Frequency and tendency of malaria in Colombia, 1990 to 2011: a descriptive study.
Malaria is a serious health problem in Colombia. This paper intends to analyse the frequency and tendencies of the disease in Colombia over the last 22 years. The researchers used the Box-Jenkins (ARIMA) methodology for the analysis of time series. This descriptive study was done retrospectively by using the morbidity records of the Ministry of Health and of the System for the Monitoring of Public Health (SIVIGILA). The information about the population was obtained from the National Administrative Department of Statistics (DANE). The incidence rate according to age and sex was calculated from 1990 to 2011. Also, the Annual Parasite Index (API) for Plasmodium falciparum and for Plasmodium vivax was calculated. The mortality rates per year, from 1990 to 2011, were determined. Finally, the Box-Jenkins (ARIMA) methodology was used for the analysis of time series, grouped weekly. Information for ARIMA modelling was used from the year 2001. The total number of reported cases from 1990 to 2011 was 2,964,818 cases with an annual average of 134,764. In the period from 2001 to 2005 and from 2006 to 2011 a significant decrease of annual cases was observed. In general, a predominance of P. vivax over P. falciparum was observed. With respect to the API, it must be noted that there were peaks in 1994 in the departments of Guainía and Guaviare, and in 1998 in Guaviare and Chocó. The department of Antioquia showed a tendency towards a decrease of the API through the years.In the time series model there were no statistically significant seasonal patterns for the total number of cases of malaria. However, for P. falciparum the number of cases was statistically significant. Lastly, between 1990 and 2009, there were 1,905 deaths caused by malaria in Colombia with a significant tendency towards a decrease in deaths over those years. Plasmodium falciparum was more lethal than P. vivax. In Colombia, the transmission of malaria occurs in an endemic and epidemic context, which keeps an unstable endemic transmission pattern. Several factors specific to a country such as Colombia encourage the dissemination and permanence of the illness.


Up-regulating pyocyanin production by amino acid addition for early electrochemical identification of Pseudomonas aeruginosa.
This work focuses on developing a faster method for electrochemically detecting a Pseudomonas aeruginosa infection through the addition of amino acids to cell culture samples. We performed square-wave voltammetry measurements of pyocyanin produced by P. aeruginosa using commercially available carbon-based electrodes connected to a Ag/AgCl reference. The electrochemical response resulting from the production of pyocyanin by bacteria was measured in the presence of various amino acids while varying three different culturing parameters: liquid media type (trypticase soy broth vs. M63 minimal media); concentration of amino acids in the solution; and initial concentration of the P. aeruginosa in the solution. Our results demonstrate a faster and stronger electrochemical response in media containing tyrosine and valine at elevated concentrations, lending promise to using amino acids as up-regulatory molecules for faster bacterial detection.


Extended phenotypes on coral reefs: cryptic phenotypes modulate coral-vermetid interactions.
Phenotypic variation can lead to variation in the strength and outcome of species interactions. Variation in phenotypic traits can arise due to plastic responses to environmental stimuli, underlying genetic variation, or both, and may reflect differences in the focal organism or aspects of the extended phenotype (e.g., associated microbes). We used a reciprocal transplant experiment of Porites corals to evaluate the role of plasticity vs. heritable diversity on phenotypic traits and performance of corals that varied in their prior exposure to vermetid gastropods, an organism known to reduce coral growth and survival. We measured a suite of phenotypic traits associated with coral performance, many of which showed a plastic response to vermetid exposure. Vermetids decreased calcification of corals, increased microbial diversity, and shifted microbial composition. Most traits also showed a signature of previous exposure environment that persisted even when exposure was reversed: i.e., under the same conditions, corals naïve to vermetids had slower calcification rates, thicker tissues, higher Symbiodiniaceae densities, and different microbiomes than corals previously exposed to vermetids. We suggest the phenotypic differences are heritable, as reefs with and without vermetids were comprised of two different mitotypes, that revealed high, consistent genetic variation. Vermetids were only found on the fast-growing coral mitotype that was characterized by thin tissue, and that likely had a history of disturbance. As extended phenotypes can have community impacts, we suggest vermetid, in addition to microbes, are part of the extended community phenotype of these corals. Coral genotypes can establish different reef trajectories, with thin-tissue types more prone to disturbance and subsequent colonization by other species, like vermetids, which can further facilitate the degradation of coral reefs. The effects of the extended phenotype of species likely influence heterogeneity across landscapes as well as temporal differences in community composition.


Adolescent self-harm and suicidal thoughts in the ALSPAC cohort: a self-report survey in England.
Substantial numbers of adolescents self-harm, but the majority of cases do not reach the attention of medical services, making community studies essential. The prevalence of suicidal thoughts and plans at this age, and the inter-relationships between suicidal thoughts, plans and self-harm remain largely unexplored. Cross-sectional analysis of self-reported questionnaire data collected from members of the Avon Longitudinal Study of Parents and Children (ALSPAC) birth cohort, England. Respondents (n = 4810) were aged 16-17 years old and have been followed up since birth. Altogether 905 (18.8%) respondents had ever self-harmed. The prevalence of lifetime self-harm was higher in females (25.6%) than males (9.1%). The most commonly used method was self-cutting: this was used alone or in combination in 73.5% of episodes, compared to 10.0% who took overdoses alone or in combination with other methods. Of those who reported self-harm, 25.3% wanted to die during the most recent episode. Concurrent depression was associated with a greatly increased risk of self-harm (OR 5.43). Only 12.4% of participants sought medical help following their most recent episode of self-harm, although this figure was higher (30.1%) where self-harm was carried out with desire to die. Of the whole sample, 15.8% had ever thought of killing themselves, and 4.3% had ever made plans to kill themselves. Compared to those who had never self-harmed, those who had self-harmed but not wanted to die during the most recent episode were at increased risk of ever having had suicidal thoughts (37.6% compared to 7.8% χ2 =102.3, p < 0.001) and ever making suicidal plans (8.7% compared to 0.7%, χ2 =166.9, p < 0.001). As the frequency of self-harm increased, so did the risk of suicidal thoughts and plans. Self-harm and suicidal thoughts are common among 16/17 year olds. Although the majority of self-harm behaviour is not accompanied by a desire to die, all self-harm regardless of motivation is associated with increased risk of suicidal thoughts and plans, particularly when it is carried out repeatedly.


Multiscale Treatment for the Molecular Mechanism of a Diels-Alder Reaction in Solution: A QM/MM-MD Study.
Thermodynamics and the solvent role in the acceleration of the Diels-Alder reaction between cyclopentadiene (CPD) and methyl vinyl ketone (MVK) have been revisited. In this work we use an ab initio hybrid QM/MM-MD scheme combined with multiple steered molecular dynamics to extract the free energy pofile in water and methanol using the bidirectional Minh-Adib estimator. We obtain 18.7 kcal mol-1 and 20.8 kcal mol-1 free energy barrier for the reaction in water and methanol, respectively. This methodology reproduces experimental values with an absolute error of about 0.8 kcal mol-1. The experimental difference between the activation free-energy barriers of water and methanol is also reproduced with an absolute error of about 0.1 kcal mol-1. We explore the charge transfer evolution along reaction coordinates to characterize the electronic behavior for this reaction. It is shown that the solvent molecules around the reaction system produce a global polarization along the reaction coordinate which is consistent with the solvent polarity. The results highlight the role of hydrogen bonding formed in the transition state to stabilize the system charge reorganization in the reaction process.


Symmetry strategies for high performance lanthanide-based single-molecule magnets.
Toward promising candidates of quantum information processing, the rapid development of lanthanide-based single-molecule magnets (Ln-SMMs) highlights design strategies in consideration of the local symmetry of lanthanide ions. In this review, crystal-field theory is employed to demonstrate the electronic structures according to the semiquantitative electrostatic model. Then, specific symmetry elements are analysed for the elimination of transverse crystal fields and quantum tunnelling of magnetization (QTM). In this way, high-performance Ln-SMMs can be designed to enable extremely slow relaxation of magnetization, namely magnetic blocking; however, their practical magnetic characterization becomes increasingly challenging. Therefore, we will attempt to interpret the experimental behaviours and clarify some issues in detail. Finally, representative Ln-SMMs with specific local symmetries are summarized in combination with the discussion on the symmetry strategies, and some of the underlying questions are put forward.


Review of the genus Cobitis in the Middle East, with the description of eight new species (Teleostei: Cobitidae).
The diversity of Cobitis in the Middle East is reviewed, resulting in the recognition of 30 species, of which eight are described herein as new. Two species, C. amphilekta and C. kellei, seem to be extinct. Hypotheses on species-level diversity derived from distance and Poisson tree process analyses of DNA barcode data are tested against morphometric and morphological characters including colour patterns. For species pairs separated by small K2P distances in COI sequence data we follow a practitioner-oriented diagnostic species concept, in which we recognise species only if differentiated morphologically (including by colour pattern). For all 30 species we provide diagnoses and identification keys. Cobitis afifeae, new species, from the Büyük Menderes River drainage in the Aegean Sea basin, is distinguished by having two laminae circularis in the male, a row of blotches below Z4, a small, roundish or comma-shaped black spot at the upper caudal-fin base, and elevated mental lobes. Cobitis aliyeae, new species, from the lower Seyhan and Ceyhan River drainages, is distinguished by having two laminae circularis in the male, the blotches in Z2 and Z4 anterior to the dorsal-fin origin usually well separated from each other, and the pigmentation in Z1 well distinguished from the pigmentation in Z2. Cobitis anabelae, new species, from the lower Orontes River drainage, is distinguished by having two laminae circularis in the male, the pigmentation in Z2 formed by small, brown spots, always much smaller than blotches in Z3, much smaller than the pupil diameter, Z2 and Z3 well separated, and no pigmentation below Z4. Cobitis erkakanae, new species, from the Gölbasi Lakes, adjacent to the Ceyhan River drainage, is distinguished by having two laminae circularis in the male, no blotches below Z4, the blotches in Z2 and Z4 being horizontally elongated and often fused with adjacent ones, and the caudal fin with 4-6 wide, regularly-shaped, brown bands. Cobitis emrei, new species, from the Lake Sapanca basin is distinguished by having one lamina circularis in the male, a large black spot at the upper caudal-fin base, and Z3 fully covered by very small spots forming a sand-like pattern. Cobitis joergbohleni, new species, from the Sultan marshes in Central Anatolia is distinguished by having two laminae circularis in the male, and the flank colour pattern being completely disorganised, not following the Gambetta zones. Cobitis pirii, new species, from the endorheic Lake Eğirdir basin and the Mediterranean Aksu and Köprü Rivers, is distinguished by having two laminae circularis in the male, a simple external part of the suborbital spine and two distinct rows of small blotches in Z4, one along the lateral midline and one distinctly below. Cobitis troasensis, new species, from the Tuzla River drainage, is distinguished by having one lamina circularis in the male and 25-36 small, comma-shaped brown blotches in Z4. A lectotype is designated for Cobitis battalgilae. As First Revisers, priority is given to Cobitis fahireae over C. kurui. Cobitis damlae and C. kurui are treated as synonyms of C. fahireae. Cobitis strumicae and C. taenia are recorded for the first time from Anatolia and C. saniae is newly documented from the Black Sea basin in Georgia. The Poisson tree process analysis of COI data proposed 31 groups, most of which could be distinguished by morphological characters. Cobitis troasensis is described based on morphological data alone.


