Meningococcal Meningitis with Waterhouse-Friderichsen Syndrome.
This scenario was developed to educate junior and senior emergency medicine (EM) residents. It can also be cut short to be used for 4th year EM bound medical students. Meningococcal meningitis is a devastating disease that can cause severe neurologic sequelae if not diagnosed early and treated appropriately. In 2017, Centers for Disease Control reports a rate of 350 cases (0.11 cases per 100,000) which makes it an extremely rare disease. The highest reported rate is under the age of 1 (0.69 in 100,000) with second peak in adolescents and young adults between the ages of 16 and 23 (0.29 in 100,000) and third peak in patients above the age of 80 (0.49 in 100,000).1 The presentation for bacterial meningitis includes neck stiffness, fever, vomiting, photophobia, positive Kernig and Brudzinski's sign, and lethargy. In addition, 80% patients with meningococcal meningitis have rash during some stage of their disease.2 A feared and rare complication of severe meningococcal disease is Waterhouse-Friderichsen Syndrome (WFS) which carries a high mortality rate of 20%. Therefore, early diagnosis and rapid management of meningococcal disease is highly imperative.3 This simulation case was written to demonstrate the presentation of meningococcal meningitis and to discuss the management of WFS. By the end of this simulation session, learners will be able to: (1) manage a patient with altered mental status (AMS) with fever while maintaining a broad differential diagnosis, (2) recognize the risk factors for meningococcal meningitis, (3) manage a patient with worsening shock and perform appropriate resuscitation, (4) develop a differential diagnosis for thrombocytopenia and elevated international normalized ratio (INR) in an altered febrile hypotensive patient with rash, (5) manage the bleeding complications from WFS, (6) discuss the complications of meningococcal meningitis including WFS, and (7) review when meningitis prophylaxis is given. This session was conducted using high-fidelity simulation. It was immediately followed by an in-depth debriefing session. The session was conducted on a total of 9 EM residents from various levels of training who actively participated during the case and 25 residents who were observers. There was 1 simulation instructor running the session and 1 simulation technician who acted as a nurse. After the simulation and debriefing session was complete, an online survey was sent via surveymonkey.com to all the learners. The survey collected responses to the following questions: (1) the case was believable, (2) the case had right amount of complexity, (3) the case helped in improving medical knowledge and patient care, (4) the simulation environment gave me a real-life experience and, (5) the debriefing session after simulation helped improve my knowledge. A ten-item Likert scale was used to collect the responses. Ten learners responded to the survey. One hundred percent of them either agreed or strongly agreed that the case was beneficial in learning and improving patient care. They also agreed that it helped in improving medical knowledge. The post-session debrief was found to be very helpful by all the learners.. This high-fidelity simulation case was not only cost-effective but also was very helpful in teaching EM residents how to manage a patient with meningococcal meningitis and WFS. The case was started with the patient presenting with altered mental status and fever, and as the case unfolded, mental status and shock worsened allowing the learners to intubate and resuscitate. Overall, learners also found the discussion of prophylaxis valuable. Meningitis, altered mental status, medical simulation, infectious disease, neurology, septic shock, Waterhouse-Friderichsen Syndrome, hematology.


Heat shock factors at a crossroad between stress and development.
Organisms must be able to sense and respond rapidly to changes in their environment in order to maintain homeostasis and survive. Induction of heat shock proteins (Hsps) is a common cellular defense mechanism for promoting survival in response to various stress stimuli. Heat shock factors (HSFs) are transcriptional regulators of Hsps, which function as molecular chaperones in protecting cells against proteotoxic damage. Mammals have three different HSFs that have been considered functionally distinct: HSF1 is essential for the heat shock response and is also required for developmental processes, whereas HSF2 and HSF4 are important for differentiation and development. Specifically, HSF2 is involved in corticogenesis and spermatogenesis, and HSF4 is needed for maintenance of sensory organs, such as the lens and the olfactory epithelium. Recent evidence, however, suggests a functional interplay between HSF1 and HSF2 in the regulation of Hsp expression under stress conditions. In lens formation, HSF1 and HSF4 have been shown to have opposite effects on gene expression. In this chapter, we present the different roles of the mammalian HSFs as regulators of cellular stress and developmental processes. We highlight the interaction between different HSFs and discuss the discoveries of novel target genes in addition to the classical Hsps.


