fibrosis is important for the estimation of prognosis, surveillance and treatment decision in patients with chronic liver diseases. At present, liver biopsy is still the reference standard for the assessment of liver fibrosis. However, it is an invasive method associated with patient discomfort and in rare cases with serious complications. In addition, the accuracy of liver biopsy is limited due to intra- and interobserver variability and sampling errors. Non-invasive markers and methods for the assessment of liver fibrosis have been intensively evaluated in many studies. The FibroScan (Echosens, France) uses the transient elastography principle for the measurement of liver stiffness. At present (January 2007), studies evaluating the FibroScan in a wide range of liver diseases have been published in 20 full papers and 76 abstracts. The present review gives an overview of the current literature. The best results are reported for the differentiation between cirrhosis and no cirrhosis. With the combination of FibroScan and non-invasive serum fibrosis markers, the accuracy for the diagnosis of significant fibrosis (Metavir F > or = 2) can be further improved. According to recent data the FibroScan can also be useful for the evaluation of treatment response in patients receiving antiviral treatment for chronic hepatitis C. In addition, several studies have shown, that the FibroScan can be applied to estimate the risk of complications associated with liver cirrhosis.


Factors associated with vaccination status among Korean submariners who are eligible for free non-mandatory influenza vaccination.
Submarine crews live in a confined setting and are vulnerable to influenza. Thus, it would be useful to identify factors that are associated with influenza vaccination. In this study, we investigated the influenza vaccination rate and the influence of health beliefs on the vaccination rate among submariners who were eligible for a free but non-mandatory vaccination program. A total of 487 Korean submariners participated in this study after the closing of a free influenza vaccination program in 2015. Data regarding the participants' general characteristics and health beliefs (based on the health belief model [HBM]) were collected using a self-administered questionnaire, and their vaccination status was determined using their medical records. Multiple logistic regression analysis were performed to evaluate the associations of the HBM components with influenza vaccination. The overall vaccination rate was 78% (921/1183). The unvaccinated and vaccinated respondents exhibited similar characteristics, although the vaccinated group was significantly more likely to have high-risk family members (chronic disease, age of <2years, or age of ⩾65years; p=0.025). Among the HBM components, perceived severity (odds ratio: 1.38, p=0.019) and cue to action (odds ratio: 1.74, p=0.002) were significantly associated with a higher likelihood of influenza vaccination. Vaccination policies that emphasize the severity of influenza and prompt individuals to undergo vaccination are needed to increase the vaccination rate among people who live in confined environments or institutions with non-mandatory vaccination programs.


Oral silicon supplementation: an effective therapy for preventing oral aluminum absorption and retention in mammals.
Silicon is an essential element for some lower forms of life. However, it is not generally considered an essential nutrient for mammals and the mechanisms underlying its potential essentiality remain partially unknown. In recent years, a possible association between the aluminum and silicon levels in drinking water and Alzheimer's disease (AD) has been suggested. It has been reported that silicon might have a protective effect for limiting oral aluminum absorption. This review is focused primarily on the potential role of silicon in preventing oral aluminum absorption and retention in mammals. The results of a number of studies suggest that dietary silicon supplementation could be of therapeutic value for preventing chronic aluminum accumulation in the brain, and hence, be a potential therapy for AD. However, it must be noted that controversy remains about whether aluminum accumulation in the brain is a cause or a consequence of AD. It is suggested that further investigation of this issue is warranted.


Effectiveness and safety of mandatory antimicrobial indications and durations and a pharmacist-driven 48-hour time-out in a pediatric hospital.
To evaluate the effectiveness and safety of mandatory antimicrobial indications and durations (MAID) and a pharmacist-driven 48-hour time-out in a pediatric hospital. MAID and a 48-hour time-out were implemented on February 14, 2017. Antibiotic days of therapy (DOT) per 1,000 patient days were compared between the pre- and postperiod for select antibiotics using unadjusted Poisson models. A prepost comparison was used to compare antimicrobial stewardship program (ASP) intervention rates between time periods. A 2-step process, including distribution of a discontinuation (DC) report to pharmacists and ASP-prompted reorders, was instituted to reduce unintentional antimicrobial discontinuation with MAID. ASP-prompted reorders occurred only when a discrepancy persisted between the order and provider-desired duration. Missed antimicrobial doses were identified by ASP and the institutional event reporting system. Safety of MAID was assessed by reviewing the rate and details of ASP-prompted reorders and missed antimicrobial doses. A significant decrease in DOT per 1,000 patient days was observed for cefazolin (39.7 to 36.9; P < 0.001), ampicillin (39.9 to 35.7; P < 0.001), clindamycin (38.2 to 35.9; P < 0.001), ceftriaxone (46.5 to 43.4; P < 0.001), and meropenem (8.7 to 6.6; P < 0.001) following implementation. No change in ASP intervention rate occurred between the pre- and postperiod (16.9 vs 16.8%; P = 0.94). With MAID, ASP-prompted reorder occurred on 7.3% of orders. Unintentional discontinuations resulting in missed antimicrobial doses occurred in 3 orders (0.07%); no patient harm resulted. MAID and a 48-hour time-out significantly reduced DOT of select antibiotics. No patient harm occurred with the 2-step safety process.


Vitamin D Supplementation and Blood Pressure in Children and Adolescents: A Systematic Review and Meta-Analysis.
Suboptimal vitamin D status is associated with elevated blood pressure (BP) in children and adolescents. Whether vitamin D supplementation reduces BP remains unclear. To systematically review whether vitamin D supplementation reduces BP in children and adolescents, we conducted a literature review according to the PRISMA statement. We included vitamin-D supplementation human interventions studies that reported on BP as an outcome. We searched PUBMED, MEDLINE, CINAHL, EMBASE, the Cochrane Library, and the clinical trials website. We also hand searched the references of the included articles and previous reviews of vitamin D therapy. No language or time restrictions were applied. We extracted data on population characteristics, baseline and endline vitamin D and BP values, and assessed the risk of bias of the included studies. We performed a narrative review of the findings, conducted a meta-analysis when possible, and performed sensitivity analyses to test the robustness of our results. We assessed the overall quality of the evidence produced in the meta-analysis. We included eight studies in our review and five studies in the meta-analysis, none of which included hypertensive only participants. The risk of bias was variable. In non-randomized studies, no effect of vitamin D supplementation was seen on systolic BP (SBP) (mean difference: 0.39 (95% confidence interval (CI): -0.9; 1.68) mmHg; p = 0.55; I2 = 0%). Only a significant decrease in diastolic BP (DBP) (mean difference: -1.87 (95% CI: -3.02; -0.72) mmHg; p = 0.001; I2 = 0%) was noted. Both analyses had a low quality of evidence. In randomized controlled trials (RCTs), no effect was noted on SBP (mean difference: -2.04 (95% CI: -5.12; 1.04) mmHg; p = 0.19; I2 = 71%) nor DBP (mean difference: 0.01 (95% CI: -1.09; 1.12) mmHg; p = 0.98; I2 = 0%). The final quality of evidence ranged between low and moderate. Sensitivity analyses did not affect the results. Vitamin D supplementation was found to be ineffective in lowering SBP and DBP in children and adolescents.


Effect of heliox on lung dynamic hyperinflation, dyspnea, and exercise endurance capacity in COPD patients.
We tested the hypothesis that heliox breathing, by reducing lung dynamic hyperinflation (DH) and dyspnea (Dys) sensation, may significantly improve exercise endurance capacity in patients with chronic obstructive pulmonary disease [n = 12, forced expiratory volume in 1 s = 1.15 (SD 0.32) liters]. Each subject underwent two cycle ergometer high-intensity constant work rate exercises to exhaustion, one on room air and one on heliox (79% He-21% O2). Minute ventilation (VE), carbon dioxide output, heart rate, inspiratory capacity (IC), Dys, and arterial partial pressure of CO2 were measured. Exercise endurance time increased significantly with heliox [9.0 (SD 4.5) vs. 4.2 (SD 2.0) min; P < 0.001]. This was associated with a significant reduction in lung DH at isotime (Iso), as reflected by the increase in IC [1.97 (SD 0.40) vs. 1.77 (SD 0.41) liters; P < 0.001] and a decrease in Dys [6 (SD 1) vs. 8 (SD 1) score; P < 0.001]. Heliox induced a state of relative hyperventilation, as reflected by the increase in VE [38.3 (SD 7.7) vs. 35.5 (SD 8.8) l/min; P < 0.01] and VE/carbon dioxide output [36.3 (SD 6.0) vs. 33.9 (SD 5.6); P < 0.01] at peak exercise and by the reduction in arterial partial pressure of CO2 at Iso [44 (SD 6) vs. 48 (SD 6) Torr; P < 0.05] and at peak exercise [46 (SD 6) vs. 48 (SD 6) Torr; P < 0.05]. The reduction in Dys at Iso correlated significantly (R = -0.75; P < 0.01) with the increase in IC induced by heliox. The increment induced by heliox in exercise endurance time correlated significantly with resting increment in resting forced expiratory in 1 s (R = 0.88; P < 0.01), increase in IC at Iso (R = 0.70; P < 0.02), and reduction in Dys at Iso (R = -0.71; P < 0.01). In chronic obstructive pulmonary disease, heliox breathing improves high-intensity exercise endurance capacity by increasing maximal ventilatory capacity and by reducing lung DH and Dys.