Advantages and disadvantages of over-the-counter availability of emergency contraception.
To compare usage patterns, accessibility and knowledge about over-the counter (OTC) emergency contraception (EC) in comparison to prescription-only EC. Self-designed, paper-based validated questionnaires containing 26 questions were distributed among students and high school pupils in Poland (PL) - 1000 questionnaires and in Lithuania (LT) - 650. In Lithuania EC is available OTC, whereas in Poland EC is a prescription-only drug. Statistical analysis was performed using SAS software with p<0.05 considered significant. 74.01% of Poles and 70.89% of Lithuanians reported a history of sexual activity. About one third of the respondents in both countries used EC at least once in a lifetime (PL: 29.01%, LT: 32.2%; p>0.05). The main reason for EC usage in both countries was a broken condom (PL: 60.63%, LT: 57.66 %; p>0.05). In case of emergency more than half of the questioned women in both countries would use EC pill. The knowledge about EC was significantly lower in Poland (PL median - 8 out of 16; LT - 10 out of 16 true/false statements; p<0.01). Over-the-counter availability of EC does not cause repetitive or increased usage. Moreover, an easier access to EC improves patients' knowledge about the drug.


Recommendations on the Use of Ultrasound Guidance for Adult Abdominal Paracentesis: A Position Statement of the Society of Hospital Medicine.
1. We recommend that ultrasound guidance should be used for paracentesis to reduce the risk of serious complications, the most common being bleeding. 2. We recommend that ultrasound guidance should be used to avoid attempting paracentesis in patients with an insufficient volume of intraperitoneal free fluid to drain. 3. We recommend that ultrasound guidance should be used with paracentesis to improve the success rates of the overall procedure. 4. We recommend that ultrasound should be used to assess the volume and location of intraperitoneal free fluid to guide clinical decision making of where paracentesis can be safely performed. 5. We recommend that ultrasound should be used to identify a needle insertion site based on size of the fluid collection, thickness of the abdominal wall, and proximity to abdominal organs. 6. We recommend that the needle insertion site should be evaluated using color flow Doppler ultrasound to identify and avoid abdominal wall blood vessels along the anticipated needle trajectory. 7. We recommend that a needle insertion site should be evaluated in multiple planes to ensure clearance from underlying abdominal organs and detect any abdominal wall blood vessels along the anticipated needle trajectory. 8. We recommend that a needle insertion site should be marked with ultrasound immediately before performing the procedure, and the patient should remain in the same position between marking the site and performing the procedure. 9. We recommend that using real-time ultrasound guidance for paracentesis should be considered when the fluid collection is small or difficult to access. 10. We recommend that dedicated training sessions, including didactics, supervised practice on patients, and simulation-based practice, should be used to teach novices how to perform ultrasound-guided paracentesis. 11. We recommend that simulation-based practice should be used, when available, to facilitate acquisition of the required knowledge and skills to perform ultrasoundguided paracentesis. 12. We recommend that competence in performing ultrasound-guided paracentesis should be demonstrated prior to independently performing the procedure on patients.


Global patterns in marine dispersal estimates: the influence of geography, taxonomic category and life history.
We examine estimates of dispersal in a broad range of marine species through an analysis of published values, and evaluate how well these values represent global patterns through a comparison with correlates of dispersal. Our analysis indicates a historical focus in dispersal studies on low-dispersal/low-latitude species, and we hypothesize that these studies are not generally applicable and representative of global patterns. Large-scale patterns in dispersal were examined using a database of correlates of dispersal such as planktonic larval duration (PLD, 318 species) and genetic differentiation (FST, 246 species). We observed significant differences in FST (p<0.001) and PLD (p<0.001) between taxonomic groups (e.g. fishes, cnidarians, etc.). Within marine fishes (more than 50% of datasets), the prevalence of demersal eggs was negatively associated with PLD (R2=0.80, p<0.001) and positively associated with genetic structure (R2=0.74, p<0.001). Furthermore, dispersal within marine fishes (i.e. PLD and FST) increased with latitude, adult body size and water depth. Of these variables, multiple regression identified latitude and body size as persistent predictors across taxonomic levels. These global patterns of dispersal represent a first step towards understanding and predicting species-level and regional differences in dispersal, and will be improved as more comprehensive data become available.


Health spending among working-age immigrants with disabilities compared to those born in the US.
Immigrants have disparate access to health care. Disabilities can amplify their health care burdens. Examine how US- and foreign-born working-age adults with disabilities differ in their health care spending patterns. Medical Expenditures Panel Survey yearly-consolidated files (2000-2010) on working-age adults (18-64 years) with disabilities. We used three operational definitions of disability: physical, cognitive, and sensory. We examined annual total, outpatient/office-based, prescription medication, inpatient, and emergency department (ED) health expenditures. We tested bivariate logistic and linear regression models to, respectively, assess unadjusted group differences in the propensity to spend and average expenditures. Second, we used multivariable two-part models to estimate and test per-capita expenditures adjusted for predisposing, enabling, health need and behavior indicators. Adjusted for age and sex differences, US-born respondents with physical, cognitive, sensory spent on average $2977, $3312, and $2355 more in total compared to their foreign-born counterparts (P < 0.01). US-born spending was also higher across the four types of health care expenditures considered. Adjusting for the behavioral model factors, especially predisposing and enabling indicators, substantially reduced nativity differences in overall, outpatient/office-based and medication spending but not in inpatient and ED expenditures. Working-age immigrants with disabilities have lower levels of health care use and expenditures compared to their US-born counterparts. Affordable Care Act provisions aimed at increasing access to insurance and primary care can potentially align the consumption patterns of US- and foreign-born disabled working-age adults. More work is needed to understand the pathways leading to differences in hospital and prescription medication care.


Contributions of hot and cool self-regulation to preschool disruptive behavior and academic achievement.
The construct of self-regulation can be meaningfully distinguished into hot and cool components. The current study investigated self-regulation in a sample of 926 children aged 3-5 years old. Children's performance on self-regulatory tasks was best described by two latent factors representing hot and cool regulation. When considered alone, hot and cool regulation were both significantly correlated with disruptive behavior and academic achievement. When considered together, cool regulation was uniquely associated with academic achievement, while hot regulation was uniquely associated with inattentive-overactive behaviors. Results are discussed with respect to treatment studies that directly target improvement in children's self-regulation.


Management of pneumonia in the child aged 0 to 8 weeks.
The group of children with the highest mortality from pneumonia is the group aged 8 weeks and younger. This group of infants is more likely to present with non-specific signs of disease, and the pneumonia is caused by a wider spectrum of organisms. For these reasons, infants aged < or = 8 weeks have to be carefully assessed, taking into account the characteristics peculiar to this age. Due to the seriousness of the pneumonia, they are only classified into three categories: very severe pneumonia, severe pneumonia and cough or cold. All infants aged < or = 8 weeks diagnosed with severe or very severe pneumonia must be hospitalised, as they require parenteral antibiotics for at least 8 days and need careful monitoring. The monitoring needs to be adapted, as they are more likely to have problems with body temperature and serum glucose control. Careful plans have to be formulated to ensure that these infants recover fully and are integrated into the well baby clinics. In the triage of sick children, it is those aged < or = 8 weeks who should receive the most urgent attention.


Correcting anterior corneal aberration and variability of lens movements in keratoconic eyes with back-surface customized soft contact lenses.
Customized contact lenses are limited in their correction performance, especially on irregular corneas, owing to decentration and rotation of the lenses. To overcome this limitation, we proposed to customize the back surface of soft contact lenses to match the anterior irregular corneal surface. These lenses were designed to correct anterior corneal aberrations and to improve lens stability. Although in keratoconic eyes the anterior corneal aberrations were effectively corrected, significant residual aberrations were observed. The internal optics, especially the posterior surface of the cornea, was the main source of these residual aberrations. Compared with conventional soft contact lenses, lens stability, on average over three eyes, was improved by a factor of 2 for horizontal and vertical decentrations and a factor of 5 in rotational orientation with the back-surface customized lenses.


Consumption of a single serving of red raspberries per day reduces metabolic syndrome parameters in high-fat fed mice.
Using an animal model for diet-induced metabolic disease, we have shown previously that the addition of raspberry juice concentrate (RJC) and raspberry puree concentrate (RPC) at a level of 10% of kcal, equivalent to four servings per day, to an obesogenic high-fat, western-style diet (HF) significantly reduced body weight gain, serum resistin levels, and altered the expression of hepatic genes related to lipid metabolism and oxidative stress. This study was designed to examine the effect of a lower level of RJC or RPC consumption, at a level representing a single serving of food per day (2.5% of kcal). For ten weeks, four groups of C57BL/6J mice (n = 8 ea.) were fed: low fat (LF), HF, HF + RJC, or HF + RPC diets. Intake of RJC and RPC decreased final body weight. Hepatic lipid accumulation was significantly decreased in HF + RPC- and HF + RJC-fed mice, compared to HF-fed mice. Further, the relative expression of hepatic genes including Heme oxygenase 1 (Hmox1) and Hormone sensitive lipase (Lipe), were altered by RPC or RJC consumption. In this mouse model of diet-induced metabolic disease, consumption of the equivalent of a single daily serving of either RPC or RJC improved metabolism in mice fed HF diet. We hypothesize that the phytochemicals contained in raspberries, and/or their subsequent metabolites, may be acting to influence gene expression and other regulatory pathways, to produce the metabolic improvements observed in this study.