Selective suppression of rapid eye movement sleep increases next-day negative affect and amygdala responses to social exclusion.
Healthy sleep, positive general affect, and the ability to regulate emotional experiences are fundamental for well-being. In contrast, various mental disorders are associated with altered rapid eye movement (REM) sleep, negative affect, and diminished emotion regulation abilities. However, the neural processes mediating the relationship between these different phenomena are still not fully understood. In the present study of 42 healthy volunteers, we investigated the effects of selective REM sleep suppression (REMS) on general affect, as well as on feelings of social exclusion, cognitive reappraisal (CRA) of emotions, and their neural underpinnings. Using functional magnetic resonance imaging we show that, on the morning following sleep suppression, REMS increases general negative affect, enhances amygdala responses and alters its functional connectivity with anterior cingulate cortex during passively experienced experimental social exclusion. However, we did not find effects of REMS on subjective emotional ratings in response to social exclusion, their regulation using CRA, nor on functional amygdala connectivity while participants employed CRA. Our study supports the notion that REM sleep is important for affective processes, but emphasizes the need for future research to systematically investigate how REMS impacts different domains of affective experience and their neural correlates, in both healthy and (sub-)clinical populations.


Transcriptional regulatory network triggered by oxidative signals configures the early response mechanisms of japonica rice to chilling stress.
The transcriptional regulatory network involved in low temperature response leading to acclimation has been established in Arabidopsis. In japonica rice, which can only withstand transient exposure to milder cold stress (10 degrees C), an oxidative-mediated network has been proposed to play a key role in configuring early responses and short-term defenses. The components, hierarchical organization and physiological consequences of this network were further dissected by a systems-level approach. Regulatory clusters responding directly to oxidative signals were prominent during the initial 6 to 12 hours at 10 degrees C. Early events mirrored a typical oxidative response based on striking similarities of the transcriptome to disease, elicitor and wounding induced processes. Targets of oxidative-mediated mechanisms are likely regulated by several classes of bZIP factors acting on as1/ocs/TGA-like element enriched clusters, ERF factors acting on GCC-box/JAre-like element enriched clusters and R2R3-MYB factors acting on MYB2-like element enriched clusters.Temporal induction of several H2O2-induced bZIP, ERF and MYB genes coincided with the transient H2O2 spikes within the initial 6 to 12 hours. Oxidative-independent responses involve DREB/CBF, RAP2 and RAV1 factors acting on DRE/CRT/rav1-like enriched clusters and bZIP factors acting on ABRE-like enriched clusters. Oxidative-mediated clusters were activated earlier than ABA-mediated clusters. Genome-wide, physiological and whole-plant level analyses established a holistic view of chilling stress response mechanism of japonica rice. Early response regulatory network triggered by oxidative signals is critical for prolonged survival under sub-optimal temperature. Integration of stress and developmental responses leads to modulated growth and vigor maintenance contributing to a delay of plastic injuries.


Independent Validation of a Diagnostic Noninvasive 3-MicroRNA Ratio Model (uCaP) for Prostate Cancer in Cell-Free Urine.
Detection of prostate cancer (PC) based on serum prostate-specific antigen (PSA) testing leads to many unnecessary prostate biopsies, overdiagnosis, and overtreatment of clinically insignificant tumors. Thus, novel and more accurate molecular biomarkers are required. Using reverse transcription quantitative PCR, we measured the concentrations of 45 preselected microRNAs (miRNAs) in extracellular vesicle-enriched cell-free urine samples from 4 independent patient cohorts from Spain and Denmark, including 758 patients with clinically localized PC, 289 noncancer controls with benign prostatic hyperplasia (BPH), and 233 patients undergoing initial transrectal ultrasound (TRUS)-guided prostate biopsy owing to PC suspicion (101 with benign and 132 with malignant outcome). Diagnostic potential was assessed by ROC and decision curve analysis. We identified and successfully validated 8 upregulated and 21 downregulated miRNAs in urine from PC patients. Furthermore, we validated a previously identified 3-miRNA diagnostic ratio model, uCaP (miR-222-3p*miR-24-3p/miR-30c-5p). High uCaP scores were distinctive of PC in urine samples from BPH vs PC patients in 3 independent cohorts [area under the curve (AUC) = 0.84, 0.71, 0.72]. Additionally, uCaP predicted TRUS biopsy results with greater accuracy than PSA (AUC uCaP = 0.644; AUC PSA = 0.527) for patients within the diagnostic gray zone (PSA ≤ 10 ng/mL). We successfully validated a urine-based diagnostic 3-miRNA signature for PC (uCaP) in 3 independent patient cohorts from 2 countries. In the future, the simple and noninvasive uCaP test may be used to help more accurately select patients for prostate biopsy. Prospective clinical validation is warranted.