Anesthesia and Poliomyelitis: A Matched Cohort Study.
Poliomyelitis is a viral infectious disease caused by 1 of the 3 strains of poliovirus. The World Health Organization launched an eradication campaign in 1988. Although the number of cases of poliomyelitis has drastically declined, eradication has not yet been achieved, and there are a substantial number of survivors of the disease. Survivors of poliomyelitis present a unique set of challenges to the anesthesiologist. The scientific literature regarding the anesthetic management of survivors of poliomyelitis, however, is limited and primarily experiential in nature. Using a retrospective, matched cohort study, we sought to more precisely characterize the anesthetic implications of poliomyelitis and to determine what risks, if any, may be present for patients with a history of the disease. Using the Mayo Clinic Life Sciences System Data Discovery and Query Builder, study subjects were identified as those with a history of paralytic poliomyelitis who had undergone major surgery at Mayo Clinic Rochester between 2005 and 2009. For each case, 2 sex- and age-matched controls that underwent the same surgical procedure during the study period were randomly selected from a pool of possible controls. Medical records were manually interrogated with respect to demographic variables, comorbid conditions, operative and anesthetic course, and postoperative course. We analyzed 100 cases with 2:1 matched controls and found that the peri- and postoperative courses were very similar for both groups of patients. Pain scores, postanesthesia care unit admission, length of postanesthesia care unit stay, intensive care unit admission, length of intensive care unit stay, and initial extubation location were not significantly different between the 2 groups. Looking at pulmonary complications in our primary outcome, there was no significant difference between the 2 groups (17% vs 14% for polio versus control, respectively; conditional logistic regression odds ratio = 1.5; 95% confidence interval, 0.7-3.3; P = 0.33). In addition, no difference was noted in those requiring a code or rapid response team intervention (4% vs 3% for polio versus control; P = 0.46) and the 30-day mortality rate was also not significantly different, with 2% of polio patients dying compared with 3% of controls (P = 0.79). The analysis of the primary outcome was repeated for the subset of patients with a history of poliomyelitis who had persistent neurologic deficits preoperatively (n = 36) and their matched controls (n = 72). In this subset analysis, there were 4 (11%) polio patients and 8 (11%) control patients who experienced pulmonary complications (conditional logistic regression odds ratio = 1.00; 95% confidence interval, 0.27-3.72; P = 1.00). The percentage of patients experiencing specific pulmonary complications of interest was similar between groups (postoperative mechanical ventilation: 6% vs 8% for polio and control patients, respectively; prolonged mechanical ventilation: 0% vs 1%; reintubation: 8% vs 4%; pulmonary infection: 6% vs 6%; and aspiration: 0% vs 1%). This study suggests that patients with a history of poliomyelitis do not seem to have an increased risk of pulmonary complications in the perioperative period. However, an odds ratio as great as 3.3-fold may be present.


Integrating basic science without integrating basic scientists: reconsidering the place of individual teachers in curriculum reform.
The call for integration of the basic and clinical sciences plays prominently in recent conversations about curricular change in medical education; however, history shows that, like other concepts related to curricular reform, integration has been continually revisited, leading to incremental change but no meaningful transformation. To redress this cycle of "change without difference," the medical education community must reexamine the approach that dominates medical education reform efforts and explore alternative perspectives that may help to resolve the cyclical "problem" of recommending but not effecting integration. To provide a different perspective on implementing integration, the authors of this Perspective look to the domain of educational change as an approach to examining the transitions that occur within complex and evolving environments. This area of literature both acknowledges the multiple levels involved in change and emphasizes the need not only to address systemic structure but also to prioritize individuals during times of transition. The struggle to implement curricular integration in medical education may stem from the fact that reform efforts appear to focus largely on transformation at the level of curricular structure as opposed to considering what learning needs to occur at each level of change and highlighting the individual as the educational change literature suggests. To bring appropriate attention to the place of individual educators, especially basic scientists, the medical education community should explore how the mandate to integrate clinically relevant material may impact these faculty and the teaching of their domains.


Interferon alpha for eradication of HCV and remission of chronic hepatitis in children.
Thirty two children (8 girls and 32 boys), aged 4-14, with chronic hepatitis C were treated with interferon alpha at a dose of 3 MU or 5 MU, given times weekly for 6 months. Five children (16%) were complete responders (defined as disappearance of viremia), none of them relapsed, 6 (19%) were partial responders (normalization of ALT), 3 (9%) were transient responders (ALT initially decreased but then rebounded to pre-treatment levels) and 18 (56%) were non responders. During the treatment, continuous decrease of median ALT, AST and GGT was noted, statistically significant differences were found for comparisons of values measured before and after treatment (for ALT p = 0.023, for AST p = 0.021 and for GGT p = 0.012). Histological evaluation revealed one case of progression (to liver cirrhosis) out of three investigated complete responders, 1/5 such cases of partial responders, 1/2 of transient responders and 14/18 of non-responders. Remission of hepatitis was found in 2/18 (10%) non-responders. There was no statistically significant difference between 16 children previously infected with HBV (anti-HBc positive but HBsAg negative at the time of our study) and the others with respect to biochemical and histological severity of hepatitis or in the response to treatment rate. Chronic hepatitis C in children may cause severe hepatitis or even liver cirrhosis. Virological, biochemical and histological features should be considered to evaluate the severity of the disease and response to interferon treatment. Past infection with HBV does not affect interferon sensitivity in children with chronic hepatitis C.


Breastfeeding Duration and Primary Reasons for Breastfeeding Cessation among Women with Postpartum Depressive Symptoms.
Although postpartum depression is associated with lower breastfeeding initiation rates and shorter breastfeeding duration, the potential mechanisms through which this relationship functions are not well understood. This study examined the breastfeeding behaviors of women with postpartum depressive symptoms (PDS) to identify potential motivations for early breastfeeding cessation. An analysis of quantitative data from the Infant Feeding Practices Study II examined the relationship between PDS and breastfeeding behaviors, including breastfeeding duration and primary reasons for early breastfeeding cessation. Of the women in the sample, 30.9% met criteria for mild PDS. Women with PDS had shorter overall (18.4 vs 21.8 weeks, P = .001) and exclusive breastfeeding duration (3.6 vs 4.7 weeks, P = .012) than women without PDS. A larger proportion of women with PDS stopped breastfeeding before 6 months (68.7% vs 57.2%, P < .001). After controlling for socioeconomic status, education, marital status, employment status, race/ethnicity, maternal age, parity, and breastfeeding intentions, presence of PDS significantly predicted higher odds of reporting "too many household duties" (OR = 1.90, P = .011) as a primary reason for breastfeeding cessation among women who stopped breastfeeding before 6 months. After controlling for these same covariates, women with PDS had, on average, 2.4 weeks shorter breastfeeding duration than women without PDS (P = .025). There is a high prevalence of depressive symptoms among new mothers, and most do not breastfeed for recommended time periods. Increased PDS screening during prenatal and postpartum visits and promotion of lactation support services may better address the high rates of PDS and suboptimal breastfeeding behavior.


Dentate gyrus-CA3 glutamate release/NMDA transmission mediates behavioral despair and antidepressant-like responses to leptin.
Compelling evidence supports the important role of the glutamatergic system in the pathophysiology of major depression and also as a target for rapid-acting antidepressants. However, the functional role of glutamate release/transmission in behavioral processes related to depression and antidepressant efficacy remains to be elucidated. In this study, glutamate release and behavioral responses to tail suspension, a procedure commonly used for inducing behavioral despair, were simultaneously monitored in real time. The onset of tail suspension stress evoked a rapid increase in glutamate release in hippocampal field CA3, which declined gradually after its offset. Blockade of N-methyl-D-aspartic acid (NMDA) receptors by intra-CA3 infusion of MK-801, a non-competitive NMDA receptor antagonist, reversed behavioral despair. A subpopulation of granule neurons that innervated the CA3 region expressed leptin receptors and these cells were not activated by stress. Leptin treatment dampened tail suspension-evoked glutamate release in CA3. On the other hand, intra-CA3 infusion of NMDA blocked the antidepressant-like effect of leptin in reversing behavioral despair in both the tail suspension and forced swim tests, which involved activation of Akt signaling in DG. Taken together, these results suggest that the DG-CA3 glutamatergic pathway is critical for mediating behavioral despair and antidepressant-like responses to leptin.


Invasive floating macrophytes reduce greenhouse gas emissions from a small tropical lake.
Floating macrophytes, including water hyacinth (Eichhornia crassipes), are dominant invasive organisms in tropical aquatic systems, and they may play an important role in modifying the gas exchange between water and the atmosphere. However, these systems are underrepresented in global datasets of greenhouse gas (GHG) emissions. This study investigated the carbon (C) turnover and GHG emissions from a small (0.6 km(2)) water-harvesting lake in South India and analysed the effect of floating macrophytes on these emissions. We measured carbon dioxide (CO2) and methane (CH4) emissions with gas chambers in the field as well as water C mineralization rates and physicochemical variables in both the open water and in water within stands of water hyacinths. The CO2 and CH4 emissions from areas covered by water hyacinths were reduced by 57% compared with that of open water. However, the C mineralization rates were not significantly different in the water between the two areas. We conclude that the increased invasion of water hyacinths and other floating macrophytes has the potential to change GHG emissions, a process that might be relevant in regional C budgets.


Persistence of visuo-constructional and executive deficits in adolescents after open-heart surgery.
This study assesses whether previously reported performance deficiencies in visuo-constructional and executive functions, using the Rey-Osterrieth Complex Figure Test (ROCFT) in pediatric patients with congenital heart disease (CHD), persist into adolescence. 53 adolescent CHD patients (mean age 13.7) and 39 healthy controls (mean age 14.1) participated. ROCFT performance was measured by three different scoring methods, focusing either on quantitative (Meyers & Meyers, 1995), qualitative (Wallon & Mesmin, 2009), or both performance aspects (Bernstein & Waber, 1996). Potential confounders (i.e., intelligence and visuomotor integration) and surgery-related risk factors were included in the data analysis. Adolescents with CHD demonstrated immature copy and recall approaches on the ROCFT using the qualitative system by Wallon and Mesmin (p<.001). Memory performance was also predicted by Bernstein and Waber scores (p<.03), whereas group differences were not significant according to the other scoring methods. Intelligence and visuomotor skills, but not surgery-related risk factors, were positively correlated with ROCFT performance (each p<.02). Interpretation: Visuoconstructional and executive deficiencies could be found in adolescent patients with CHD. However, not all ROCFT scoring methods were equally apt to detect group differences: especially the qualitative scoring method developed by Wallon and Mesmin seems sufficiently sensitive to detect long-lasting visuo-constructional and executive deficiencies in CHD patients.


A hybrid classifier for automated radiologic diagnosis: preliminary results and clinical applications.
We describe the design, implementation, and preliminary evaluation of a computer system to aid clinicians in the interpretation of cranial magnetic-resonance (MR) images. The system classifies normal and pathologic tissues in a test set of MR scans with high accuracy. It also provides a simple, rapid means whereby an unassisted expert may reliably label an image with his best judgment of its histologic composition, yielding a gold-standard image; this step facilitates objective evaluation of classifier performance. This system consists of a preprocessing module; a semiautomatic, reliable procedure for obtaining objective estimates of an expert's opinion of an image's tissue composition; a classification module based on a combination of the maximum-likelihood (ML) classifier and the isodata unsupervised-clustering algorithm; and an evaluation module based on confusion-matrix generation. The algorithms for classifier evaluation and gold-standard acquisition are advances over previous methods. Furthermore, the combination of a clustering algorithm and a statistical classifier provides advantages not found in systems using either method alone.