A fast algorithm for the multiple genome rearrangement problem with weighted reversals and transpositions.
Due to recent progress in genome sequencing, more and more data for phylogenetic reconstruction based on rearrangement distances between genomes become available. However, this phylogenetic reconstruction is a very challenging task. For the most simple distance measures (the breakpoint distance and the reversal distance), the problem is NP-hard even if one considers only three genomes. In this paper, we present a new heuristic algorithm that directly constructs a phylogenetic tree w.r.t. the weighted reversal and transposition distance. Experimental results on previously published datasets show that constructing phylogenetic trees in this way results in better trees than constructing the trees w.r.t. the reversal distance, and recalculating the weight of the trees with the weighted reversal and transposition distance. An implementation of the algorithm can be obtained from the authors. The possibility of creating phylogenetic trees directly w.r.t. the weighted reversal and transposition distance results in biologically more realistic scenarios. Our algorithm can solve today's most challenging biological datasets in a reasonable amount of time.


Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma.
The programmed death 1 (PD-1) receptor is a negative regulator of T-cell effector mechanisms that limits immune responses against cancer. We tested the anti-PD-1 antibody lambrolizumab (previously known as MK-3475) in patients with advanced melanoma. We administered lambrolizumab intravenously at a dose of 10 mg per kilogram of body weight every 2 or 3 weeks or 2 mg per kilogram every 3 weeks in patients with advanced melanoma, both those who had received prior treatment with the immune checkpoint inhibitor ipilimumab and those who had not. Tumor responses were assessed every 12 weeks. A total of 135 patients with advanced melanoma were treated. Common adverse events attributed to treatment were fatigue, rash, pruritus, and diarrhea; most of the adverse events were low grade. The confirmed response rate across all dose cohorts, evaluated by central radiologic review according to the Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, was 38% (95% confidence interval [CI], 25 to 44), with the highest confirmed response rate observed in the cohort that received 10 mg per kilogram every 2 weeks (52%; 95% CI, 38 to 66). The response rate did not differ significantly between patients who had received prior ipilimumab treatment and those who had not (confirmed response rate, 38% [95% CI, 23 to 55] and 37% [95% CI, 26 to 49], respectively). Responses were durable in the majority of patients (median follow-up, 11 months among patients who had a response); 81% of the patients who had a response (42 of 52) were still receiving treatment at the time of analysis in March 2013. The overall median progression-free survival among the 135 patients was longer than 7 months. In patients with advanced melanoma, including those who had had disease progression while they had been receiving ipilimumab, treatment with lambrolizumab resulted in a high rate of sustained tumor regression, with mainly grade 1 or 2 toxic effects. (Funded by Merck Sharp and Dohme; ClinicalTrials.gov number, NCT01295827.).


Colonial history and contemporary transmission shape the genetic diversity of hepatitis C virus genotype 2 in Amsterdam.
Evolutionary analysis of hepatitis C virus (HCV) genome sequences has provided insights into the epidemic history and transmission of this widespread human pathogen. Here we report an exceptionally diverse set of 178 HCV genotype 2 (HCV-2) isolates from 189 patients in Amsterdam, comprising 8 distinct HCV subtypes and 10 previously not recognized, unclassified lineages. By combining study subjects' demographic information with phylogeographic and molecular clock analyses, we demonstrate for the first time that the trans-Atlantic slave trade and colonial history were the driving forces behind the global dissemination of HCV-2. We detect multiple HCV-2 movements from present-day Ghana/Benin to the Caribbean during the peak years of the slave trade (1700 to 1850) and extensive transfer of HCV-2 among the Netherlands and its former colonies Indonesia and Surinam over the last 150 years. The latter coincides with the bidirectional migration of Javanese workers between Indonesia and Surinam and subsequent immigration to the Netherlands. In addition, our study sheds light on contemporary trends in HCV transmission within the Netherlands. We observe multiple lineages of the epidemic subtypes 2a, 2b, and 2c (together 67% of HCV-2 infections in Amsterdam), which cluster according to their suspected routes of transmission, specifically, injecting drug use (IDU) and contaminated blood/blood products. Understanding the epidemiological processes that generated the global pattern of HCV diversity seen today is critical for exposing associations between populations, risk factors, and specific HCV subtypes and might help HCV screening and prevention campaigns to minimize the future burden of HCV-related liver disease.


Comprehensive Morpho-Electrotonic Analysis Shows 2 Distinct Classes of L2 and L3 Pyramidal Neurons in Human Temporal Cortex.
There have been few quantitative characterizations of the morphological, biophysical, and cable properties of neurons in the human neocortex. We employed feature-based statistical methods on a rare data set of 60 3D reconstructed pyramidal neurons from L2 and L3 in the human temporal cortex (HL2/L3 PCs) removed after brain surgery. Of these cells, 25 neurons were also characterized physiologically. Thirty-two morphological features were analyzed (e.g., dendritic surface area, 36 333 ± 18 157 μm2; number of basal trees, 5.55 ± 1.47; dendritic diameter, 0.76 ± 0.28 μm). Eighteen features showed a significant gradual increase with depth from the pia (e.g., dendritic length and soma radius). The other features showed weak or no correlation with depth (e.g., dendritic diameter). The basal dendritic terminals in HL2/L3 PCs are particularly elongated, enabling multiple nonlinear processing units in these dendrites. Unlike the morphological features, the active biophysical features (e.g., spike shapes and rates) and passive/cable features (e.g., somatic input resistance, 47.68 ± 15.26 MΩ, membrane time constant, 12.03 ± 1.79 ms, average dendritic cable length, 0.99 ± 0.24) were depth-independent. A novel descriptor for apical dendritic topology yielded 2 distinct classes, termed hereby as "slim-tufted" and "profuse-tufted" HL2/L3 PCs; the latter class tends to fire at higher rates. Thus, our morpho-electrotonic analysis shows 2 distinct classes of HL2/L3 PCs.


Comparison of LCD and CRT displays based on efficacy for digital mammography.
To compare two display technologies, cathode ray tube (CRT) and liquid crystal display (LCD), in terms of diagnostic accuracy for several common clinical tasks in digital mammography. Simulated masses and microcalcifications were inserted into normal digital mammograms to produce an image set of 400 images. Images were viewed on one CRT and one LCD medical-quality display device by five experienced breast-imaging radiologists who rated the images using a categorical rating paradigm. The observer data were analyzed to determine overall classification accuracy, overall lesion detection accuracy, and accuracy for four specific diagnostic tasks: detection of benign masses, malignant masses, and microcalcifications, and discrimination of benign and malignant masses. Radiologists had similar overall classification accuracy (LCD: 0.83 +/- 0.01, CRT: 0.82 +/- 0.01) and lesion detection accuracy (LCD: 0.87 +/- 0.01, CRT: 0.85 +/- 0.01) on both displays. The difference in accuracy between LCD and CRT for the detection of benign masses, malignant masses, and microcalcifications, and discrimination of benign and malignant masses was -0.019 +/- 0.009, 0.020 +/- 0.008, 0.012 +/- 0.013, and 0.0094 +/- 0.011, respectively. Overall, the two displays did not exhibit any statistically significant difference (P > .05). This study explored the suitability of two different soft-copy displays for the viewing of mammographic images. It found that LCD and CRT displays offer similar clinical utility for mammographic tasks.


Predictors of self-perceived cultural responsiveness in entry-level physiotherapy students in Australia and Aotearoa New Zealand.
Ensuring physiotherapy students are well prepared to work safely and effectively in culturally diverse societies upon graduation is vital. Therefore, determining whether physiotherapy programs are effectively developing the cultural responsiveness of students is essential. This study aimed to evaluate the level of self-perceived cultural responsiveness of entry level physiotherapy students during their training, and explore the factors that might be associated with these levels. A cross sectional study of physiotherapy students from nine universities across Australia and Aotearoa New Zealand was conducted using an online self-administered questionnaire containing three parts: The Cultural Competence Assessment tool, Altemeyer's Dogmatism scale, and the Marlowe-Crowne social desirability scale- short form. Demographic data relating to university, program, and level of study were also collected. Data was analysed using one-way ANOVA, t-tests and multiple regression analysis. A total of 817 (19% response rate) students participated in this study. Overall, students had a moderate level of self-perceived cultural responsiveness (Mean (SD) = 5.15 (0.67)). Fewer number of weeks of clinical placement attended, lower levels of dogmatism, and greater social desirability were related to greater self-perceived cultural responsiveness. Additionally, fourth year undergraduate students perceived themselves to be less culturally responsive than first and second year students (p < 0.05). These results provide educators with knowledge about the level of self-perceived cultural responsiveness in physiotherapy students, and the factors that may need to be assessed and addressed to support the development of culturally responsive practice.


Understanding the impact of flooding on trait-displacements and shifts in assemblage structure of predatory arthropods on river banks.
1. Species assemblages of naturally disturbed habitats are governed by the prevailing disturbance regime. Consequently, stochastic flood events affect river banks and the inhabiting biota. Predatory arthropods occupy predominantly river banks in relation to specific habitat conditions. Therefore, species sorting and stochastic processes as induced by flooding are supposed to play important roles in structuring riparian arthropod assemblages in relation to their habitat preference and dispersal ability. 2. To ascertain whether assemblages of spiders and carabid beetles from disturbed river banks are structured by stochastic or sorting mechanisms, diversity patterns and assemblage-wide trait-displacements were assessed based on pitfall sampling data. We tested if flooding disturbance within a lowland river reach affects diversity patterns and trait distribution in both groups. 3. Whereas the number of riparian spider species decreased considerably with increased flooding, carabid beetle diversity benefited from intermediate degrees of flooding. Moreover, regression analyses revealed trait-displacements, reflecting sorting mechanisms particularly for spiders. Increased flooding disturbance was associated with assemblage-wide increases of niche breadth, shading and hygrophilic preference and ballooning propensity for spider (sub)families. Trait patterns were comparable for Bembidiini carabids, but were less univocal for Pterostichini species. Body size decreased for lycosid spiders and Bembidiini carabids with increased flooding, but increased in linyphiid spiders and Pterostichini carabids. 4. Our results indicate that mainly riparian species are disfavoured by either too high or too low degrees of disturbance, whereas eurytopic species benefit from increased flooding. Anthropogenic alterations of flooding disturbance constrain the distribution of common hygrophilous species and/or species with high dispersal ability, inducing shifts towards less specialized arthropod assemblages. River banks with divergent degrees of flooding impact should be maintained throughout dynamic lowland river reaches in order to preserve typical riparian arthropod assemblages.