Human amniotic fluid stem cells can integrate and differentiate into epithelial lung lineages.
A new source of stem cells has recently been isolated from amniotic fluid; these amniotic fluid stem cells have significant potential for regenerative medicine. These cells are multipotent, showing the ability to differentiate into cell types from each embryonic germ layer. We investigated the ability of human amniotic fluid stem cells (hAFSC) to integrate into murine lung and to differentiate into pulmonary lineages after injury. Using microinjection into cultured mouse embryonic lungs, hAFSC can integrate into the epithelium and express the early human differentiation marker thyroid transcription factor 1 (TTF1). In adult nude mice, following hyperoxia injury, tail vein-injected hAFSC localized in the distal lung and expressed both TTF1 and the type II pneumocyte marker surfactant protein C. Specific damage of Clara cells through naphthalene injury produced integration and differentiation of hAFSC at the bronchioalveolar and bronchial positions with expression of the specific Clara cell 10-kDa protein. These results illustrate the plasticity of hAFSC to respond in different ways to different types of lung damage by expressing specific alveolar versus bronchiolar epithelial cell lineage markers, depending on the type of injury to recipient lung. Disclosure of potential conflicts of interest is found at the end of this article.


Ethanol attenuates spatial memory deficits and increases mGlu1a receptor expression in the hippocampus of rats exposed to prenatal stress.
Although it is generally believed that chronic ethanol consumption impairs learning and memory, results obtained in experimental animals are not univocal, and there are conditions in which ethanol paradoxically improves cognitive functions. In the present work, we investigated the effects of prenatal stress and of chronic ethanol exposure during adulthood on spatial memory in rats. Rats were subjected to a prenatal stress delivered as 3 daily 45-minute sections of restraint stress to the mothers during the last 10 days of pregnancy (PRS rats). After 7 months of ethanol exposure (ethanol 10%, oral intake), memory performances were evaluated in a spatial discrimination test in control and PRS male rats. Then, the oxidative damages and the expression of metabotropic glutamate (mGlu) receptors were assessed in their hippocampus. Chronic ethanol exposure resulted in a reduced performance in a spatial recognition task in control animals. Unexpectedly, however, the same treatment attenuated spatial memory deficits in rats that had been subjected to prenatal stress. This paradigm of ethanol administration did not produce detectable signs of oxidative damage in the hippocampus in either unstressed or PRS rats. Interestingly, ethanol intake resulted in differential effects in the expression of mGlu receptor subtypes implicated in mechanisms of learning and memory. In control rats, ethanol intake reduced mGlu2/3 and mGlu5 receptor levels in the hippocampus; in PRS rats, which exhibited a constitutive reduction in the levels of these mGlu receptor subtypes, ethanol increased the expression of mGlu1a receptors but did not change the expression of mGlu2/3 or mGlu5 receptors. Our findings support the idea that stress-related events occurring before birth have long-lasting effects on brain function and behavior, and suggest that the impact of ethanol on cognition is not only dose- and duration-dependent, but also critically influenced by early life experiences.


Aberrantly up-regulated miR-20a in pre-eclampsic placenta compromised the proliferative and invasive behaviors of trophoblast cells by targeting forkhead box protein A1.
Preeclampsia is a serious complication in pregnancy. Dysregulation of trophoblast cell proliferation and invasion is a major pathological alteration observed in preeclampsia. Recently, microRNAs were shown to participate in the pathogenesis of preeclampsia. In this study we explored the effect of miR-20a on the proliferation and invasion of trophoblast cells and the underlying mechanism. We verified the distribution of miR-20a in human placenta by in situ hybridization. Real time PCR data showed that the level of miR-20a increased by 2.6 folds in human preeclampsia than normal tissues. We then cultured trophoblast-like JEG-3 cells and evaluated the effect of miR-20a on JEG-3 cell proliferation, migration and invasion. Overexpression of miR-20a significantly inhibited the proliferation, migration and invasion of cultured JEG-3 cells, which were abolished by co-transfection of AMO-20a. Transfection of miR-20a also inhibited JEG-3 cell xenograft tumor growth in nude mice. Luciferase assay technique was used to identify the direct regulation of miR-20a on Forkhead Box Protein A1(FOXA1). Transfection of miR-20a markedly reduced the luciferase activity of the chimeric plasmid containing the 3'UTR of FOXA1, indicating FOXA1 is the target of miR-20a. Furthermore, transfection of miR-20a inhibited both protein and mRNA expression of FOXA1 in JEG-3 cells. In summary, the upregulated miR-20a in human preeclampsia tissue can inhibit the proliferative and invasive activities of trophoblast cells by repressing the expression of FOXA1.