Explicit and implicit information needs of people with depression: a qualitative investigation of problems reported on an online depression support forum.
Health management is impeded when consumers do not possess adequate knowledge about their illness. At a public health level, consumer knowledge about depression is particularly important because depression is highly prevalent and causes substantial disability and burden. However, currently little is known about the information needs of people with depression. This study aimed to investigate the explicit and implicit information needs of users of an online depression support forum. A sample of 2680 posts was systematically selected from three discussion forums on an online depression bulletin board (blueboard.anu.edu.au). Data were examined for evidence of requests for information (reflecting explicit needs) and reports of past or current problems (implicit needs). Thematic analysis was conducted using a data-driven inductive approach with the assistance of NVivo 7, and instances of questions and people reporting particular types of problems were recorded. A total of 134 participants with personal experience of depression contributed to the data analysed. Six broad themes represented participant queries and reported problems: Understanding depression; disclosure and stigma; medication; treatment and services; coping with depression; and comorbid health problems. A variety of specific needs were evident within these broad thematic areas. Some people (n = 46) expressed their information needs by asking direct questions (47 queries) but the majority of needs were expressed implicitly (351 problems) by the 134 participants. The most evident need for information related to coping with depression and its consequences, followed by topics associated with medication, treatment and services. People with depression have substantial unmet information needs and require strategies to deal with the difficulties they face. They require access to high quality and relevant online resources and professionals; thus, there is a need to rectify current gaps in the provision of information and limitations of dissemination. Greater knowledge about depression and its treatment is also needed at the general community level.


BMI in childhood and adolescence is associated with impaired reproductive function-a population-based cohort study from birth to age 50 years.
What is the association between childhood and adolescent BMI and reproductive capacity in women? Adolescent girls with obesity had an increased risk of infertility and childlessness in adulthood independently of their marital status or the presence of polycystic ovary syndrome (PCOS). Girls with obesity (BMI (kg/m2)>95th percentile) more often exhibit menstrual irregularities and infertility problems as compared to those with normal weight, and premenarcheal girls with obesity have an increased risk of childlessness and infertility in adulthood. Follow-up studies on the relation between childhood and adolescence growth patterns and fertility or parity throughout the reproductive life span are limited. A prospective, population-based cohort study (the Northern Finland birth cohort 1966) was performed with 5889 women born in 1966 and followed from birth to age 50 years. Postal questionnaires at ages 31 and 46 years addressed questions on reproductive capacity evaluated by decreased fecundability, need for infertility assessment and treatment by 46 years of age. Childlessness and number of children by age 50 years were recovered from registers. Women who did not report ever having attempted to achieve pregnancy (n = 1507) were excluded. The final study population included 4382 women who attempted to achieve pregnancy before age 46 years. Data on BMI were collected by trained personnel at all stages. We assessed association with both prospectively measured BMI at various time points and with early adiposity phenotypes derived from linear mixed models including the timing and the BMI at adiposity peak (AP) and adiposity rebound (AR). Self-reported infertility assessments and treatments were assessed at ages 31 and 46 years. Data on deliveries were collected from the national birth register. Decreased fecundability was defined at age 31 years as time to achieve pregnancy over 12 months. Logistic regression analyses were conducted with adjustments for marital status, education level and smoking at age 31 years. Women with PCOS were excluded from stratification-based sensitivity analyses. Obesity at a specific age group was defined by having at least one BMI value above the 95th percentile during the related period. BMI at the age of AR (5-7 years) was not associated with fertility outcomes after adjustments, but girls with AR <5.1 years had a higher risk of remaining childless compared to girls with AR over 5.1 years (adjusted odds ratio (OR): 1.45 (1.10-1.92)). At ages 7-10 and 11-15 years, obesity was associated with decreased fecundability (adjusted OR 2.05 (1.26-3.35) and 2.04 (1.21-3.44), respectively) and a lower number of children. At age 11-15 years, both overweight and obesity were associated with a higher risk of childlessness (adjusted OR 1.56 (1.06-2.27), 1.77 (1.02-3.07), respectively), even after excluding women with PCOS. Underweight at age 11-15 years was associated with an increased risk for infertility treatment (adjusted OR 1.55 (1.02-2.36)) and a tendency for an increased risk for infertility assessment (adjusted OR 1.43 (0.97-2.10)) after excluding women with PCOS. Despite a high participation rate throughout the follow-up, some growth data for children over the different age groups were missing. Infertility outcomes were self-reported. A potential over-diagnosis of obesity may have reduced the significance of the association between childhood obesity and fertility outcomes, and the diagnosis of PCOS was self-reported. This study supports previous results showing that girls with obesity in late childhood and in adolescence displayed reduced fertility and an increased risk of remaining childless in adulthood, independently of marital history and PCOS in adulthood. These findings corroborate the body of evidence for a causal relation between early adiposity and the reproductive functions in women. We recommend reinforcing the prevention of obesity in school-age girls to reduce the risk of impaired reproductive functions. NFBC1966 received financial support from University of Oulu Grant no. 65354, Oulu University Hospital Grant no. 2/97, 8/97, Ministry of Health and Social Affairs Grant no. 23/251/97, 160/97, 190/97, National Institute for Health and Welfare, Helsinki Grant no. 54121, Regional Institute of Occupational Health, Oulu, Finland Grant no. 50621, 54231. The Finnish Medical Foundation, the North Ostrobothnia Regional Fund, the Academy of Finland (project grants 315921, 104781, 120315, 129269, 1114194, 24300796), Center of Excellence in Complex Disease Genetics and SALVE, the Sigrid Juselius Foundation, Biocenter Oulu, University Hospital Oulu and University of Oulu (75617), Jalmari ja Rauha Ahokkaan säätiö, The Finnish Medical Foundation, Medical Research Center Oulu, National Institute for Health Research (UK). M. R. J., S. S. and R. N. received funding by the Academy of Finland (#268336) and the European Union's Horizon 2020 research and innovation program (under Grant agreement no. 633595 for the DynaHEALTH action and GA 733206 for LifeCycle). The funders had no role in study design, in the collection, analysis and interpretation of the data, in the writing of the article and in the decision to submit it for publication. The authors have no conflict of interest to disclose. N/A.


Colonic mucosal eosinophilia in children without inflammatory bowel disease.
Children undergoing colonoscopy and mucosal biopsies may show increased colonic mucosal eosinophils, which may or may not be associated with inflammatory bowel disease. There is not much clinical data on American children who have isolated increased colonic mucosal eosinophils. We sought to study the clinical correlates of children without inflammatory bowel disease who show increased mucosal eosinophils to understand their clinical presentation, etiological associations, and outcome. A retrospective analysis of children seen at a tertiary-level Children's hospital was performed by reviewing their medical charts and extracting pertinent data. There were 110 children in the study who had increased colonic mucosal eosinophils. Most children presented with abdominal pain, but several of them also had constipation, blood in stools, and diarrhea. Food allergies, irritable bowel syndrome, asthma, and lactase deficiency were the top four conditions present in these patients. Pathology of the colonic distribution revealed involvement of more than two colonic regions in 86% of the subjects, and only two subjects showing epithelial or crypt involvement by eosinophils. All subjects had a good outcome. Children with colonic mucosal eosinophilia (CME) who do not have an inflammatory bowel disease most frequently present with abdominal pain and primarily an increase of lamina propria eosinophils in two or more colonic regions. Based on the etiological associations we noted in the study, a work-up of children with CME may encompass detailed history for functional gastrointestinal disorders and lactose intolerance, testing for food and environmental allergies, stool examination for parasites, and peripheral blood counts. Almost all children had resolution of symptoms in the studied period suggesting that CME in children has a good clinical outcome.


Spline surface interpolation for calculating 3-D ventricular strains from MRI tissue tagging.
A method is developed and validated for approximating continuous smooth distributions of finite strains in the ventricles from the deformations of magnetic resonance imaging (MRI) tissue tagging "tag lines" or "tag surfaces." Tag lines and intersections of orthogonal tag lines are determined using a semiautomated algorithm. Three-dimensional (3-D) reconstruction of the displacement field on tag surfaces is performed using two orthogonal sets of MRI images and employing spline surface interpolation. The 3-D regional ventricular wall strains are computed from an initial reference image to a deformed image in diastole or systole by defining a mapping or transformation of space between the two states. The resultant mapping is termed the measurement analysis solution and is defined by determining a set of coefficients for the approximating functions that best fit the measured tag surface displacements. Validation of the method is performed by simulating tag line or surface deformations with a finite element (FE) elasticity solution of the heart and incorporating the measured root-mean-square (rms) errors of tag line detection into the simulations. The FE-computed strains are compared with strains calculated by the proposed procedure. The average difference between two-dimensional (2-D) FE-computed strains and strains calculated by the measurement analysis was 0.022 +/- 0.009 or 14.2 +/- 3.6% of the average FE elasticity strain solution. The 3-D displacement reconstruction errors averaged 0.087 +/- 0.002 mm or 2.4 +/- 0.1% of the average FE solution, and 3-D strain fitting errors averaged 0.024 +/- 0.011 or 15.9 +/- 2.8% of the average 3-D FE elasticity solution. When the rms errors in tag line detection were included in the 2-D simulations, the agreement between FE solution and fitted solution was 24.7% for the 2-D simulations and 19.2% for the 3-D simulations. We conclude that the 3-D displacements of MRI tag lines may be reconstructed accurately; however, the strain solution magnifies the small errors in locating tag lines and reconstructing 3-D displacements.


When the world becomes 'too real': a Bayesian explanation of autistic perception.
Perceptual experience is influenced both by incoming sensory information and prior knowledge about the world, a concept recently formalised within Bayesian decision theory. We propose that Bayesian models can be applied to autism - a neurodevelopmental condition with atypicalities in sensation and perception - to pinpoint fundamental differences in perceptual mechanisms. We suggest specifically that attenuated Bayesian priors - 'hypo-priors' - may be responsible for the unique perceptual experience of autistic people, leading to a tendency to perceive the world more accurately rather than modulated by prior experience. In this account, we consider how hypo-priors might explain key features of autism - the broad range of sensory and other non-social atypicalities--in addition to the phenomenological differences in autistic perception.