Risks from circumcision during the first month of life compared with those for uncircumcised boys.
The records of 136,086 boys born in US Army hospitals from 1980 to 1985 were reviewed for indexed complications related to circumcision status during the first month of life. For 100,157 circumcised boys, there were 193 complications (0.19%). These included 62 local infections, eight cases of bacteremia, 83 incidences of hemorrhage (31 requiring ligature and three requiring transfusion), 25 instances of surgical trauma, and 20 urinary tract infections. There were no deaths or reported losses of the glans or entire penis. By contrast, the complications in the 35,929 uncircumcised infants were all related to urinary tract infections. Of the 88 boys with such infections (0.24%), 32 had concomitant bacteremia, three had meningitis, two had renal failure, and two died. The frequencies of urinary tract infection (P less than .0001) and bacteremia (P less than .0002) were significantly higher in the uncircumcised boys. Serious complications from routine prepuce removal are rare and relatively minor. Circumcision may be beneficial in reducing the occurrence of urinary tract infections and their associated sequelae.


Spectroscopic properties and near-infrared broadband luminescence of Bi-doped SrB4O7 glasses and crystalline materials.
Spectroscopic properties of Bi-doped SrB(4)O(7) glasses, sintered compounds, polycrystalline materials, and single crystals were investigated. Broadband near-infrared luminescence was realized in Bi-doped SrB(4)O(7) glasses with basicity and polycrystalline materials with non-bridging oxygens. In Bi:SrB(4)O(7) single crystals, only visible luminescence of Bi(3+) and Bi(2+) was observed, but no near-infrared. The rigid three-dimensional network of SrB(4)O(7) crystal is proved to be unfavorable for accommodation of Bi(+) ions.


Monoclonal antibodies against an H-2Kb-specific cytotoxic T cell clone detect several clone-specific molecules.
Monoclonal antibodies (mAb) were prepared from the spleen of a BALB.K mouse immunized with a H-2Kb-specific alloreactive cytolytic T cell (CTL) clone of B10.BR origin, KB5-C20. Six of these mAb were selected for specific binding to the immunizing clone. Only one of these mAb, Désiré-1, inhibited the CTL activity of clone KB5-C20. Functional and biochemical evidence showed mAb Désiré-1 to be anti-clonotypic (anti-Ti). This mAb immunoprecipitated from lysates of clone KB5-C20 a protein that migrated at 80 KD in nonreducing conditions and at 40 to 45 KD in reducing conditions. Analysis in NEPHGE resolved the latter into an acidic chain of 43 KD and a basic chain of 40 KD. An additional protein was coprecipitated at 25 KD in nonreducing and 27 KD in reducing conditions, which was distinct from the Thy-1 antigen. Expression of the clonotype defined by Désiré-1 was found on clone KB5-C20 and on clone KB5-A7 originating from the same B10.BR T cell population. These two clones exhibited a similar pattern of reactivity on H-2Kbm mutant target cells. Another clone (KB5-C1) from the same B10.BR T population showed a distinct reactivity pattern on the H-2Kbm mutant target cells and did not express the Désiré-1 clonotype, nor did Con A-activated B10.BR blast cells or H-2Kb-specific clone BM3.3 of CBA/J origin. Among the five other selected mAb, one reacted with the three Kb-specific CTL clones of B10.BR, but not with the Kb-specific clone of CBA origin, whereas the last four mAb bound only to clone KB5-C20. None of these mAb could immunoprecipitate the Ti alpha/beta chains. Ti modulation induced by mAb Désiré-1 on clone KB5-C20 did not induce comodulation of the structures bound by the other five mAb on clone KB5-C20, thus indicating that these structures were not part of the Ti-T3 complex. These results characterize a clonotypic mAb reacting with an H-2Kb-specific CTL clone that will be useful in future studies. They also indicate that screening for clone-specific mAb by selective binding assays may select for mAb against as yet undefined structures, some of which exhibit an apparently clone-specific distribution.


SOCS3 and IRS-1 gene expression differs between genotype 1 and genotype 2 hepatitis C virus-infected HepG2 cells.
The poor response to antiviral treatment of hepatitis C virus (HCV)-infected patients with genotype 1b has been associated with a higher prevalence of metabolic syndrome. However, the molecular link between these clinical entities is not clear. The goal of this study was to clarify the role of genotype 1b and 2 in the genetic expression of suppressor of cytokine signaling 3 (SOCS3) and insulin receptor substrate 1 (IRS-1). We infected human hepatocellular carcinoma cell line (HepG2) cells with human HCV genotype 1b or 2 and measured the gene and protein expression of SOCS3 at various times. We also evaluated impairment in the insulin pathway by analysis of IRS-1 and phospho-AKT. For the control, we used HepG2 cell cultures treated with non-infectious serum. We also demonstrated the occurrence of HCV infection by the detection of both positive and negative strands in the cells and culture medium. To test infection of the HepG2 cells, we performed quantitative real-time polymerase chain reaction (qRT-PCR) of viral load at different time points. We analyzed the viral genotype in the pellet and supernatant. At each time point, we found positive and negative strands in the infected cells, while in the medium we found positive, but no negative strands. We also detected the presence of the correct genotype in the medium. Two weeks following infection when the viral load was higher, we tested genotype 1b and 2 infected cells. SOCS3 gene expression was significantly higher in genotype 1b-infected cells (median 2.56; mean 2.82+/-0.59) compared with genotype 2 (median 1.34; mean 1.46+/-0.31) (p=0.04) and control cells (median 1.09; mean 1.02+/-0.11, p=0.02). There was no difference between cells exposed to genotype 2 and control cells. Conversely, IRS-1 was significantly lower in genotype 1b-infected cells (median 15.97; mean 15.45+/-0.67) compared with genotype 2-infected cells (median 16.45; mean 16.44+/-0.01, p=0.04). Statistically significant differences were seen when comparing the pAKT/AKT ratio in genotype 1b-infected cells (0.19+/-0.034) and not genotype 1b-infected (genotype 2-infected and non-infected) cells (0.253+/-0.004, p=0.03). This inverse regulation is compatible with interactions between the molecular expression of SOCS3, IRS-1 and phospho-AKT mediated by the genotype 1b virus. Up-regulation of the SOCS3 gene might be one of the mechanisms governing non-response to therapy and expression of insulin resistance mediated via a direct mechanism at this level of genotype 1b HCV.


EGLN1 involvement in high-altitude adaptation revealed through genetic analysis of extreme constitution types defined in Ayurveda.
It is being realized that identification of subgroups within normal controls corresponding to contrasting disease susceptibility is likely to lead to more effective predictive marker discovery. We have previously used the Ayurvedic concept of Prakriti, which relates to phenotypic differences in normal individuals, including response to external environment as well as susceptibility to diseases, to explore molecular differences between three contrasting Prakriti types: Vata, Pitta, and Kapha. EGLN1 was one among 251 differentially expressed genes between the Prakriti types. In the present study, we report a link between high-altitude adaptation and common variations rs479200 (C/T) and rs480902 (T/C) in the EGLN1 gene. Furthermore, the TT genotype of rs479200, which was more frequent in Kapha types and correlated with higher expression of EGLN1, was associated with patients suffering from high-altitude pulmonary edema, whereas it was present at a significantly lower frequency in Pitta and nearly absent in natives of high altitude. Analysis of Human Genome Diversity Panel-Centre d'Etude du Polymorphisme Humain (HGDP-CEPH) and Indian Genome Variation Consortium panels showed that disparate genetic lineages at high altitudes share the same ancestral allele (T) of rs480902 that is overrepresented in Pitta and positively correlated with altitude globally (P < 0.001), including in India. Thus, EGLN1 polymorphisms are associated with high-altitude adaptation, and a genotype rare in highlanders but overrepresented in a subgroup of normal lowlanders discernable by Ayurveda may confer increased risk for high-altitude pulmonary edema.


The state of desalination and brine production: A global outlook.
Rising water demands and diminishing water supplies are exacerbating water scarcity in most world regions. Conventional approaches relying on rainfall and river runoff in water scarce areas are no longer sufficient to meet human demands. Unconventional water resources, such as desalinated water, are expected to play a key role in narrowing the water demand-supply gap. Our synthesis of desalination data suggests that there are 15,906 operational desalination plants producing around 95 million m3/day of desalinated water for human use, of which 48% is produced in the Middle East and North Africa region. A major challenge associated with desalination technologies is the production of a typically hypersaline concentrate (termed 'brine') discharge that requires disposal, which is both costly and associated with negative environmental impacts. Our estimates reveal brine production to be around 142 million m3/day, approximately 50% greater than previous quantifications. Brine production in Saudi Arabia, UAE, Kuwait and Qatar accounts for 55% of the total global share. Improved brine management strategies are required to limit the negative environmental impacts and reduce the economic cost of disposal, thereby stimulating further developments in desalination facilities to safeguard water supplies for current and future generations.


Mechanistic study of styrene aziridination by iron(iv) nitrides.
A combined experimental and computational investigation was undertaken to investigate the mechanism of aziridination of styrene by the tris(carbene)borate iron(iv) nitride complex, PhB( t BuIm)3Fe[triple bond, length as m-dash]N. While mechanistic investigations suggest that aziridination occurs via a reversible, stepwise pathway, it was not possible to confirm the mechanism using only experimental techniques. Density functional theory calculations support a stepwise radical addition mechanism, but suggest that a low-lying triplet (S = 1) state provides the lowest energy path for C-N bond formation (24.6 kcal mol-1) and not the singlet ground (S = 0) state. A second spin flip may take place in order to facilitate ring closure and the formation of the quintet (S = 2) aziridino product. A Hammett analysis shows that electron-withdrawing groups increase the rate of reaction σ p (ρ = 1.2 ± 0.2). This finding is supported by the computational results, which show that the rate-determining step drops from 24.6 kcal mol-1 to 18.3 kcal mol-1 when (p-NO2C6H4)CH[double bond, length as m-dash]CH2 is used and slightly increases to 25.5 kcal mol-1 using (p-NMe2C6H4)CH[double bond, length as m-dash]CH2 as the substrate.