Development of an Italian RM Y-STR haplotype database: Results of the 2013 GEFI collaborative exercise.
Recently introduced rapidly mutating Y-chromosomal short tandem repeat (RM Y-STR) loci, displaying a multiple-fold higher mutation rate relative to any other Y-STRs, including those conventionally used in forensic casework, have been demonstrated to improve the resolution of male lineage differentiation and to allow male relative separation usually impossible with standard Y-STRs. However, large and geographically-detailed frequency haplotype databases are required to estimate the statistical weight of RM Y-STR haplotype matches if observed in forensic casework. With this in mind, the Italian Working Group (GEFI) of the International Society for Forensic Genetics launched a collaborative exercise aimed at generating an Italian quality controlled forensic RM Y-STR haplotype database. Overall 1509 male individuals from 13 regional populations covering northern, central and southern areas of the Italian peninsula plus Sicily were collected, including both "rural" and "urban" samples classified according to population density in the sampling area. A subset of individuals was additionally genotyped for Y-STR loci included in the Yfiler and PowerPlex Y23 (PPY23) systems (75% and 62%, respectively), allowing the comparison of RM and conventional Y-STRs. Considering the whole set of 13 RM Y-STRs, 1501 unique haplotypes were observed among the 1509 sampled Italian men with a haplotype diversity of 0.999996, largely superior to Yfiler and PPY23 with 0.999914 and 0.999950, respectively. AMOVA indicated that 99.996% of the haplotype variation was within populations, confirming that genetic-geographic structure is almost undetected by RM Y-STRs. Haplotype sharing among regional Italian populations was not observed at all with the complete set of 13 RM Y-STRs. Haplotype sharing within Italian populations was very rare (0.27% non-unique haplotypes), and lower in urban (0.22%) than rural (0.29%) areas. Additionally, 422 father-son pairs were investigated, and 20.1% of them could be discriminated by the whole set of 13 RM Y-STRs, which was very close to the theoretically expected estimate of 19.5% given the mutation rates of the markers used. Results obtained from a high-coverage Italian haplotype dataset confirm on the regional scale the exceptional ability of RM Y-STRs to resolve male lineages previously observed globally, and attest the unsurpassed value of RM Y-STRs for male-relative differentiation purposes.


The 2011 Tuscaloosa tornado: integration of pediatric disaster services into regional systems of care.
To empirically describe the integration of pediatric disaster services into regional systems of care after the April 27, 2011, tornado in Tuscaloosa, Alabama, a community with no pediatric emergency department or pediatric intensive care unit and few pediatric subspecialists. Data were obtained in interviews with key informants including professional staff and managers from public health and emergency management agencies, prehospital emergency medical services, fire departments, hospital nurses, physicians, and the trauma program coordinator. A single hospital in Tuscaloosa served 800 patients on the night of the tornado. More than 100 of these patients were children, including more than 20 with critical injuries. Many children were unaccompanied and unidentified on arrival. Resuscitation and stabilization were performed by nonpediatric prehospital and emergency department staff. More than 20 children were secondarily transported to the nearest children's hospital an hour's drive away under the care of nonpediatric local emergency medical services providers. No preventable adverse events were identified in the resuscitation and secondary transport phases of care. Stockpiled supplies and equipment were adequate to serve the needs of the disaster victims, including the children. Essential aspects of preparation include pediatric-specific clinical skills, supplies and equipment, operational disaster plans, and interagency practice embedded in everyday work. Opportunities for improvement identified include more timely response to warnings, improved practices for identifying unaccompanied children, and enhanced child safety in shelters. Successful responses depended on integration of pediatric services into regional systems of care.