Development and Evaluation of a TaqMan Real-Time PCR Assay for Fusarium oxysporum f. sp. spinaciae.
Fusarium oxysporum f. sp. spinaciae, causal agent of spinach Fusarium wilt, is an important soilborne pathogen in many areas of the world where spinach is grown. The pathogen is persistent in acid soils of maritime western Oregon and Washington, the only region of the United States suitable for commercial spinach seed production. A TaqMan real-time polymerase chain reaction (PCR) assay was developed for rapid identification and quantification of the pathogen, based on sequencing the intergenic spacer (IGS) region of rDNA of isolates of the pathogen. A guanine single-nucleotide polymorphism (G SNP) was detected in the IGS sequences of 36 geographically diverse isolates of F. oxysporum f. sp. spinaciae but not in the sequences of 64 isolates representing other formae speciales and 33 isolates representing other fungal species or genera. The SNP was used to develop a probe for a real-time PCR assay. The real-time PCR assay detected F. oxysporum f. sp. spinaciae at 3-14,056 CFU/g of soil in 82 soil samples collected over 3 years from naturally infested spinach seed production sites in western Washington, although a reliable detection limit of the assay was determined to be 11 CFU/g of soil. A significant (P < 0.05), positive correlation between enumeration of F. oxysporum on Komada's agar and quantification of the pathogen using the TaqMan assay was observed in a comparison of 82 soil samples. Correlations between pathogen DNA levels, Fusarium wilt severity ratings, and spinach biomass were significantly positive for one set of naturally infested soils but not between pathogen DNA levels, wilt incidence ratings, and spinach biomass for other soil samples, suggesting that soilborne pathogen population is not the sole determinant of spinach Fusarium wilt incidence or severity. The presence of the G SNP detected in one isolate of each of F. oxysporum ff. spp. lageneriae, lilii, melongenae, and raphani and reaction of the real-time PCR assay with 16 of 22 nonpathogenic isolates of F. oxysporum associated with spinach plants or soil in which spinach had been grown potentially limits the application of this assay. Nonetheless, because all isolates of F. oxysporum f. sp. spinaciae tested positive with the real-time PCR assay, the assay may provide a valuable means of screening for resistance to Fusarium wilt by quantifying development of the pathogen in spinach plants inoculated with the pathogen.


The Potential Role of Endogenous Viral Elements in the Evolution of Bats as Reservoirs for Zoonotic Viruses.
Despite a small genome size, bats have comparable diversity of retroviral and non-retroviral endogenous sequences to other mammals. These include Class I and Class II retroviral sequences, foamy viruses, and deltaretroviruses, as well as filovirus, bornavirus, and parvovirus endogenous viral elements. Some of these endogenous viruses are sufficiently preserved in bat genomes to be expressed, with potential effects for host biology. It is clear that the bat immune system differs when compared with other mammals, yet the role that virus-derived endogenous elements may have played in the evolution of bat immunity is poorly understood. In this review, we discuss some of the bat-specific immune mechanisms that may have resulted in a virus-tolerant phenotype and link these to the long-standing virus-host coevolution that may have allowed a large diversity of endogenous retroviruses and other endogenous viral elements to colonize bat genomes. We also consider the possible effects of endogenization in the evolution of the bat immune system.


α-synuclein genetic variability: A biomarker for dementia in Parkinson disease.
The relationship between Parkinson disease (PD), PD with dementia (PDD), and dementia with Lewy bodies (DLB) has long been debated. Although PD is primarily considered a motor disorder, cognitive impairment is often present at diagnosis, and only ∼20% of patients remain cognitively intact in the long term. Alpha-synuclein (SNCA) was first implicated in the pathogenesis of the disease when point mutations and locus multiplications were identified in familial parkinsonism with dementia. In worldwide populations, SNCA genetic variability remains the most reproducible risk factor for idiopathic PD. However, few investigators have looked at SNCA variability in terms of cognitive outcomes. We have used targeted high-throughput sequencing to characterize the 135kb SNCA locus in a large multinational cohort of patients with PD, PDD, and DLB and healthy controls. An analysis of 43 tagging single nucleotide polymorphisms across the SNCA locus shows 2 distinct association profiles for symptoms of parkinsonism and/or dementia, respectively, toward the 3' or the 5' of the SNCA gene. In addition, we define a specific haplotype in intron 4 that is directly associated with PDD. The PDD risk haplotype has been interrogated at single nucleotide resolution and is uniquely tagged by an expanded TTTCn repeat. Our data show that PD, PDD, and DLB, rather than a disease continuum, have distinct genetic etiologies albeit within one genomic locus. Such results may serve as prognostic biomarkers to these disorders, to inform physicians and patients, and to assist in the design and stratification of clinical trials aimed at disease modification. Ann Neurol 2016;79:991-999.


Formation of nanometer-scale grooves in silicon with a scanning tunneling microscope.
Grooves a few nanometers wide can be formed on a Si(111) surface with a scanning tunneling microscope when the tip is above a critical voltage. This may provide a promising approach to nanodevice fabrication. The dependence of the critical voltage on tunneling current, tip polarity, and tip material was studied with silver, gold, platinum, and tungsten tips. The results are consistent with field emission of positive and negative silicon ions. The variation of critical voltage with current is explained quantitatively by a simple tunneling equation that includes the effect of the contact potential between tip and sample.


Persistent C3 vegetation accompanied Plio-Pleistocene hominin evolution in the Malawi Rift (Chiwondo Beds, Malawi).
The development of East African savannas is crucial for the origin and evolution of early hominins. These ecosystems, however, vary widely in their fraction of woody cover and today range from closed woodland to open grassland savanna. Here, we present the first Plio-Pleistocene long-term carbon isotope (δ(13)C) record from pedogenic carbonate and Suidae teeth in the southern East African Rift (EAR). These δ(13)C data from the Chiwondo and Chitimwe Beds (Karonga Basin, Northern Malawi) represent a southern hemisphere record in the EAR, a key region for reconstructing vegetation patterns in today's Zambezian Savanna, and permit correlation with data on the evolution and migration of early hominins in today's Somali-Masai Endemic Zone. The sediments along the northwestern shore of Lake Malawi contain fossils attributed to Homo rudolfensis and Paranthropus boisei. The associated hominin localities (Uraha, Malema) are situated between the well-known hominin bearing sites of the Somali-Masai Endemic Zone in the Eastern Rift and the Highveld Grassland in southern Africa, and fill an important geographical gap for hominin research. Persistent δ(13)C values around -9‰ from pedogenic carbonate and suid enamel covering the last ∼4.3 Ma indicate a C3-dominated closed environment with regional patches of C4-grasslands in the Karonga Basin. The overall fraction of woody cover of 60-70% reflects significantly higher canopy density in the Malawi Rift than the Eastern Rift through time. The discrepancy between the two savanna types originated in the Late Pliocene, when the Somali-Masai ecosystem started to show increasing evidence for open, C4-dominated landscapes. Based on the Malawi δ(13)C data, the evolution of savanna ecosystems in Eastern Africa followed different patterns along the north-south extent of the EAR. The appearance of C4-grasses is considered a driver of evolutionary faunal shifts, but despite the difference of ecosystem evolution in the north, similar hominins and suids occurred in both landscapes, pointing to distinct habitat flexibility and also nutritional versatility.


Prior Podcast Experience Moderates Improvement in Electroencephalography Evaluation After Educational Podcast Module.
There is continued interest in using technology to enhance medical education and the variables that may affect its success. Anesthesiology residents and fourth-year medical students participated in an electroencephalography (EEG) educational video podcast module. A 25-item evaluation tool was administered before any EEG education was provided (baseline), and the podcast was then viewed. Another 25-item evaluation tool was administered after podcast viewing (after podcast). Ten EEG interpretations were completed with a neurophysiologist with an additional 25-item evaluation tool administered after the interpretations (after 10 EEG interpretations). Participants were surveyed concerning technology and podcasting experience before the educational module and their responses to the podcast educational model. Multiple analyses were performed (1) to evaluate differences in improvement in EEG evaluation scores between the podcast module and the standard didactics (control group); and (2) to evaluate potential moderation by technology and the podcast experience on the change in mean EEG evaluation scores from after the podcast module to after 10 EEG interpretations. A total of 21 anesthesiology residents and 12 fourth-year medical students participated. Scores on the 25-item evaluation tool increased with each evaluation time (P ≤ 0.001). Moderation analyses revealed that individuals with more podcast experience (≥4 previous podcasts) had greater increases in scores after a podcast and 10 EEG interpretations compared with individuals with less experience (≤3 previous podcasts) (P = 0.027). Furthermore, compared with a control group with similar baseline characteristics that received only standard didactics without a podcast, those in the podcast group had greater increases in mean EEG evaluation scores between baseline and after 10 EEG interpretations. In reviewing the improvement in EEG evaluation after a podcast education module, those with more podcast experience achieved greater gains in EEG evaluation scores. For EEG education, those receiving the podcast education module showed greater increases in scores compared with those receiving didactic teaching without podcasting, as measured by change in a mean EEG evaluation scores.


A systems framework for remedying dysfunction in US democracy.
Democracy often fails to meet its ideals, and these failures may be made worse by electoral institutions. Unwanted outcomes include elite polarization, unresponsive representatives, and the ability of a faction of voters to gain power at the expense of the majority. Various reforms have been proposed to address these problems, but their effectiveness is difficult to predict against a backdrop of complex interactions. Here we outline a path for systems-level modeling to help understand and optimize repairs to US democracy. Following the tradition of engineering and biology, models of systems include mechanisms with dynamical properties that include nonlinearities and amplification (voting rules), positive feedback mechanisms (single-party control, gerrymandering), negative feedback (checks and balances), integration over time (lifetime judicial appointments), and low dimensionality (polarization). To illustrate a systems-level approach, we analyze three emergent phenomena: low dimensionality, elite polarization, and antimajoritarianism in legislatures. In each case, long-standing rules now contribute to undesirable outcomes as a consequence of changes in the political environment. Theoretical understanding at a general level will also help evaluate whether a proposed reform's benefits will materialize and be lasting, especially as conditions change again. In this way, rigorous modeling may not only shape new lines of research but aid in the design of effective and lasting reform.