Open-ended formulation of self-consistent field response theory with the polarizable continuum model for solvation.
The study of high-order absorption properties of molecules is a field of growing importance. Quantum-chemical studies can help design chromophores with desirable characteristics. Given that most experiments are performed in solution, it is important to devise a cost-effective strategy to include solvation effects in quantum-chemical studies of these properties. We here present an open-ended formulation of self-consistent field (SCF) response theory for a molecular solute coupled to a polarizable continuum model (PCM) description of the solvent. Our formulation relies on the open-ended, density matrix-based quasienergy formulation of SCF response theory of Thorvaldsen, et al., [J. Chem. Phys., 2008, 129, 214108] and the variational formulation of the PCM, as presented by Lipparini et al., [J. Chem. Phys., 2010, 133, 014106]. Within the PCM approach to solvation, the mutual solute-solvent polarization is represented by means of an apparent surface charge (ASC) spread over the molecular cavity defining the solute-solvent boundary. In the variational formulation, the ASC is an independent, variational degree of freedom. This allows us to formulate response theory for molecular solutes in the fixed-cavity approximation up to arbitrary order and with arbitrary perturbation operators. For electric dipole perturbations, pole and residue analyses of the response functions naturally lead to the identification of excitation energies and transition moments. We document the implementation of this approach in the Dalton program package using a recently developed open-ended response code and the PCMSolver libraries and present results for one-, two-, three-, four- and five-photon absorption processes of three small molecules in solution.


Advanced paternal age is a risk factor for schizophrenia in Iranians.
Since 1958 many, but not all studies have demonstrated that paternal age is a risk factor for schizophrenia. There may be many different explanations for differences between studies, including study design, sample size, collection criteria, heterogeneity and the confounding effects of environmental factors that can for example perturb epigenetic programming and lead to an increase in disease risk. The small number of children in Western families makes risk comparisons between siblings born at different paternal ages difficult. In contrast, more Eastern families have children both at early and later periods of life. In the present study, a cross-sectional population study in an Iranian population was performed to compare frequency of schizophrenia in younger offspring (that is, older paternal age) versus older offspring. A total of 220 patients with the diagnosis of schizophrenia (cases) from both psychiatric hospitals and private clinics and 220 individuals from other hospital wards (controls), matched for sex and age were recruited for this study. Patients with neurological problem, substance abuse, mental retardation and mood disorder were excluded from both groups. Birth rank comparisons revealed that 35% vs 24% of the cases vs the controls were in the third or upper birth rank (P = 0.01). Also, the mean age of fathers at birth in case group (30 ± 6.26 years) was significantly more than the control group (26.45 ± 5.64 years; P = 0.0001). The age of 76 fathers at birth in case group was over 32 versus 33 fathers in control group. Individuals whose fathers' age was more than 32 (at birth) were at higher risk (2.77 times) for schizophrenia versus others (P < 0.0001, 95% CI 1.80 to 4.27). The maternal age at parturition of the case versus controls groups was 26.1 ± 5.41 vs 25.07 ± 4.47 (P = 0.02). Logistic regression analysis suggests that maternal age is less likely to be involved in the higher risk of schizophrenia than advanced parental age. This study demonstrates a relationship between paternal age and schizophrenia in large families of an Iranian population. Arguments have been put forth that DNA bases changes or epigenetic changes in sperm account for the increased risk associated with older fathers. However, it would not be surprising that both de novo germline mutations and epigenetic changes contribute to disease occurrence because DNA replication and DNA methylation are closely linked at both the macromolecular level (that is, methylation closely follows replication), and at the metabolic level (both processes require folate), and susceptible to modulation by the environment. Further research on samples such as those collected here are needed to sort out the contributions of de novo mutations versus epigenetic changes to schizophrenia.


Choice of Prosthetic Implant Combinations in Total Hip Replacement: Cost-Effectiveness Analysis Using UK and Swedish Hip Joint Registries Data.
Prosthetic implants used in total hip replacements (THR) have a range of bearing surface combinations (metal-on-polyethylene, ceramic-on-polyethylene, ceramic-on-ceramic, and metal-on-metal), head sizes (small [<36 mm in diameter] and large [≥36 mm in diameter]), and fixation techniques (cemented, uncemented, hybrid, and reverse hybrid). These can influence prosthesis survival, patients' quality of life, and healthcare costs. To compare the lifetime cost-effectiveness of implants for patients of different age and sex profiles. We developed a Markov model to compare the cost-effectiveness of various implants against small-head cemented metal-on-polyethylene implants. The probability that patients required 1 or more revision surgeries was estimated from analyses of more than 1 million patients in the UK and Swedish hip joint registries, for men and women younger than 55, 55 to 64, 65 to 74, 75 to 84, and 85 years and older. Implant and healthcare costs were estimated from local procurement prices, national tariffs, and the literature. Quality-adjusted life-years were calculated using published utility estimates for patients undergoing THR in the United Kingdom. Small-head cemented metal-on-polyethylene implants were the most cost-effective for men and women older than 65 years. These findings were robust to sensitivity analyses. Small-head cemented ceramic-on-polyethylene implants were most cost-effective in men and women younger than 65 years, but these results were more uncertain. The older the patient group, the more likely that the cheapest implants, small-head cemented metal-on-polyethylene implants, were cost-effective. We found no evidence that uncemented, hybrid, or reverse hybrid implants were the most cost-effective option for any patient group. Our findings can influence clinical practice and procurement decisions for healthcare payers worldwide.


Cholinesterase inhibitors from botanicals.
Alzheimer's disease (AD) is a progressive neurodegenerative disease, wherein a progressive loss of cholinergic synapses occurs in hippocampus and neocortex. Decreased concentration of the neurotransmitter, acetylcholine (ACh), appears to be critical element in the development of dementia, and the most appropriate therapeutic approach to treat AD and other form of dementia is to restore acetylcholine levels by inhibiting both major form of cholinesterase: Acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). Consequently, researches have focused their attention towards finding cholinesterase inhibitors from natural products. A large number of such inhibitors have been isolated from medicinal plants. This review presents a comprehensive account of the advances in field of cholinesterase inhibitor phytoconstituents. The structures of some important phytoconstituents (collected through www.Chemspider.com) are also presented and the scope for future research is discussed.


Studies on the mechanisms of autophagy: maturation of the autophagic vacuole.
Data presented in the accompanying paper suggests nascent autophagic vacuoles are formed from RER (Dunn, W. A. 1990. J. Cell Biol. 110:1923-1933). In the present report, the maturation of newly formed or nascent autophagic vacuoles into degradative vacuoles was examined using morphological and biochemical methods combined with immunological probes. Within 15 min of formation, autophagic vacuoles acquired acid hydrolases and lysosomal membrane proteins, thus becoming degradative vacuoles. A previously undescribed type of autophagic vacuole was also identified having characteristics of both nascent and degradative vacuoles, but was different from lysosomes. This intermediate compartment contained only small amounts of cathepsin L in comparison to lysosomes and was bound by a double membrane, typical of nascent vacuoles. However, unlike nascent vacuoles vet comparable to degradative vacuoles, these vacuoles were acidic and contained the lysosomal membrane protein, lgp120, at the outer limiting membrane. The results were consistent with the stepwise acquisition of lysosomal membrane proteins and hydrolases. The presence of mannose-6-phosphate receptor in autophagic vacuoles suggested a possible role of this receptor in the delivery of newly synthesized hydrolases from the Golgi apparatus. However, tunicamycin had no significant effect on the amount of mature acid hydrolases present in a preparation of autophagic vacuoles isolated from a metrizamide gradient. Combined, the results suggested nascent autophagic vacuoles mature into degradative vacuoles in a stepwise fashion: (a) acquisition of lysosomal membrane proteins by fusing with a vesicle deficient in hydrolytic enzymes (e.g., prelysosome); (b) vacuole acidification; and (c) acquisition of hydrolases by fusing with preexisting lysosomes or Golgi apparatus-derived vesicles.


Canonical Cortical Circuit Model Explains Rivalry, Intermittent Rivalry, and Rivalry Memory.
It has been shown that the same canonical cortical circuit model with mutual inhibition and a fatigue process can explain perceptual rivalry and other neurophysiological responses to a range of static stimuli. However, it has been proposed that this model cannot explain responses to dynamic inputs such as found in intermittent rivalry and rivalry memory, where maintenance of a percept when the stimulus is absent is required. This challenges the universality of the basic canonical cortical circuit. Here, we show that by including an overlooked realistic small nonspecific background neural activity, the same basic model can reproduce intermittent rivalry and rivalry memory without compromising static rivalry and other cortical phenomena. The background activity induces a mutual-inhibition mechanism for short-term memory, which is robust to noise and where fine-tuning of recurrent excitation or inclusion of sub-threshold currents or synaptic facilitation is unnecessary. We prove existence conditions for the mechanism and show that it can explain experimental results from the quartet apparent motion illusion, which is a prototypical intermittent rivalry stimulus.


Effective stiffness and formation of secondary structures in a protein-like model.
We use Wang-Landau and replica exchange techniques to study the effect of an increasing stiffness on the formation of secondary structures in protein-like systems. Two possible models are considered. In both models, a polymer chain is formed by tethered beads where non-consecutive backbone beads attract each other via a square-well potential representing the tendency of the chain to fold. In addition, smaller hard spheres are attached to each non-terminal backbone bead along the direction normal to the chain to mimic the steric hindrance of side chains in real proteins. The two models, however, differ in the way bending rigidity is enforced. In the first model, partial overlap between consecutive beads is allowed. This reduces the possible bending angle between consecutive bonds thus producing an effective entropic stiffness that competes with a short-range attraction, and leads to the formation of secondary structures characteristic of proteins. We discuss the low-temperature phase diagram as a function of increasing interpenetration and find a transition from a planar, beta-like structure, to helical shape. In the second model, an energetic stiffness is explicitly introduced by imposing an infinitely large energy penalty for bending above a critical angle between consecutive bonds, and no penalty below it. The low-temperature phase of this model does not show any sign of protein-like secondary structures. At intermediate temperatures, however, where the chain is still in the coil conformation but stiffness is significant, we find the two models to predict a quite similar dependence of the persistence length as a function of the stiffness. This behaviour is rationalized in terms of a simple geometrical mapping between the two models. Finally, we discuss the effect of shrinking side chains to zero and find the above mapping to still hold true.