Trends in Outpatient Antibiotic Use in 3 Health Plans.
Previous analyses of data from 3 large health plans suggested that the substantial downward trend in antibiotic use among children appeared to have attenuated by 2010. Now, data through 2014 from these same plans allow us to assess whether antibiotic use has declined further or remained stable. Population-based antibiotic-dispensing rates were calculated from the same health plans for each study year between 2000 and 2014. For each health plan and age group, we fit Poisson regression models allowing 2 inflection points. We calculated the change in dispensing rates (and 95% confidence intervals) in the periods before the first inflection point, between the first and second inflection points, and after the second inflection point. We also examined whether the relative contribution to overall dispensing rates of common diagnoses for which antibiotics were prescribed changed over the study period. We observed dramatic decreases in antibiotic dispensing over the 14 study years. Despite previous evidence of a plateau in rates, there were substantial additional decreases between 2010 and 2014. Whereas antibiotic use rates decreased overall, the fraction of prescribing associated with individual diagnoses was relatively stable. Prescribing for diagnoses for which antibiotics are clearly not indicated appears to have decreased. These data revealed another period of marked decline from 2010 to 2014 after a relative plateau for several years for most age groups. Efforts to decrease unnecessary prescribing continue to have an impact on antibiotic use in ambulatory practice.


Oxidation of butylated hydroxytoluene to toxic metabolites. Factors influencing hydroxylation and quinone methide formation by hepatic and pulmonary microsomes.
The effects of inducing agents and inhibitors on the cytochrome P-450-catalyzed oxidations of butylated hydroxytoluene (BHT) to form three metabolites were investigated with liver and lung microsomes from rats and mice. These compounds, the quinone methide (QM) formed by two-electron oxidation of BHT, the hydroxy-tert-butyl analog of BHT (BHT-OH) resulting from aliphatic hydroxylation, and the hydroxy-quinone methide (QM-OH) derived from BHT-OH, have been implicated previously as intermediates or products involved in BHT bioactivation and toxicity. Although there was little or no increase in BHT metabolism in pulmonary microsomes from either species following phenobarbital (PB) administration, 6- to 37-fold enhancements occurred in the transformation of BHT to QM, and the conversion of BHT-OH to QM-OH with hepatic microsomes from both species. The first step in QM-OH formation, hydroxylation of BHT to BHT-OH, is a minor pathway with hepatic microsomes from treated or untreated rats, thereby explaining the lack of QM-OH formation from BHT by that species. The two-step oxidation of BHT to QM-OH, however, is a relatively important metabolic pathway with hepatic microsomes from PB-treated mice, due to an unusually large (111-fold) PB-induced increase in the tert-butyl hydroxylation step. These results demonstrate that pulmonary microsomes from mice, but not rats, have relatively high constitutive P-450 activity for the formation of QM-OH from BHT, supporting the proposal that this metabolite is involved in BHT-induced pneumotoxicity.(ABSTRACT TRUNCATED AT 250 WORDS)


Lennard-Jones Parameters Determined to Reproduce the Solubility of NaCl and KCl in SPC/E, TIP3P, and TIP4P/2005 Water.
Most classical nonpolarizable ion potential models underestimate the solubility values of NaCl and KCl in water significantly. We determine Lennard-Jones parameters of Na+, K+, and Cl- that reproduce the solubility as well as the hydration free energy in dilute aqueous solutions for three water potential models, SPC/E, TIP3P, and TIP4P/2005. The ion-oxygen distance in the solution and the cation-anion distance in salt are also considered in the parametrization. In addition to the target properties, the hydration enthalpy, hydration entropy, self-diffusion coefficient, coordination number, lattice energy, enthalpy of solution, density, viscosity, and number of contact ion pairs are calculated for comparison with 17 frequently used or recently developed ion potential models. The overall performance of each ion model is represented by a global score using a scheme that was originally developed for comparison of water potential models. The global score is better for our models than for the other 17 models not only because of the quite good prediction for the solubility but also because of the relatively small deviation from the experimental value for many of the other properties.