Action Sounds Modulate Arm Reaching Movements.
Our mental representations of our body are continuously updated through multisensory bodily feedback as we move and interact with our environment. Although it is often assumed that these internal models of body-representation are used to successfully act upon the environment, only a few studies have actually looked at how body-representation changes influence goal-directed actions, and none have looked at this in relation to body-representation changes induced by sound. The present work examines this question for the first time. Participants reached for a target object before and after adaptation periods during which the sounds produced by their hand tapping a surface were spatially manipulated to induce a representation of an elongated arm. After adaptation, participants' reaching movements were performed in a way consistent with having a longer arm, in that their reaching velocities were reduced. These kinematic changes suggest auditory-driven recalibration of the somatosensory representation of the arm morphology. These results provide support to the hypothesis that one's represented body size is used as a perceptual ruler to measure objects' distances and to accordingly guide bodily actions.


Promoter hypermethylation of CDH13 is a common, early event in human esophageal adenocarcinogenesis and correlates with clinical risk factors.
Although the CDH13 gene has been shown to undergo epigenetic silencing by promoter methylation in many types of tumors, hypermethylation of this gene in Barrett's-associated esophageal adenocarcinogenesis has not been studied. Two hundred fifty-nine human esophageal tissues were therefore examined for CDH13 promoter hypermethylation by real-time methylation-specific PCR. CDH13 hypermethylation showed discriminative receiver-operator characteristic curve profiles, sharply demarcating esophageal adenocarcinoma (EAC) from esophageal squamous cell carcinoma (ESCC) and normal esophagus (NE) (p < 0.0001). CDH13 normalized methylation values (NMV) were significantly higher in Barrett's esophagus (BE), dysplastic BE (D) and EAC than in NE (p < 0.0000001). CDH13 hypermethylation frequency was 0% in NE but increased early during neoplastic progression, rising to 70% in BE, 77.5% in D and 76.1% in EAC. Both CDH13 hypermethylation frequency and its mean NMV were significantly higher in BE with than without accompanying EAC. In contrast, only 5 (19.2%) of 26 ESCCs exhibited CDH13 hypermethylation. Furthermore, both CDH13 hypermethylation frequency and its mean NMV were significantly higher in EAC than in ESCC, as well as in BE or D vs. ESCC. Interestingly, mean CDH13 NMV was significantly lower in short-segment than in long-segment BE, a known clinical risk factor for neoplastic progression. Similarly, BE segment length was significantly lower in specimens with unmethylated than with methylated CDH13 promoters. 5-aza-2'-deoxycytidine treatment of OE33 EAC and KYSE220 ESCC cells reduced CDH13 methylation and increased CDH13 mRNA expression. These findings suggest that hypermethylation of CDH13 is a common, tissue-specific event in human EAC, occurs early during BE-associated neoplastic progression, and correlates with known clinical neoplastic progression risk factors.


STABILIZED1 Modulates Pre-mRNA Splicing for Thermotolerance.
High-temperature stress often leads to differential RNA splicing, thus accumulating different types and/or amounts of mature mRNAs in eukaryotic cells. However, regulatory mechanisms underlying plant precursor mRNA (pre-mRNA) splicing in the environmental stress conditions remain elusive. Herein, we describe that a U5-snRNP-interacting protein homolog STABILIZED1 (STA1) has pre-mRNA splicing activity for heat-inducible transcripts including HEAT STRESS TRANSCRIPTION FACTORs and various HEAT SHOCK PROTEINs for the establishment of heat stress tolerance in Arabidopsis (Arabidopsis thaliana). Our cell-based splicing reporter assay demonstrated STA1 acts on pre-mRNA splicing for specific subsets of stress-related genes. Cellular reconstitution of heat-inducible transcription cascades supported the view that STA1-dependent pre-mRNA splicing plays a role in DREB2A-dependent HSFA3 expression for heat-responsive gene expression. Further genetic analysis with a loss-of-function mutant sta1-1, STA1-expressing transgenic plants in Col background, and STA1-expressing transgenic plants in the sta1-1 background verified that STA1 is essential in expression of necessary genes including HSFA3 for two-step heat stress tolerance in plants. However, constitutive overexpression of the cDNA version of HSFA3 in the sta1-1 background is unable to execute plant heat stress tolerance in sta1-1 Consistently our global target analysis of STA1 showed that its splicing activity modulates a rather broad range of gene expression in response to heat treatment. The findings of this study reveal that heat-inducible STA1 activity for pre-mRNA splicing serves as a molecular regulatory mechanism underlying the plant stress tolerance to high-temperature stress.


Adolescent girls' migration and its impact on early marriage: Qualitative findings in Mali.
Adolescent girls in West Africa are migrating in search of educational and livelihood opportunities. In Mali, early marriage (before the legal age of 16) is a common practice. This paper builds on prior research on female migration that focused on the direct influences of migration on marriage and explores the wider social impact of rising female migration in sending communities by examining direct and indirect effects and intended and unintended consequences. This study examines perceptions about migration among girls and their parents including how it influences marital timing, marriage preparations, marriage practices, and marital relations. Qualitative data were collected from 140 adolescent girls and 115 parents of adolescent girls in rural areas in focus group discussions (FGDs) (n = 31) and in-depth interviews (IDIs) (n = 41) to inform how girls' migration patterns might influence program recruitment strategies and content for an intervention aimed at addressing early marriage in Mali. Our findings concur with earlier studies that migration has direct effects on marriage because it allows girls to both avoid early marriage and prepare for marriage through the assembly of goods and wares to bring to their conjugal homes. Despite some of the perceived risks of migration on marriage, the indirect effects of migration include allowing girls to see different types of marriage practices and marital relationships between husbands and wives and potentially allowing migrant girls to exert more influence over the marital process compared to non-migrants. However, migration can expose girls to new ideas and alternatives that may be incongruent with cultural expectations for them once they return to their communities. This study suggests that migration is seen as an inevitable part of life for many adolescent girls in Mali. Girls who migrate may return to their villages with not only items or income that provide direct benefits to a marriage, but also viewpoints on the expectations for women and girls in their communities that indirectly influence marital relationships. Although this can be challenging for individual returned girls in terms of reintegration, these new expectations may, over time, lead to social changes that influence migrants and non-migrants. Program strategies and approaches must consider the possibility of migration as an important aspect of every adolescent girl's opportunity structure. The qualitative data suggests that certain skills are critical for adolescent girls. Programs should emphasize the acquisition of relevant skills such as communication, risk assessment, negotiation and money management in ways that are relevant for migrants and non-migrants.


20-125Iodo-14,15-epoxyeicosa-5(Z)-enoic acid: a high-affinity radioligand used to characterize the epoxyeicosatrienoic acid antagonist binding site.
Epoxyeicosatrienoic acids (EETs) are endothelium-derived metabolites of arachidonic acid. They relax vascular smooth muscle by membrane hyperpolarization. These actions are inhibited by the EET antagonist, 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EE5ZE). We synthesized 20-(125)iodo-14,15-EE5ZE (20-(125)I-14,15-EE5ZE), a radiolabeled EET antagonist, and characterized its binding to cell membranes. 14,15-EET (10(-9)-10(-5)M) caused a concentration-related relaxation of the preconstricted bovine coronary artery and phosphorylation of p38 in U937 cells that were inhibited by 20-(125)I-14,15-EE5ZE. Specific 20-(125)I-14,15-EE5ZE binding to U937 cell membranes reached equilibrium within 5 min and remained unchanged for 30 min. The binding was saturable and reversible, and it exhibited K(D) and B(max) values of 1.11 +/- 0.13 nM and 1.13 +/- 0.04 pmol/mg protein, respectively. Guanosine 5'-O-(3-thio)triphosphate (10 muM) did not change the binding, indicating antagonist binding of the ligand. Various EETs and EET analogs (10(-10)-10(-5)M) competed for 20-(125)I-14,15-EE5ZE binding with an order of potency of 11,12-EET = 14,15-EET > 8,9-EET = 14,15-EE5ZE > 15-hydroxyeicosatetraenoic acid = 14,15-dihydroxyeicosatrienoic acid. 8,9-Dihydroxyeicosatrienoic acid and 11-hydroxyeicosatetraenoic acid did not compete for binding. The soluble and microsomal epoxide hydrolase inhibitors (1-cyclohexyl-3-dodecyl-urea, elaidamide, and 12-hydroxyl-elaidamide) and cytochrome P450 inhibitors (sulfaphenazole and proadifen) did not compete for the binding. However, two cytochrome P450 inhibitors, N-methylsulfonyl-6-(2-propargyloxyphenyl)hexanamide (MS-PPOH) and miconazole competed for binding with K(i) of 1558 and 315 nM, respectively. Miconazole and MS-PPOH, but not proadifen, inhibited 14,15-EET-induced relaxations. These findings define an EET antagonist's binding site and support the presence of an EET receptor. The inhibition of binding by some cytochrome P450 inhibitors suggests an alternative mechanism of action for these drugs and could lead to new drug candidates that target the EET binding sites.


Menopausal hormone therapy and risk of colorectal cancer.
We evaluated colorectal cancer risk associated with the duration and recency of specific menopausal hormone therapy formulations (i.e., unopposed estrogen versus estrogen plus progestin) and regimens (i.e., sequential versus continuous estrogen plus progestin use) among 56,733 postmenopausal women participating in the Breast Cancer Detection Demonstration Project follow-up study. Hormone therapy use and other risk factors were ascertained through telephone interviews and mailed questionnaires from 1979 to 1998. The final cancer group included 960 women who were identified from self-report, medical records, state registry data, and the National Death Index. Poisson regression was used to generate multivariable rate ratios (RR) and 95% confidence intervals (95% CI). We observed a decreased risk of colorectal cancer among ever users of unopposed estrogen therapy (RR, 0.83; 95% CI, 0.70-0.99). Among estrogen users, the largest reduced risk was observed for current users (RR, 0.75; 95% CI, 0.54-1.05) and users of >or=ten years duration (RR, 0.74; 95% CI, 0.56-0.96). We found a reduced risk among users of estrogen plus progestin therapy (RR, 0.78; 95% CI, 0.60-1.02), with sequential regimen users (progestin <15 days per cycle) having the largest risk reduction (RR, 0.64; 95% CI, 0.43-0.95). Past users of >or=5 years ago (RR, 0.55; 95% CI, 0.32-0.98) had the largest risk reduction. In this study, estrogen plus progestin use, especially sequential regimen use, was associated with the largest overall reduction of colorectal cancer risk.