Synthesis and structural analyses of phenylethynyl-substituted tris(2-pyridylmethyl)amines and their copper(ii) complexes.
Three new tris(2-pyridylmethyl)amine-based ligands possessing phenylethynyl units have been prepared using Sonogashira couplings and substitution reactions. Copper(ii) complexes of those tetradentate ligands have also been synthesized. Solid-state structures of the six new compounds have been determined by single-crystal X-ray diffraction analyses. Examination of the molecular structures of the ligands revealed the expected triangular geometries with virtually undeformed carbon-carbon triple bonds. While the tertiary nitrogen of the free ligands seem to be prevented from participation in supramolecular non-covalent interactions by the pyridyl hydrogen at the 3-position, the pyridyl nitrogens play a crucial role in the packing mode of the crystal structure. The nitrogens form weak hydrogen bonds, varied in length between 2.32 and 2.66 Å, with the pyridyl hydrogen of its neighbouring molecule. The [NH-C] contacts enforce one-dimensional columnar assemblies on ligands that organize into wall-like structures, which in turn assemble into three-dimensional structures through CH-π interactions. Structural analyses of Cu(ii) complexes of the ligands revealed propeller-like structures caused by steric crowding of three pyridine ligands. The copper complexes of the ligands having three phenylethynyl substituents showed a remarkably deformed carbon-carbon triple bond enforced by a steric effect of the three phenyl groups. Most significantly, a total of seventy non-covalent interactions, classified into twelve types of hydrogen-involving short contacts, were identified in this study. The phenylethynyl substituent participated in forty-two interactions as a hydrogen bond acceptor, and its role was more distinctive in the crystal structures of the Cu(ii) complexes.


Effects of seated and standing cold water immersion on recovery from repeated sprinting.
This study investigated the effects of two different hydrostatic pressures (seated or standing) during cold water immersion at attenuating the deleterious effects of strenuous exercise on indices of damage and recovery. Twenty four male well-trained games players (age 23 ± 3 years; body mass 81.4 ± 8.7 kg: [Formula: see text]O2max 57.5 ± 4.9 ml∙kg(-1)∙min(-1)) completed the Loughborough Intermittent Shuttle Test (LIST) and were randomly assigned to either a control, seated cold water immersion or a standing cold water immersion (14 min at 14°C). Maximal isometric voluntary contraction, counter-movement jump, creatine kinase, C-reactive protein, interleukin-6 and delayed onset muscle soreness (DOMS) were measured before and up to 72 h following the LIST. All dependent variables showed main effects for time (P < 0.05) following the LIST, indicating physiological stress and muscle damage following the exercise. There were no significant group differences between control and either of the cold water immersion interventions. Seated cold water immersion was associated with lower DOMS than standing cold water immersion (effect size = 1.86; P = 0.001). These data suggest that increasing hydrostatic pressure by standing in cold water does not provide an additional recovery benefit over seated cold water immersion, and that both seated and standing immersions have no benefit in promoting recovery following intermittent sprint exercise.


The effects of knowledge availability and knowledge accessibility on coherence and elaborative inferencing in children from six to fifteen years of age.
Two experiments are presented in which a novel knowledge base was acquired by 6- to 15-year-old children prior to hearing a multiepisode story, and where inferences from the story drew only on that knowledge base. Making knowledge equally available to all children did not attenuate age-related differences in either coherence or elaborative inferencing. Easily accessible knowledge was generally twice as likely to be used to make inferences during text comprehension as was knowledge that took longer to retrieve, though knowledge accessibility was more important for coherence inferencing in younger than in older children. Children made more coherence than elaborative inferences in the context of text comprehension, even though elaborative inferencing was more frequent in a simpler processing situation. Within the context of an available knowledge base, the results provide evidence for the importance of knowledge accessibility in children's inferencing, and for the changing developmental relevance of knowledge accessibility for coherence and elaborative inferencing.


ISG15 Is a Novel Regulator of Lipid Metabolism during Vaccinia Virus Infection.
Interferon-stimulated gene 15 (ISG15) is a 15-kDa ubiquitin-like modifier that binds to target proteins in a process termed ISGylation. ISG15, first described as an antiviral molecule against many viruses, participates in numerous cellular processes, from immune modulation to the regulation of genome stability. Interestingly, the role of ISG15 as a regulator of cell metabolism has recently gained strength. We previously described ISG15 as a regulator of mitochondrial functions in bone marrow-derived macrophages (BMDMs) in the context of Vaccinia virus (VACV) infection. Here, we demonstrate that ISG15 regulates lipid metabolism in BMDMs and that ISG15 is necessary to modulate the impact of VACV infection on lipid metabolism. We show that Isg15-/- BMDMs demonstrate alterations in the levels of several key proteins of lipid metabolism that result in differences in the lipid profile compared with Isg15+/+ (wild-type [WT]) BMDMs. Specifically, Isg15-/- BMDMs present reduced levels of neutral lipids, reflected by decreased lipid droplet number. These alterations are linked to increased levels of lipases and are independent of enhanced fatty acid oxidation (FAO). Moreover, we demonstrate that VACV causes a dysregulation in the proteomes of BMDMs and alterations in the lipid content of these cells, which appear exacerbated in Isg15-/- BMDMs. Such metabolic changes are likely caused by increased expression of the metabolic regulators peroxisome proliferator-activated receptor-γ (PPARγ) and PPARγ coactivator-1α (PGC-1α). In summary, our results highlight that ISG15 controls BMDM lipid metabolism during viral infections, suggesting that ISG15 is an important host factor to restrain VACV impact on cell metabolism. IMPORTANCE The functions of ISG15 are continuously expanding, and growing evidence supports its role as a relevant modulator of cell metabolism. In this work, we highlight how the absence of ISG15 impacts macrophage lipid metabolism in the context of viral infections and how poxviruses modulate metabolism to ensure successful replication. Our results open the door to new advances in the comprehension of macrophage immunometabolism and the interaction between VACV and the host.


Mitogen-activated protein kinase acts as a negative regulator of the heat shock response in NIH3T3 cells.
Exposure of NIH3T3 cells to elevated temperatures induces the phosphorylation and activation of mitogen-activated protein (MAP) kinases [or extracellular signal-regulated kinases (ERKs)]. To investigate the significance of MAP kinase activation by heat shock, we examined the effect of inhibiting the activity of MAP kinase on heat shock protein 70 (hsp 70) expression. Overexpression of a dominant inhibitory mutant of ERK1, but not ERK2, in heat-shocked cells increased hsp70 reporter gene activity, suggesting that ERK1 acts as a repressor of hsp70 gene expression. Increases in ERK1 activity through treatment of cells with sodium vanadate (SV), an inhibitor of the dual-specificity MAP kinase phosphatase 1 (PAC1), resulted in increased phosphorylation of the heat shock transcription factor-1 (HSF-1) in unheated cells, delayed the activation of HSF-1 by heat shock, and inhibited the induction of hsp 70 by heat shock. Furthermore, the induction of thermotolerance was reduced significantly in cells that increased ERK1 activity by SV pretreatment. Immune complex kinase assays of heat shocked or SV-pretreated cells indicated that HSF-1 is a potential in vivo substrate for ERK1 phosphorylation. Taken together, these results suggest that agents that modulate MAP kinase act as negative regulators of the heat shock response in mammalian cells by modulating HSF-1 activity and hsp 70 expression.


Quality improvement initiative: enhanced communication of newly identified, suspected GI malignancies with direct critical results messaging to surgical specialist.
To improve timely evaluation and management of newly identified, suspected, gastrointestinal (GI) malignancies discovered on radiologic imaging at a safety-net hospital through direct critical results messaging to surgical specialists. To address delays in evaluating patients for suspected GI malignancies identified on imaging, an enhanced workflow was created--electronically routed critical results messaging to the ordering provider was supplemented with parallel messaging to the surgical oncology clinic. Messaging data obtained for 10 months pre and post intervention were compared. Using chart reviews, time intervals were recorded to assess the impact on (1) being seen by a specialist, (2) completing a diagnostic workup and (3) initiating definitive management. Significant improvements were achieved: (1) patients seen by a specialist increased from 45.9% to 98.0% (p<0.001), with median time decreasing from 35 to 7 days (p<0.001); (2) patients completing a diagnostic workup increased from 77.1% to 93.9% (p<0.05), with median time decreasing from 44 to 18 days (p<0.001); (3) patients with initiation of definitive management increased from 72.1% to 89.8% (p<0.05), with median time decreasing from 62 to 35 days (p<0.05). Further study is needed to assess impact on fragmentation of care and financial implications. Direct critical results messaging from the radiologist to the surgical oncologist at a safety-net hospital significantly improves the time to complete a diagnostic workup and initiate definitive management with significantly more patients being seen by a relevant specialist.


A feasibility study of photoacoustic imaging of ex vivo endoscopic mucosal resection tissues from Barrett's esophagus patients.
Accurate endoscopic detection of dysplasia in patients with Barrett's esophagus (BE) remains a major clinical challenge. The current standard is to take multiple biopsies under endoscopic image guidance, but this leaves the majority of the tissue unsampled, leading to significant risk of missing dysplasia. Furthermore, determining whether there is submucosal invasion is essential for proper staging. Hence, there is a clinical need for a rapid in vivo wide-field imaging method to identify dysplasia in BE, with the capability of imaging beyond the mucosal layer. We conducted an ex vivo feasibility study using photoacoustic imaging (PAI) in patients undergoing endoscopic mucosal resection (EMR) for known dysplasia. The objective was to characterize the esophageal microvascular pattern, with the long-term goal of performing in vivo endoscopic PAI for dysplasia detection and therapeutic guidance. EMR tissues were mounted luminal side up. The tissues were scanned over a field of view of 14 mm (width) by 15 mm (depth) at 680, 750, and 850 nm (40 MHz acoustic central frequency). Ultrasound and photoacoustic images were simultaneously acquired. Tissues were then sliced and fixed in formalin for histopathology with hematoxylin and eosin staining. A total of 13 EMR specimens from eight patients were included in the analysis, which consisted of co-registration of the photoacoustic images with corresponding pathologist-classified histological images. We conducted mean difference test of the total hemoglobin distribution between tissue classes. Dysplastic and nondysplastic BE can be distinguished from squamous tissue in 84 % of region-of-interest comparisons (42/50). However, the ability of intrinsic PAI to distinguish dysplasia from NDBE, which is the clinically important challenge, was only about 33 % (10/30). We demonstrated the technical feasibility of this approach. Based on our ex vivo data, changes in total hemoglobin content from intrinsic PAI (i. e. without exogenous contrast) can differentiate BE from squamous esophageal mucosa. However, most likely intrinsic PAI is unable to differentiate dysplastic from nondysplastic BE with adequate sensitivity for clinical translation.