Growth Hormone Treatment Improves Cognitive Function in Short Children with Growth Hormone Deficiency.
We investigated the association between cognition and growth hormone (GH) status and GH treatment in short prepubertal children with broadly ranging GH secretion. A total of 99 children (age 3-11 years), 41 with GH deficiency (GHD) and 58 with idiopathic short stature (ISS), were randomized to a fixed dose (43 µg/kg/day) or a prediction model-guided individualized dose (17-100 µg/kg/day) and followed up for 24 months. In a longitudinal and mixed within- and between-subjects study, we examined clinical effect size changes, measured by Cohen's d, in full-scale IQ (FSIQ) and secondary IQ indices. Significant increases giving medium effect size in FSIQ (p = 0.001, Cohen's d = 0.63), performance IQ (p = 0.001, Cohen's d = 0.65) and processing speed (p = 0.005, Cohen's d = 0.71) were found in the GH-deficient group. In contrast, perceptual organization only increased in the ISS group (p = 0.001, Cohen's d = 0.53). Baseline IQ was normally distributed with small but significant differences between the groups: GH-deficient children had lower FSIQ (p = 0.042) and lower performance IQ (p = 0.021). Using multiple regression analysis, 40% of the variance in delta processing speed scores (0-24 months) was explained by GHmax and IGF-ISDS at baseline. IQ, specifically fluid intelligence, increased in the GH-deficient children. The pretreatment status of the GH/IGF-I axis was significantly predictive for these changes. © 2015 S. Karger AG, Basel.


The spectrum of practice in the diagnosis and management of pneumonia in patients requiring mechanical ventilation. Australian and New Zealand practice in intensive care (ANZPIC II).
This study of ventilated patients investigated current clinical practice in 476 episodes of pneumonia (48% community-acquired pneumonia, 24% hospital-acquired pneumonia, 28% ventilator-associated pneumonia) using a prospective survey in 14 intensive care units (ICUs) within Australia and New Zealand. Diagnostic methods and confidence, disease severity, microbiology and antibiotic use were assessed. All pneumonia types had similar mortality (community-acquired pneumonia 33%, hospital-acquired pneumonia 37% and ventilator-associated pneumonia 24%, P=0.15) with no inter-hospital differences (P=0.08-0.91). Bronchoscopy was performed in 26%, its use predicted by admission hospital (one tertiary: OR 9.98, CI 95% 5.11-19.49, P< 0.001; one regional: OR 6.29, CI 95% 3.24-12.20, P<0.001), clinical signs of consolidation (OR 3.72, CI 95% 2.09-6.62, P<0.001) and diagnostic confidence (OR 2.19, CI 95% 1.29-3.72, P=0.004). Bronchoscopy did not predict outcome (P=0.11) or appropriate antibiotic selection (P=0.69). Inappropriate antibiotic prescription was similar for all pneumonia types (11-13%, P=0.12) and hospitals (0-16%, P=0.25). Blood cultures were taken in 51% of cases. For community-acquired pneumonia, 70% received a third generation cephalosporin and 65% a macrolide. Third generation cephalosporins were less frequently used for mild infections (OR 0.38, CI 95% 0.16-0.90, P=0.03), hospital-acquired pneumonia (OR 0.40, CI 95% 0.23-0.72, P<0.01), ventilator-associated pneumonia (OR 0.04, CI 95% 0.02-0.13, P<0.001), suspected aspiration (OR 0.20, CI 95% 0.04-0.92, P=0.04), in one regional (OR 0.26, CI95% 0.07-0.97, P=0.05) and one tertiary hospital (OR 0.14, CI 95% 0.03-0. 73, P=0.02) but were more commonly used in older patients (OR 1.02, CI 95% 1.01-1.03, P=0.01). There is practice variability in bronchoscopy and antibiotic use for pneumonia in Australian and New Zealand ICUs without significant impact on patient outcome, as the prevalence of inappropriate antibiotic prescription is low. There are opportunities for improving microbiological diagnostic work-up for isolation of aetiological pathogens.