Edge detection in microscopy images using curvelets.
Despite significant progress in imaging technologies, the efficient detection of edges and elongated features in images of intracellular and multicellular structures acquired using light or electron microscopy is a challenging and time consuming task in many laboratories. We present a novel method, based on the discrete curvelet transform, to extract a directional field from the image that indicates the location and direction of the edges. This directional field is then processed using the non-maximal suppression and thresholding steps of the Canny algorithm to trace along the edges and mark them. Optionally, the edges may then be extended along the directions given by the curvelets to provide a more connected edge map. We compare our scheme to the Canny edge detector and an edge detector based on Gabor filters, and show that our scheme performs better in detecting larger, elongated structures possibly composed of several step or ridge edges. The proposed curvelet based edge detection is a novel and competitive approach for imaging problems. We expect that the methodology and the accompanying software will facilitate and improve edge detection in images available using light or electron microscopy.


Exploration of Structured Symmetric Cyclic Peptides as Ligands for Metal-Organic Frameworks.
Despite remarkable advances in the assembly of highly structured coordination polymers and metal-organic frameworks, the rational design of such materials using more conformationally flexible organic ligands such as peptides remains challenging. In an effort to make the design of such materials fully programmable, we first developed a computational design method for generating metal-mediated 3D frameworks using rigid and symmetric peptide macrocycles with metal-coordinating sidechains. We solved the structures of six crystalline networks involving conformationally constrained 6 to 12 residue cyclic peptides with C2, C3, and S2 internal symmetry and three different types of metals (Zn2+, Co2+, or Cu2+) by single-crystal X-ray diffraction, which reveals how the peptide sequences, backbone symmetries, and metal coordination preferences drive the assembly of the resulting structures. In contrast to smaller ligands, these peptides associate through peptide-peptide interactions without full coordination of the metals, contrary to one of the assumptions underlying our computational design method. The cyclic peptides are the largest peptidic ligands reported to form crystalline coordination polymers with transition metals to date, and while more work is required to develop methods for fully programming their crystal structures, the combination of high chemical diversity with synthetic accessibility makes them attractive building blocks for engineering a broader set of new crystalline materials for use in applications such as sensing, asymmetric catalysis, and chiral separation.


Nonlinearity of two-photon Ca2+ imaging yields distorted measurements of tuning for V1 neuronal populations.
We studied the relative accuracy of drifting gratings and noise stimuli for functionally characterizing neural populations using two-photon calcium imaging. Calcium imaging has the potential to distort measurements due to nonlinearity in the conversion from spikes to observed fluorescence. We demonstrate a dramatic impact of fluorescence saturation on functional measurements in ferret V1 by showing that responses to drifting gratings strongly violate contrast invariance of orientation tuning, a fundamental property of the spike rates. The observed relationship is consistent with saturation that clips the high-contrast tuning curve peaks by ∼40%. The nonlinearity was also apparent in mouse V1 responses to drifting gratings, but not as strong as in the ferret. Contrast invariance holds, however, for tuning curves measured with a randomized grating stimulus. This finding is consistent with prior work showing that the linear portion of a linear-nonlinear system can be recovered with reverse correlation. Furthermore, we demonstrate that a noise stimulus is more effective at keeping spike rates in the linear operating regime of a saturating nonlinearity, which both maximizes signal-to-noise ratios and simplifies the recovery of fast spike dynamics from slow calcium transients. Finally, we uncover spatiotemporal receptive fields by removing the nonlinearity and slow calcium transient from a model of fluorescence generation, which allowed us to observe dynamic sharpening of orientation tuning. We conclude that for two-photon recordings it is imperative that one considers the nonlinear distortion when designing stimuli and interpreting results, especially in sensory areas, species, or cell types with high firing rates.


Virtual reality training in neurosurgery: Review of current status and future applications.
Over years, surgical training is changing and years of tradition are being challenged by legal and ethical concerns for patient safety, work hour restrictions, and the cost of operating room time. Surgical simulation and skill training offer an opportunity to teach and practice advanced techniques before attempting them on patients. Simulation training can be as straightforward as using real instruments and video equipment to manipulate simulated "tissue" in a box trainer. More advanced virtual reality (VR) simulators are now available and ready for widespread use. Early systems have demonstrated their effectiveness and discriminative ability. Newer systems enable the development of comprehensive curricula and full procedural simulations. A PubMed review of the literature was performed for the MESH words "Virtual reality, "Augmented Reality", "Simulation", "Training", and "Neurosurgery". Relevant articles were retrieved and reviewed. A review of the literature was performed for the history, current status of VR simulation in neurosurgery. Surgical organizations are calling for methods to ensure the maintenance of skills, advance surgical training, and credential surgeons as technically competent. The number of published literature discussing the application of VR simulation in neurosurgery training has evolved over the last decade from data visualization, including stereoscopic evaluation to more complex augmented reality models. With the revolution of computational analysis abilities, fully immersive VR models are currently available in neurosurgery training. Ventriculostomy catheters insertion, endoscopic and endovascular simulations are used in neurosurgical residency training centers across the world. Recent studies have shown the coloration of proficiency with those simulators and levels of experience in the real world. Fully immersive technology is starting to be applied to the practice of neurosurgery. In the near future, detailed VR neurosurgical modules will evolve to be an essential part of the curriculum of the training of neurosurgeons.


A phenotypic high-content, high-throughput screen identifies inhibitors of NLRP3 inflammasome activation.
Inhibition of the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome has recently emerged as a promising therapeutic target for several inflammatory diseases. After priming and activation by inflammation triggers, NLRP3 forms a complex with apoptosis-associated speck-like protein containing a CARD domain (ASC) followed by formation of the active inflammasome. Identification of inhibitors of NLRP3 activation requires a well-validated primary high-throughput assay followed by the deployment of a screening cascade of assays enabling studies of structure-activity relationship, compound selectivity and efficacy in disease models. We optimized a NLRP3-dependent fluorescent tagged ASC speck formation assay in murine immortalized bone marrow-derived macrophages and utilized it to screen a compound library of 81,000 small molecules. Our high-content screening assay yielded robust assay metrics and identified a number of inhibitors of NLRP3-dependent ASC speck formation, including compounds targeting HSP90, JAK and IKK-β. Additional assays to investigate inflammasome priming or activation, NLRP3 downstream effectors such as caspase-1, IL-1β and pyroptosis form the basis of a screening cascade to identify NLRP3 inflammasome inhibitors in drug discovery programs.


Telomerase activity in human hematopoietic progenitor cells.
Telomerase is the enzyme that stabilizes and elongates the telomeric ends of chromosomes. It is expressed in germline and malignant cells and absent in most human somatic cells. The selective expression of telomerase has thus been proposed to be a basis for the immortality of germline and malignant cells. Recently, telomerase activity has been observed in human bone marrow (BM) and peripheral blood (PB) samples. The objective of our study was to further characterize the telomerase-expressing population in BM and PB. CD34+ cells were isolated from BM and PB, cultured in vitro, and telomerase activity was assessed by the PCR-based TRAP assay. Telomerase activity in human BM and PB could be almost exclusively assigned to the hematopoietic progenitor cell fraction expressing the CD34 antigen. We observed telomerase activity in CD34+ cells from BM and cytokine-mobilized PB. CD34+ cells lacking co-expression of CD33 demonstrated higher levels of telomerase than myeloid committed CD34+/CD33+ cells. In vitro culture of CD34+ cells in the presence of a cocktail of growth factors inducing differentiation resulted in a decrease of telomerase activity. Telomerase activity increased in peripheral blood during cytokine-induced mobilization of hematopoietic progenitor cells. Our data demonstrate that at least a portion of the hematopoietic stem/progenitor cell fraction expresses telomerase and downregulates its expression through differentiation.


The Functions of Histone Modification Enzymes in Cancer.
Posttranslational modifications of proteins critically regulate the function, localization, and stability of target proteins. Histone modification is one of the regulatory mechanisms that modulate the chromatin structure and thereby affect various DNA-templated processes, such as gene transcription, DNA replication, DNA recombination, and DNA repair in cells. These molecular processes contribute to basic cellular functions, including cell cycle, cell growth, and apoptosis. Histone modifications consist of acetylation, methylation, phosphorylation, ubiquitination, sumoylation biotination, citrullination, poly-ADPribosylation, and N-glycosylation. The modification status of histone is balanced by two enzyme families with opposing catalytic activities: histone modifying and de-modifying enzymes. Recent studies have shown that dysfunction of histone modification enzymes is a major cause for human cancer initiation and progression. In this review, we will summarize the functions of histone modification enzymes in cancer, and the mechanisms that histone modification enzymes use to drive or suppress human malignancies.


The Impact of Nighttime on First Pass Success During the Emergent Endotracheal Intubation of Critically Ill Patients.
While numerous investigations have described worse outcomes for patients undergoing emergent procedures at night, few studies have investigated the impact of nighttime on the outcomes of emergent endotracheal intubation (EEI). We hypothesized that for patients requiring EEI at night, the outcome of first pass success would be lower as compared to during the day. We performed a retrospective cohort study of all patients admitted to our institution between January 1st, 2016 and July 17st, 2019 who underwent EEI outside of an emergency department or operating room. Nighttime was defined as between 7:00 pm and 6:59 am. The primary outcome was the rate of first pass success. Logistic regression was utilized with adjustment for demographic, morbidity and procedure related covariables. The final examined cohort included 1,674 EEI during the day and 1,229 EEI at night. The unadjusted rate of first pass success was not different between the day and night (77.5% vs. 74.6%, unadjusted odds ratio (OR): 0.85; 95% confidence interval (CI): 0.72, 1.0; P = 0.073 though following adjustment for prespecified covariables the odds of first pass success was lower at night (adjusted OR: 0.83, 95% CI: 0.69, 0.99; P = 0.042. Obesity was found to be an effect modifier on first pass success rate for day vs. night intubations. In obese patients, nighttime intubations had significantly lower odds of first pass success (adjusted OR: 0.71, 95% CI: 0.52, 0.98; P = 0.037). After adjustment for patient and procedure related factors, we have found that the odds of first pass success is lower at night as compared to the day. This finding was, to some degree, driven by obesity which was found to be a significant effect modifier in this relationship.