Risk and protection in the development of problem behaviors in adolescents.
The development of problem behaviors among adolescents is affected by complex interactions between risk and protective factors. This study was designed to determine whether selected risk and protective factors described among participants in the National Longitudinal Study of Adolescent Health predicted problem behavior cluster membership. Approximately, 13,000 adolescents from the Add Health study were examined. Three clusters of adolescents (exhibiting normal, problem, and deviant behaviors) and changes in cluster membership over 1 year were examined for relationships to specific risk and protective factors. Findings revealed that factors for current behavior problems differ from those for changes in cluster membership. These results suggest that approaches to preventing problems may differ from those required to help adolescents who are already manifesting problems.


National recommendations for donation after cardiocirculatory death in Canada: Donation after cardiocirculatory death in Canada.
These recommendations are the result of a national, multidisciplinary, year-long process to discuss whether and how to proceed with organ donation after cardiocirculatory death (DCD) in Canada. A national forum was held in February 2005 to discuss and develop recommendations on the principles, procedures and practice related to DCD, including ethical and legal considerations. At the forum's conclusion, a strong majority of participants supported proceeding with DCD programs in Canada. The forum also recognized the need to formulate and emphasize core values to guide the development of programs and protocols based on the medical, ethical and legal framework established at this meeting. Although end-of-life care should routinely include the opportunity to donate organs and tissues, the duty of care toward dying patients and their families remains the dominant priority of health care teams. The complexity and profound implications of death are recognized and should be respected, along with differing personal, ethnocultural and religious perspectives on death and donation. Decisions around withdrawal of life-sustaining therapies, management of the dying process and the determination of death by cardiocirculatory criteria should be separate from and independent of donation and transplant processes. The recommendations in this report are intended to guide individual programs, regional health authorities and jurisdictions in the development of DCD protocols. Programs will develop based on local leadership and advance planning that includes education and engagement of stakeholders, mechanisms to assure safety and quality and public information. We recommend that programs begin with controlled DCD within the intensive care unit where (after a consensual decision to withdraw life-sustaining therapy) death is anticipated, but has not yet occurred, and unhurried consent discussions can be held. Uncontrolled donation (where death has occurred after unanticipated cardiac arrest) should only be considered after a controlled DCD program is well established. Although we recommend that programs commence with kidney donation, regional transplant expertise may guide the inclusion of other organs. The impact of DCD, including pre-and post-mortem interventions, on donor family experiences, organ availability, graft function and recipient survival should be carefully documented and studied.


Habitat dependence and correlations between elasticities of long-term growth rates.
In population biology, elasticity is a measure of the importance of a demographic rate on population growth. A relatively small amount of stochasticity can substantially impact the dynamics of a population whose growth is a function of deterministic and stochastic processes. Analyses of natural populations frequently neglect the latter. Even in a population that fluctuates substantially with time, the results of a deterministic perturbation analysis correlated strongly with results of a perturbation analysis of the long-run stochastic growth rate. Population growth was, however, not uniformly sensitive to demographic rates across different environmental conditions. The overall correlation between deterministic and stochastic perturbation analysis may be high, but environmental variability can dramatically alter the contributions of demographic rates in different environmental conditions. This potentially informative detail is neglected by deterministic analysis, yet it highlights one difficulty when extrapolating results from long-term analysis to shorter-term environmental change.


Effect of immunosuppression on dengue virus infection in mice.
Mean survival time following intracerebral inoculation of dengue virus was reduced and the titre of the virus in the brain of immunosuppressed mice was markedly increased. A single dose of cyclophosphamide given 24 h after dengue virus i.c. or i.p. substantially reduced the number of antibody forming cells in the spleen. Three doses of dengue virus, each followed by cyclophosphamide 24 h later, produced specific hyporesponsiveness to the dengue virus but not to a heterologous virus (Coxsackie B4), with a reduction in antibody forming cells in the spleen of such animals against dengue virus but not against Coxsackie B4 virus. Adoptive immunity by antiserum was abolished along with increased titres of the virus in the brain of immunosuppressed mice but the protection could be restored by a second dose of antiserum. Pre-treatment of mice with immune or normal spleen cells i.v. or reconstitution of immunosuppressed mice by such cells had no effect. Thus, humoral antibodies play a crucially important role in host defence mechanism in recovery of mice from primary dengue virus infection.


Merkel cell polyomavirus: a specific marker for Merkel cell carcinoma in histologically similar tumors.
The recently described Merkel cell polyomavirus (MCPyV) is reportedly present in 50% to 80% of Merkel cell carcinomas (MCC). Although the virus has been shown to be absent from other cutaneous neoplasms, its association with malignancies that are histologically similar to MCC, specifically small cell carcinoma of the lung and other high-grade neuroendocrine tumors, has yet to be thoroughly investigated. To address this issue, we identified a set of 74 cases of visceral high-grade neuroendocrine tumors from a variety of anatomic sites, including 32 cases from the lung, 16 cases from the gastrointestinal tract, 20 cases from the female reproductive system, 3 cases from soft tissue, 2 cases from the head and neck region, and 1 case from the bladder. Using a set of primers optimized to detect MCPyV in formalin-fixed tissue, polymerase chain reaction (PCR)-based testing showed evidence of MCPyV DNA in only 1 of the 74 tumors; however, clinicopathologic review of the positive case (a neuroendocrine tumor of the small intestine) disclosed that the patient had a history of primary MCC of the buttock. PCR-based testing also showed no evidence of the related WU and KI polyomaviruses in the set of 74 cases. We conclude that, when evaluated by PCR-based testing, MCPyV is a specific marker for MCC that can be helpful in distinguishing cases of metastatic MCC from other high-grade neuroendocrine tumors. Our results also suggest that MCPyV does not have a role in the oncogenesis of visceral high-grade neuroendocrine tumors.


Periparturient climatic, animal, and management factors influencing the incidence of milk Fever in grazing systems.
The objective of the present study was to quantify the climatic, animal, and management factors influencing incidence of milk fever (MF) in cows exposed to grazing systems. Data were extracted on 4,469 calvings of multiparous cows in a seasonal calving research herd between 1970 and 2000. Climatic data during the calving period also were extracted for these years. Poisson regression was used to investigate the effect of climate on frequency of MF within year; the offset variable was the number of cows at risk for MF at that time. Generalized estimating equations, with cow included as a repeated effect, were used to quantify the effect of parturition-associated cow and management factors on the logit of the probability of MF. Both univariate and multivariate analyses were performed. Explanatory variables investigated included time of calving relative to the herd-year calving period, parity, body weight, breed of cow, body condition score at calving, weight and gender of the calf, incidence of twin calves, calving inductions, and calving assistance. Odds of recurring MF within cow, as well as the timing of MF relative to day of calving, was quantified using generalized estimating equations with cow included as a repeated effect. Results show significant effects of evaporation, minimum grass temperature, difference between ambient maximum and minimum temperature, and rainfall on the odds of MF occurring, with a greater incidence at greater evaporation, larger diurnal variation in air temperature, greater rainfall, and lesser grass minimum temperature. Cow factors, such as age, excessive or poor body condition score, and requirement for calving assistance increased the odds of MF; a lesser odds ratio was observed in cows hormonally induced to calve and those that had twin births. Results indicate that herd managers may identify the day of greatest risk for MF and cows that are at greatest risk of MF based on climatic, cow, and management factors.


Evaluation of mandibular invasion by head and neck cancers using 99mTc-methylene diphosphonate or 99mTc-hydroxymethylene diphosphonate and 201Tl chloride dual isotope single photon emission computed tomography.
Whether a patient with head and neck cancer has mandibular invasion or not is important in determining the method of resection surgery. But, no modality is adequately reliable when used alone in the evaluation of mandibular invasion. Therefore, to more accurately diagnose mandibular invasion in head and neck cancer, we used a new modality, namely, 99mTc methylene diphosphonate (MDP) or 99mTc hydroxymethylene diphosphonate (HMDP) and 201Tl chloride dual isotope single photon emission computed tomography (Tc/Tl SPECT). The aim of this study is to disclose the usefulness of Tc/Tl SPECT in the assessment of mandibular invasion by head and neck cancers. 99mTc-MDP or -HMDP SPECT (Tc SPECT)s and 201Tl chloride SPECT (Tl SPECT)s were performed in 34 patients with suspected mandibular involvement of head and neck cancer. Thirty of 34 cases underwent both TcMTl SPECT and CT examination. Tc/Tl SPECT fusion images were obtained using the Automatic Registration Tool (ART, TOSHIBA, Japan) system. In the diagnosis of mandibular invasion on Tc/Tl SPECT fusion images, a problem was that the range of Tc and Tl uptake was changed by the condition of display used in the reconstruction and expression of the images. Then, prior to clinical evaluation, to reveal the most appropriate upper window level for display, a phantom study was performed. In a clinical study, the upper window level was set at 40 or 50%, which were verified to be the proper values in the preliminary study. The diagnostic accuracy obtained using Tc SPECT, TcMTl SPECT and CT was compared with the histopathological findings. Tc/Tl SPECT at 40 and 50% upper window level had higher specificity, accuracy, and positive predictive value (73.3%, 85.3%, 81.8%) than Tc SPECT alone (21.4%, 67.6%, 64.5%) and higher sensitivity and negative predictive value (94.7%, 91.7%) than CT (70.6%, 72.2%) for detecting mandibular invasion. Tc/Tl SPECT was a useful diagnostic procedure for the assessment of mandibular invasion by head and neck cancers.