Dietary cholesterol and the risk of cardiovascular disease in patients: a review of the Harvard Egg Study and other data.
For many years, both the medical community and the general public have incorrectly associated eggs with high serum cholesterol and being deleterious to health, even though cholesterol is an essential component of cells and organisms. It is now acknowledged that the original studies purporting to show a linear relation between cholesterol intake and coronary heart disease (CHD) may have contained fundamental study design flaws, including conflated cholesterol and saturated fat consumption rates and inaccurately assessed actual dietary intake of fats by study subjects. Newer and more accurate trials, such as that conducted by Frank B. Hu of the Harvard School of Public Health (1999), have shown that consumption of up to seven eggs per week is harmonious with a healthful diet, except in male patients with diabetes for whom an association in higher egg intake and CHD was shown. The degree to which serum cholesterol is increased by dietary cholesterol depends upon whether the individual's cholesterol synthesis is stimulated or down-regulated by such increased intake, and the extent to which each of these phenomena occurs varies from person to person. Several recent studies have shed additional light on the specific interplay between dietary cholesterol and cardiovascular health risk. It is evident that the dynamics of cholesterol homeostasis, and of development of CHD, are extremely complex and multifactorial. In summary, the earlier purported adverse relationship between dietary cholesterol and heart disease risk was likely largely over-exaggerated.


Regiospecific [2 + 2] photocyclodimerization of trans-4-styrylpyridines templated by cucurbit[8]uril.
Addition of HCl accelerated the photocyclodimerization of trans-4-styrylpyridine 1a in methanol and increased the yield of syn-head-to-tail (syn-HT) dimer 2a through the effect of cation-π interactions between the pyridinium ion of one molecule and the phenyl group of the other. We examined the photoirradiation products of derivatives of 1a having alkyl substituents on the phenyl group (1b-1f). The effect of the alkyl substituent on product distribution was rather limited for the photoreaction in MeOH solutions. However, the substituents had a distinct effect on the product distribution for the photoreaction of the inclusion complexes of hydrochloride salts of trans-4-styrylpyridines with cucurbit[8]uril in aqueous solutions. Introducing an alkyl group at the 2- or 3-position of the phenyl group completely shifted the major product from the syn-HT dimer to the syn-head-to-head (syn-HH) dimer. By adjusting the balance of host-guest interactions and cation-π interactions between guest molecules through systematic changes in the substituents on the phenyl ring of trans-4-styrylpyridine, we could change the orientation of the reactant molecules in the host cavity, resulting in a change of the major regioisomer of the photocyclodimerization products.


Hamster Weight Patterns Predict the Intensity and Course of Schistosoma haematobium Infection.
Although Syrian golden hamsters are widely used as hosts for experimental infection by Schistosoma haematobium , surprisingly little is known about the course of infection and associated intensity (as defined by measures of parasite burden). As such, we sought to define inexpensive, simple, noninvasive, and accurate methods for assessing and predicting the severity of disease in S. haematobium -infected hamsters in order to prevent premature hamster sacrifice and unexpected morbidity and mortality. Through monitoring the weight and behavior of infected hamsters, we determined that the weight-loss patterns of infected hamsters are highly correlated with commonly used measures of the severity of infection (i.e., numbers of eggs passed in the stool, worm burdens, and total egg yields). In contrast, we found no significant correlation between hamster weight-loss patterns and egg yields from liver and intestinal tissues. Our findings suggest that a more complex relationship exists among worm burden, fecundity, and egg passage in the feces than previously appreciated. Regardless, our data may be useful for workers seeking to optimize harvests of S. haematobium eggs and worms from infected hamsters for downstream applications.


Cannabis health knowledge and risk perceptions among Canadian youth and young adults.
Although recreational cannabis is now legal in Canada, little empirical evidence exists regarding young Canadians' cannabis literacy, cannabis-related risk perceptions, and risk of different forms of cannabis or the effect that public health education may have on these perceptions. The present study sought to address these knowledge gaps to examine health knowledge and risk perceptions associated with cannabis use. An online survey was conducted with a national sample (N = 870) of Canadians aged 16 to 30 years in October 2017 using a commercial panel. The study examined young Canadians' awareness of negative health effects related to cannabis, evaluation of known risks, and risk perceptions of different forms of administration. Most respondents were aware of a cannabis-related physical health effect (78.0%). Approximately one-third reported having been exposed to public health messaging about cannabis; digital media was reported most frequently. Compared to never users, ever users were less likely to report general likelihood of addiction (p < 0.001) and harm to mental health (p < 0.001). Approximately one-quarter of past 3-month cannabis users reported they were at least "a little" addicted. Respondents who reported using a particular form of cannabis self-administration (e.g., edibles, smokables) were less likely to perceive harm than those who did not use each form (p < 0.001). The current study is among the first to measure the knowledge and perceptions of risks of Canadian youth about cannabis. The study, conducted in the time immediately preceding legalization, may serve as a reference point for future studies examining changes in cannabis knowledge and risk perceptions. This will be important in addressing the need for monitoring and enhancing public awareness of the impact and potential harms of this newly legalized substance.