Genomic DNA extraction from medicinal plants available in Malaysia using a TriOmic(TM) improved extraction kit.
DNA extraction was carried out on 32 medicinal plant samples available in Malaysia using the TriOmic(TM) extraction kit. Amounts of 0.1 g flowers or young leaves were ground with liquid nitrogen, lysed at 65°C in RY1(plus) buffer and followed by RNAse treatment. Then, RY2 buffer was added to the samples and mixed completely by vortexing before removal of cell debris by centrifugation. Supernatants were transferred to fresh microcentrifuge tubes and 0.1 volume RY3 buffer was added to each of the transferred supernatant. The mixtures were applied to spin columns followed by a centrifugation step to remove buffers and other residues. Washing step was carried out twice by applying 70% ethanol to the spin columns. Genomic DNA of the samples was recovered by applying 50 μL TE buffer to the membrane of each spin column, followed by a centrifugation step at room temperature. A modification of the TriOmic(TM) extraction procedure was carried out by adding chloroform:isoamyl alcohol (24:1) steps in the extraction procedure. The genomic DNA extracted from most of the 32 samples showed an increase of total yield when chloroform:isoamyl alcohol (24:1) steps were applied in the TriOmicTM extraction procedure. This preliminary study is very important for molecular studies of medicinal plants available in Malaysia since the DNA extraction can be completed in a shorter period of time (within 1 h) compared to manual extraction, which entails applying phenol, chloroform and ethanol precipitation, and requires 1-2 days to complete.


Risk of recurrence estimates with IHC4+C are tolerant of variations in staining and scoring: an analytical validity study.
The IHC4+C score combines assessment of oestrogen receptor (ER), progesterone receptor (PgR), HER2 and Ki67 with clinicopathological parameters to identify the risk of distant disease recurrence in patients with breast cancer, so, aiding treatment decision-making on adjuvant chemotherapy. Despite low cost and wide availability, the reported use of IHC4+C remains limited; one explanation for this is the perception that immunohistochemistry (IHC)-based methods and assessment of them lack precision, reproducibility and portability. We examined the effects of decentralised testing and easily reproducible estimate-based scoring methods on IHC4+C scores to determine its suitability for wider adoption. Sections from a breast cancer tissue micro-array (TMA) were distributed to three centres undertaking diagnostic breast cancer IHC. Centres stained sections using their standard procedures, and returned them for central assessment. The results were compared with those obtained at IHC4+C's originating hospital (Royal Marsden Hospital (RMH)). In parallel, TMA sections stained at RMH were scored by a variety of simplified non-counting-based methods. The results were compared with those produced using counting. There was a high degree of correlation between individual IHC results produced by external centres and those of RMH (r: 0.797-0.982), and between risk of distant recurrence scores derived from them (r: 0.972-0.984). Scoring methods for ER and PgR could be adapted to require less precision without significantly affecting correlation with counted results (r: 0.933 and 0.980, respectively), but correlation between estimating and counting for Ki67 was poorer (r: 0.855). IHC4+C is tolerant of variation in staining and scoring methods. Although additional confirmatory comparative studies are required, these data support use of IHC4+C in clinical practice outside RMH.


Neurovascular coupling during cognitive activity in adults with controlled hypertension.
Hypertension, even when controlled, may accelerate arterial stiffening and impair the ability of the cerebrovasculature to increase blood flow to support neural activity, i.e., neurovascular coupling (NVC). Optimal NVC depends on continuous, nonpulsatile flow, which is partially determined by extra- and intracranial vessel function. We sought to compare extra- and intracranial hemodynamics during cognitive activity (Stroop task) in 30 middle-aged, well-controlled medicated hypertensive and 30 age-, sex-, and body mass index (BMI)-matched nonhypertensive adults (56 ± 6 years, 28.2 ± 2.9 kg/m2 BMI; 32 men). Aortic and carotid (single point) pulse wave velocity (PWV) were assessed via tonometry and ultrasound, respectively. Carotid and middle cerebral artery (MCA) blood velocity pulsatility were measured via ultrasound and Doppler. Prefrontal cortex (PFC) oxygenation was measured via tissue saturation index (TSI) using near-infrared spectroscopy. Accuracy and reaction times were computed to assess cognitive performance. Stroop performance was similar between groups ( P > 0.01). Aortic and carotid PWV increased, carotid flow pulsatility decreased ( P < 0.01), and MCA flow pulsatility and PFC TSI were maintained during Stroop ( P > 0.01). Our findings indicate that middle-age adults with medically controlled hypertension and adults without hypertension demonstrate similar intra- and extracranial cerebrovascular reactivity during cognitive engagement. Despite increases in large artery stiffness, middle-aged adults with controlled hypertension and without hypertension exhibit reductions in extracranial flow pulsatility during cognitive engagement that may be part of a concerted cerebrovascular response to support downstream cerebral oxygenation and overall NVC. NEW & NOTEWORTHY Hypertension is associated with accelerated arterial stiffening, which may alter extra- and intracranial vascular reactivity during cognitive activity and impair neurovascular coupling. Middle-aged adults with medicated hypertension exhibit similar neurovascular coupling and extra-/intracranial vascular reactivity during sustained cognitive activity. Extracranial modulation of central hemodynamics may be an important component of optimal neurovascular coupling.


Frequency and etiology of solitary hot spots in the pelvis at whole-body positron emission tomography/computed tomography imaging.
To determine the frequency and etiology of a single hypermetabolic focus within the pelvis with no other areas of increased 18-fluorodeoxyglucose (FDG) uptake in the reminder of the whole body in an oncological population. We retrospectively examined the first 700 whole-body PET/CT scans performed at our institution for baseline staging or follow-up of cancer and identified all patients with a solitary focus of increased FDG uptake in the pelvis. All available medical records and imaging findings in these patients were reviewed in order to determine the etiology of increased FDG uptake. Eight (1.1%) of the 700 patients had a solitary hot spot in the pelvis at positron emission tomography (PET)/computed tomography (CT) imaging, consisting of seven of 380 women and one of 320 men. In the seven women, increased FDG uptake was due to physiological endometrial uptake (n=2), leiomyoma (n=1), corpus luteum cyst (n=1), physiological ovarian uptake (n=1), urinary leak (n=1), and nonspecific colitis (n=1). In the man, uptake was due to recurrent rectosigmoid adenocarcinoma. None of the 700 patients was found to have metastatic disease in the pelvis. Isolated pelvic hot spots at PET/CT imaging in an oncological population are not common and usually benign; physiological endometrial or ovarian uptake is the single commonest cause.


Cancer-Related Anemia and Frailty in Older Persons.
Anemia, defined by the World Health Organization as a hemoglobin concentration lower than 13 g/dL in men and 12 g/dL in women, is particularly prevalent at advanced age. Nevertheless, it is not a condition simply explained by the normal aging process. Anemia represents a potentially reversible condition associated with numerous adverse health-related events, including hospitalization, disability, and mortality in older persons. Low haemoglobin concentrations are particularly common among patients with cancer due to direct (e.g., micro- and macroscopic blood losses) and indirect causes (e.g., increased production of pro-inflammatory cytokines with consequent reduction of erythropoietin release and erythropoiesis). The impaired oxygen-carrying capacity caused by the presence of anemia may play a major role in multiple clinical manifestations of cancer, such as dyspnea, fatigue, exhaustion, dizziness and/or headache. In the present review, we discuss the importance of low hemoglobin concentrations and anemia as important determinants of the frailty syndrome, a condition commonly present among cancer patients. Treatment of cancer-related anemia may improve quality of life and health-related outcomes (including disability and mortality) in older patients with oncological conditions.


Adverse events associated with nevirapine and efavirenz-based first-line antiretroviral therapy: a systematic review and meta-analysis.
Since 2002, the WHO has recommended either nevirapine (NVP) or efavirenz (EFV) as part of first-line antiretroviral therapy. These two drugs are known to have differing toxicity profiles, but the risk of these toxicities overall is not well established. We systematically reviewed adverse events among treatment-naive HIV-positive adults and children receiving either NVP or EFV as part of first-line antiretroviral therapy. The primary outcome was drug discontinuation as a result of any adverse event; specific toxicities were evaluated as secondary outcomes. Point estimates and 95% confidence intervals (95% CIs) were calculated and proportions and odds ratios (ORs) pooled using fixed-effects meta-analysis. We reviewed data on 26,446 adults and 3975 children from eight randomized trials and 26 prospective cohorts. Overall, adults on NVP were more than two times more likely to discontinue treatment due to any adverse event compared to patients on EFV (OR 2.2, 95% CI 1.9-2.6). Severe hepatotoxicity (OR 3.3, 95% CI 2.5-4.2), severe skin toxicity (OR 3.9, 95% CI 2.5-5.4), and severe hypersensitivity reactions (OR 2.4, 95% CI 1.9-2.9) were more likely to occur among patients on NVP. Patients receiving EFV were more likely to experience severe central nervous system events (OR 3.4, 95% CI 2.1-5.4). Similar associations were seen in children. Compared to NVP, EFV is associated with a lower frequency of severe adverse events, in particular treatment discontinuations. This finding supports a move toward EFV-based therapy as the preferred first-line treatment regimen for HIV treatment within a public health approach.


An improved refractive index sensor based on genetic optimization of plasmon waveguide resonance.
Plasmon waveguide resonance (PWR) sensors are particularly useful for biosensing due to their unique ability to perform sensing with two different polarizations. In this paper we report a comprehensive performance comparison between the surface plasmon resonance (SPR) sensor and the PWR sensor in terms of the sensitivity and the refractive index resolution. Both sensors were optimized using a genetic algorithm to acquire their best performance for bulk sensing applications. The experimental results show that the PWR sensor has a refractive index resolution of 5 × 10(-7) RIU which is 6 times smaller than that of the optimized SPR sensor. The TE polarization in the PWR sensor has a resolution of 1.4 × 10(-6) RIU which is smaller than the SPR sensor. The polarization diversity in the PWR sensor is another advantage which can be used to improve the measurement reliability.