Release Factor Inhibiting Antimicrobial Peptides Improve Nonstandard Amino Acid Incorporation in Wild-type Bacterial Cells.
We report a tunable chemical genetics approach for enhancing genetic code expansion in different wild-type bacterial strains that employ apidaecin-like, antimicrobial peptides observed to temporarily sequester and thereby inhibit Release Factor 1 (RF1). In a concentration-dependent matter, these peptides granted a conditional lambda phage resistance to a recoded Escherichia coli strain with nonessential RF1 activity and promoted multisite nonstandard amino acid (nsAA) incorporation at in-frame amber stop codons in vivo and in vitro. When exogenously added, the peptides stimulated specific nsAA incorporation in a variety of sensitive, wild-type (RF1+) strains, including Agrobacterium tumefaciens, a species in which nsAA incorporation has not been previously reported. Improvement in nsAA incorporation was typically 2-15-fold in E. coli BL21, MG1655, and DH10B strains and A. tumefaciens with the >20-fold improvement observed in probiotic E. coli Nissle 1917. In-cell expression of these peptides promoted multisite nsAA incorporation in transcripts with up to 6 amber codons, with a >35-fold increase in BL21 showing moderate toxicity. Leveraging this RF1 sensitivity allowed multiplexed partial recoding of MG1655 and DH10B that rapidly resulted in resistant strains that showed an additional approximately twofold boost to nsAA incorporation independent of the peptide. Finally, in-cell expression of an apidaecin-like peptide library allowed the discovery of new peptide variants with reduced toxicity that still improved multisite nsAA incorporation >25-fold. In parallel to genetic reprogramming efforts, these new approaches can facilitate genetic code expansion technologies in a variety of wild-type bacterial strains.


Mediastinitis: Could your case be a candidate for candida?
Candida mediastinitis is rare, but mortality has been reported as high as 50%. There are no clinical trials evaluating treatment of Candida mediastinitis and there are only a limited number of reports in the literature. We present two cases of mediastinitis after coronary artery bypass grafting due to Candida albicans. Immunosuppression and long surgical procedures were likely risk factors for the infections. After multiple hospitalizations and debridements there was concern for the development of resistance. However, the isolates were determined to be fluconazole-susceptible and the patients were treated with long-term oral fluconazole. Candida mediastinitis is difficult to treat. Even with appropriate treatment, patients may require numerous surgical debridements.


Identification and functional characterization of cardiac troponin I as a novel disease gene in autosomal dominant dilated cardiomyopathy.
Idiopathic dilated cardiomyopathy (DCM) is inherited in approximately one third of cases, usually as an autosomal dominant trait. More than 30 loci have been identified, several of which encode sarcomeric proteins which can also be mutated to cause hypertrophic cardiomyopathy. One contractile protein gene well known as a hypertrophic cardiomyopathy disease gene, but with no reported mutation in autosomal dominant DCM, is TNNI3 which encodes cardiac troponin I. To test TNNI3 as a candidate gene, a panel of 96 probands with DCM was analyzed. Genomic DNA was isolated and TNNI3 exons screened by heteroduplex analysis. Exons with aberrant profiles were sequenced and variants evaluated by segregation analysis and study of normal controls. We report 2 novel TNNI3 missense mutations, Lys36Gln and Asn185Lys, each associated with severe and early onset familial DCM. Of the 5 mutation carriers, cardiac transplantation was required in 3, at ages 6, 15, and 24 years. Analysis of Ca(2+) regulation of actin-tropomyosin-activated myosin ATPase by troponin revealed that troponin reconstituted with either mutant troponin I gave lower maximum ATPase rates and lower Ca(2+) sensitivity than wild type. Furthermore, mutant thin filaments had reduced Ca(2+) affinity compared with normal. The functional alterations mirror closely a consistent phenotype found in proven DCM mutations in other thin filament proteins, thus supporting the interpretation that these mutations are disease-causing. These are the first reported autosomal dominant DCM-causing mutations in TNNI3, and so the findings expand the spectrum of disease-causing genes that lead to either hypertrophic cardiomyopathy or DCM depending on the specific mutation.


Biobehavioral Insights into Adaptive Behavior in Complex and Dynamic Operational Settings: Lessons learned from the Soldier Performance and Effective, Adaptable Response Task.
The purpose of this study was to explore the biobehavioral correlates of adaptive behavior in the context of a standardized laboratory-based mission-relevant challenge [the Soldier Performance and Effective, Adaptable Response (SPEAR) task]. Participants were 26 healthy male volunteers (M = 34.85 years, SD = 4.12) with active military duty and leadership experience within the last 5 years (i.e., multiple leadership positions, operational deployments in combat, interactions with civilians and partner nation forces on the battlefield, experience making decisions under fire). The SPEAR task simultaneously engages perception, cognition, and action aspects of human performance demands similar to those encountered in the operational setting. Participants must engage with military-relevant text, visual, and auditory stimuli, interpret new information, and retain the commander's intent in working memory to create a new plan of action for mission success. Time-domain measures of heart period and respiratory sinus arrhythmia (RSA) were quantified, and saliva was sampled [later assayed for cortisol and alpha-amylase (sAA)] before-, during-, and post-SPEAR. Results revealed a predictable pattern of withdraw and recovery of the cardiac vagal tone during repeated presentation of battlefield challenges. Recovery of vagal inhibition following executive function challenge was strongly linked to better task-related performance. Rate of RSA recovery was also associated with better recall of the commander's intent. Decreasing magnitude in the skin conductance response prior to the task was positively associated with better overall task-related performance. Lower levels of RSA were observed in participants who reported higher rates of combat deployments, and reduced RSA flexibility was associated with higher rates of casualty exposure. Greater RSA flexibility during SPEAR was associated with greater self-reported resilience. There was no consistent pattern of task-related change in cortisol or sAA. We conclude that individual differences in psychophysiological reactivity and regulation in response to an ecologically valid, military-relevant task are associated with performance-related adaptive behavior in this standardized operational setting. The implications for modern day warfare, where advancing our understanding of the nature of individual differences in adaptive problem solving is critical to mission success, fitness for duty, and other occupational health-related outcomes, are discussed.


Impact of percutaneous mitral valve repair using the MitraClip system on tricuspid regurgitation.
Tricuspid regurgitation (TR) severity and right ventricular (RV) dysfunction have been identified as significant predictors of outcome after mitral valve surgery. The aim of the present study was to investigate the impact of percutaneous mitral valve repair (PMVR) with the MitraClip system on functional TR severity and RV function. Among 119 consecutive patients with severe mitral regurgitation who underwent PMVR, 67 had complete baseline and follow-up transthoracic echocardiography after 3-12 months (6.8±2.9 months). TR severity was graded as mild, moderate, and severe. RV systolic function was assessed by fractional area change (FAC) and tricuspid annular plane systolic excursion (TAPSE). Clinical endpoints at follow-up included mortality, reoperation of the mitral valve, hospitalisation for congestive heart failure and New York Heart Association (NYHA) functional class. After PMVR, a significant decrease in TR severity (by at least one grade) was observed in 22 (33%) patients, while an increase occurred in only seven (10%) patients (p=0.02). Overall, systolic RV function (FAC and TAPSE), RV dimensions, and tricuspid annular diameter did not change significantly. Baseline SPAP was significantly higher (57±15 vs. 43±14 mmHg, p=0.002) and SPAP reduction significantly larger (-14±13 versus 1±15 mmHg, p=0.012) in patients who improved their TR. Multivariate logistic regression analysis identified the change in SPAP as the only significant predictor of changes in TR (odds ratio [OR] [for every change in SPAP by 10 mmHg] 1.90, 95% CI: 1.02±3.54; p=0.044). Patients with mild/moderate TR at follow-up after PMVR had lower event rates compared to those with severe TR (35% vs. 78%, respectively, p=0.025). PMVR using the MitraClip device improves functional TR severity in approximately one third of patients, particularly in those who experience a significant SPAP reduction after the procedure.


Low previous cardiovascular risk of patients with ST-elevation myocardial infarction.
Myocardial infarction is frequently the initial form of presentation of coronary artery disease (CAD). Systemic Coronary Risk Estimation (SCORE) risk tables are used in primary prevention and provide an estimate of cardiovascular (CV) risk through known risk factors. The aim of this study was to evaluate the performance of the SCORE, calculated using data previous to the event, to estimate CV risk of a population of patients presenting with ST-elevation myocardial infarction (STEMI) as the first manifestation of CAD. From a prospective registry including 3056 patients with STEMI subjected to coronary angiography between 2004 and 2014, 1628 patients with STEMI as the first manifestation of CAD were included after the exclusion of patients with known CAD (n=748, 24.5%), patients with high-risk equivalents (n=930, 30.4%), and patients with normal coronaries (n=57, 1.87%). The individual risk profile was calculated using data previous to the event and patients were classified into three established subgroups: low risk (SCORE<5%; n=1162, 71.4%), high risk (SCORE 5-10%; n=409, 25.1%), and very high risk (SCORE≥10%; n=57, 3.5%). In a population of patients with STEMI as the first manifestation of CAD, the CV risk stratification with the SCORE risk charts, if calculated before the event, would classify as low risk more than two-thirds of the patients (71.4%) and only 3.5% would be classified as very high-risk patients. The high prevalence of low-risk patients indicates the current challenge of CV risk stratification, underlying the need for additional tools in primary prevention to better identify patients at risk.


Basal ganglia play a unique role in task switching within the frontal-subcortical circuits: evidence from patients with focal lesions.
The performance of patients with lesions involving the basal ganglia (BG) was compared to that of patients with prefrontal (PFC) lesions, thalamic (TH) lesions, and age-matched controls in order to examine the specific role of the BG within the frontal-subcortical circuits (FSCC) in task switching. All the BG patients and none of the other participants showed a marked increase in error rate in incongruent trials where correct responses depended upon the choice of the correct task rule. Some BG patients erred in failing to switch tasks and others failed despite their attempt to switch tasks. Additionally, reaction time results indicate abnormal response repetition effects among the BG patients; failure in benefiting from advance task information among all the patients; and increased task mixing costs following PFC lesions. The authors conclude that although the frontal-subcortical circuits jointly determine some behaviors (such as benefiting from preparation), the BG play a unique role within the FSCC in action selection and/or the inhibition of irrelevant information.