Lung tumor promotion by curcumin.
Curcumin exhibits anti-inflammatory and antitumor activity and is being tested in clinical trials as a chemopreventive agent for colon cancer. Curcumin's chemopreventive activity was tested in a transgenic mouse model of lung cancer that expresses the human Ki-ras(G12C) allele in a doxycycline (DOX) inducible and lung-specific manner. The effects of curcumin were compared with the lung tumor promoter, butylated hydroxytoluene (BHT), and the lung cancer chemopreventive agent, sulindac. Treatment of DOX-induced mice with dietary curcumin increased tumor multiplicity (36.3 +/- 0.9 versus 24.3 +/- 0.2) and progression to later stage lesions, results which were similar to animals that were co-treated with DOX/BHT. Microscopic examination showed that the percentage of lung lesions that were adenomas and adenocarcinomas increased to 66% in DOX/BHT, 66% in DOX/curcumin and 49% in DOX/BHT/curcumin-treated groups relative to DOX only treated mice (19%). Immunohistochemical analysis also showed increased evidence of inflammation in DOX/BHT, DOX/curcumin and DOX/BHT/curcumin mice relative to DOX only treated mice. In contrast, co-treatment of DOX/BHT mice with 200 p.p.m. [DOSAGE ERROR CORRECTED] of sulindac inhibited the progression of lung lesions and reduced the inflammation. Lung tissue from DOX/curcumin-treated mice demonstrated a significant increase (33%; P = 0.01) in oxidative damage, as assessed by the levels of carbonyl protein formation, relative to DOX-treated control mice after 1 week on the curcumin diet. These results suggest that curcumin may exhibit organ-specific effects to enhance reactive oxygen species formation in the damaged lung epithelium of smokers and ex-smokers. Ongoing clinical trials thus may need to exclude smokers and ex-smokers in chemopreventive trials of curcumin.


Long-lived dichotomous lineages of the proteasome subunit beta type 8 (PSMB8) gene surviving more than 500 million years as alleles or paralogs.
On an evolutionary time scale, polymorphic alleles are believed to have a short life, persisting at most tens of millions of years even under long-term balancing selection. Here, we report highly diverged trans-species dimorphism of the proteasome subunit beta type 8 (PSMB8) gene, which encodes a catalytic subunit of the immunoproteasome responsible for the generation of peptides presented by major histocompatibility complex (MHC) class I molecules, in lower teleosts including Cypriniformes (zebrafish and loach) and Salmoniformes (trout and salmon), whose last common ancestor dates to 300 Ma. Moreover, phylogenetic analyses indicated that these dimorphic alleles share lineages with two shark paralogous genes, suggesting that these two lineages have been maintained for more than 500 My either as alleles or as paralogs, and that conversion between alleles and paralogs has occurred at least once during vertebrate evolution. Two lineages termed PSMB8A and PSMB8F show an A(31)F substitution that would probably affect their cleaving specificity, and whereas the PSMB8A lineage has been retained by all analyzed jawed vertebrates, the PSMB8F lineage has been lost by most jawed vertebrates except for cartilaginous fish and basal teleosts. However, a possible functional equivalent of the PSMB8F lineage has been revived as alleles within the PSMB8A lineage at least twice during vertebrate evolution in the amphibian Xenopus and teleostean Oryzias species. Dynamic evolution of the PSMB8 polymorphism through long-term persistence, loss, and regaining of dimorphism and conversion between alleles and paralogs implies the presence of strong selective pressure for functional polymorphism of this gene.


hrpf of Xanthomonas campestris pv. vesicatoria encodes an 87-kDa protein with homology to NoIX of Rhizobium fredii.
The gram-negative bacterium Xanthomonas campestris pv. vesicatoria is the causal agent of bacterial spot disease on pepper and tomato plants. The main hrp (hypersensitive reaction and pathogenicity) gene cluster in X. campestris pv. vesicatoria spans a 23-kb chromosomal region, comprising six complementation groups designated hrpA to hrpF. Analysis of the hrpF locus revealed a single open reading frame encoding HrpF (86.4 kDa). HrpF is predominantly hydrophilic, and contains two hydrophobic domains in the C terminus. An interesting feature is the presence of two imperfect direct repeats in the N-terminal region. Deletion studies showed that one repeat is sufficient for function. Epitope tagging of HrpF allowed detection of the protein in X. campestris pv. vesicatoria. Subcellular localization studies suggest that HrpF is both in the soluble fraction and in the inner membrane. Interestingly, HrpF is 48% identical (67% similar) to the Rhizobium fredii NoIX protein that is part of the host specificity locus. Since several Hrp proteins are believed to be components of the types of III hrp protein secretion apparatus, allowing export of proteins essential for the interaction with the plant, the possible role of hrpF and NoIX in secretion is discussed.


Increased risk of stroke and transient ischemic attack in 5-year survivors of Hodgkin lymphoma.
Information on clinically verified stroke and transient ischemic attack (TIA) following Hodgkin lymphoma is scarce. We quantified the long-term risk of cerebrovascular disease associated with the use of radiotherapy and chemotherapy in survivors of Hodgkin lymphoma and explored potential pathogenic mechanisms. We performed a retrospective cohort study among 2201 five-year survivors of Hodgkin lymphoma treated before age 51 between 1965 and 1995. We compared incidence rates of clinically verified stroke and TIA with those in the general population. We used multivariable Cox regression techniques to study treatment-related factors and other risk factors. All statistical tests were two-sided. After a median follow-up of 17.5 years, 96 patients developed cerebrovascular disease (55 strokes, 31 TIAs, and 10 with both TIA and stroke; median age = 52 years). Most ischemic events were from large-artery atherosclerosis (36%) or cardioembolisms (24%). The standardized incidence ratio for stroke was 2.2 (95% confidence interval [CI] = 1.7 to 2.8), and for TIA, it was 3.1 (95% CI = 2.2 to 4.2). The risks remained elevated, compared with those in the general population, after prolonged follow-up. The cumulative incidence of ischemic stroke or TIA 30 years after Hodgkin lymphoma treatment was 7% (95% CI = 5% to 8%). Radiation to the neck and mediastinum was an independent risk factor for ischemic cerebrovascular disease (hazard ratio = 2.5, 95% CI = 1.1 to 5.6 vs without radiotherapy). Treatment with chemotherapy was not associated with an increased risk. Hypertension, diabetes mellitus, and hypercholesterolemia were associated with the occurrence of ischemic cerebrovascular disease, whereas smoking and overweight were not. Patients treated for Hodgkin lymphoma experience a substantially increased risk of stroke and TIA, associated with radiation to the neck and mediastinum. Physicians should consider appropriate risk-reducing strategies.


Universal fractality of morphological transitions in stochastic growth processes.
Stochastic growth processes give rise to diverse and intricate structures everywhere in nature, often referred to as fractals. In general, these complex structures reflect the non-trivial competition among the interactions that generate them. In particular, the paradigmatic Laplacian-growth model exhibits a characteristic fractal to non-fractal morphological transition as the non-linear effects of its growth dynamics increase. So far, a complete scaling theory for this type of transitions, as well as a general analytical description for their fractal dimensions have been lacking. In this work, we show that despite the enormous variety of shapes, these morphological transitions have clear universal scaling characteristics. Using a statistical approach to fundamental particle-cluster aggregation, we introduce two non-trivial fractal to non-fractal transitions that capture all the main features of fractal growth. By analyzing the respective clusters, in addition to constructing a dynamical model for their fractal dimension, we show that they are well described by a general dimensionality function regardless of their space symmetry-breaking mechanism, including the Laplacian case itself. Moreover, under the appropriate variable transformation this description is universal, i.e., independent of the transition dynamics, the initial cluster configuration, and the embedding Euclidean space.


Phenotypic traits of mesenchymal stem cell sheets fabricated by temperature-responsive cell culture plate: structural characteristics of MSC sheets.
In most stem cell therapy strategies reported to date, stem cells are introduced to damaged tissue sites to repair and regenerate the original tissue structure and function. MSC therapeutic efficacies are inconsistent, largely attributed to transplanted MSC difficulties both in engrafting at tissue sites and in retaining their therapeutic functions from suspension formulations. MSC functional components, including cell adhesion and cell-cell junction proteins, and ECM that contribute to essential cellular therapeutic effects, are damaged or removed by proteolytic enzymes used in stem cell harvesting strategies from culture. To overcome these limitations, methods to harvest and transplant cells without disrupting critical stem cell functions are required. Cell sheet technology, exploiting temperature-responsive cell culture surfaces, permits cell harvest without cell protein damage. This study is focused on phenotypic traits of MSC sheets structurally and functionally to understand therapeutic benefits of cell sheets. This study verified cleaved cellular proteins (vinculin, fibronectin, laminin, integrin β-1, and connexin 43) and increased apoptotic cell death produced under standard trypsin harvesting treatment in a time-dependent manner. However, MSC sheets produced without trypsin using only temperature-controlled sheet harvest from culture plastic exhibited intact cellular structures. Also, MSCs harvested using enzymatic treatment (i.e., chemical disruption) showed higher pYAP expression compared to MSC sheets. Retention of cellular structures such as ECM, cell-cell junctions, and cell-ECM junctions is correlated with human umbilical cord mesenchymal stem cell (hUC-MSC) survival after detachment from cell culture surfaces. Retaining these proteins intact in MSC cultures using cell sheet technology is proposed to enhance stem cell survival and their function in stem cell-based therapy.


The efficacy of two electrodes radiofrequency technique: comparison study using a cadaveric interspinous ligament and temperature measurement using egg white.
One technique in radiofrequency neurotomies uses 2 electrodes that are simultaneously placed to lie parallel to one another. Comparing lesions on cadaveric interspinous ligament tissue and measuring the temperature change in egg white allows us to accurately measure quantitatively the area of the lesion. Fresh cadaver spinal tissue and egg white tissue were used. A series of samples were prepared with the electrodes placed 1 to 7 mm apart. Using radiofrequency, the needle electrodes were heated in sequential or simultaneous order and the distance of the escaped lesion area and temperature were measured. Samples of cadaver interspinous ligament showed sequential heating of the needles limits the placement of the needle electrodes up to 2 mm apart from each other and up to 4 mm apart when heated simultaneously. The temperature at the escaped lesion area decreased according to the distance for egg white. There was a significant difference in temperature at the escaped lesion area up to 6 mm apart and the temperature was above 50 degrees celsius up to 5 mm in simultaneous lesion and 3 mm in the sequential lesion. The limitations of this study include cadaveric experimentation and use of intraspinous ligament rather than medial branch of the dorsal ramus which is difficult to identify. Heating the 2 electrodes simultaneously appears to coagulate a wider area and potentially produce better results in less time.