Nanometrology optical ruler imaging system using diffraction from a quasiperiodic structure.
This work demonstrates wafer-scale, path-independent, atomically-based long term-stable, position nanometrology. This nanometrology optical ruler imaging system uses the diffraction pattern of an atomically stabilized laser from a microfabricated quasiperiodic aperture array as a two-dimensional optical ruler. Nanometrology is accomplished by cross correlations of image samples of this optical ruler. The quasiperiodic structure generates spatially dense, sharp optical features. This work demonstrates new results showing positioning errors down to 17.2 nm over wafer scales and long term stability below 20 nm over six hours. This work also numerically demonstrates robustness of the optical ruler to variations in the microfabricated aperture array and discretization noise in imagers.


Genome diversity of Leishmania aethiopica.
Leishmania aethiopica is a zoonotic Old World parasite transmitted by Phlebotomine sand flies and causing cutaneous leishmaniasis in Ethiopia and Kenya. Despite a range of clinical manifestations and a high prevalence of treatment failure, L. aethiopica is one of the most neglected species of the Leishmania genus in terms of scientific attention. Here, we explored the genome diversity of L. aethiopica by analyzing the genomes of twenty isolates from Ethiopia. Phylogenomic analyses identified two strains as interspecific hybrids involving L. aethiopica as one parent and L. donovani and L. tropica respectively as the other parent. High levels of genome-wide heterozygosity suggest that these two hybrids are equivalent to F1 progeny that propagated mitotically since the initial hybridization event. Analyses of allelic read depths further revealed that the L. aethiopica - L. tropica hybrid was diploid and the L. aethiopica - L. donovani hybrid was triploid, as has been described for other interspecific Leishmania hybrids. When focusing on L. aethiopica, we show that this species is genetically highly diverse and consists of both asexually evolving strains and groups of recombining parasites. A remarkable observation is that some L. aethiopica strains showed an extensive loss of heterozygosity across large regions of the nuclear genome, which likely arose from gene conversion/mitotic recombination. Hence, our prospection of L. aethiopica genomics revealed new insights into the genomic consequences of both meiotic and mitotic recombination in Leishmania.


Effect of desensitizing agents on the microtensile bond strength of a two-step self-etch adhesive to dentin.
The aim of this in vitro study was to evaluate the effect of cervical hypersensitivity treatments (neodymium yttrium aluminum garnet [Nd:YAG] laser and conventional techniques) on the microtensile bond strengths of adhesives to treated dentin. The buccal cervical enamel of 42 freshly extracted human mandibular third molars was ground flat to expose the cervical dentin. The dentin surfaces were polished with a series of silicon carbide papers, and the smear was removed with an ethylenediamine tetra-acetic acid solution. The teeth were randomly divided into six groups as follows: group 1, Vivasens; group 2, BisBlock; group 3, fluoride gel; group 4, Nd:YAG laser; group 5, Clearfil SE + Nd:YAG laser; and group 6, no treatment (control). The specimens were then restored with a two-step self-etch adhesive, with the exception of group 5. Five specimens from each group were restored with a nanohybrid composite resin. The adhesive interface of two specimens from each group was examined using scanning electron microscopy. The specimens were sectioned perpendicularly to the adhesive interface to produce beams (adhesive area 1 mm(2)). The beams were then attached to a microtensile tester and stressed to failure at 1 mm/min. The data were compared using one-way analysis of variance at a significance level of 0.05. The microtensile bond strengths of the control group were significantly higher than those found for group 1, group 2, group 3, and group 4 (p< 0.05). No significant difference was found between group 5 and the control group. Most of the premature failures were seen in group 2 (80%), and the fewest premature failures were seen in group 5 (13.3%). The SEM findings verified the microtensile test findings. In conclusion, desensitizing treatment procedures (with the exception of Clearfil SE + Nd:YAG laser) reduced the microtensile bond strength of a two-step self-etch adhesive to dentin.


The origins of multicellularity: a multi-taxon genome initiative.
The emergence of multicellular organisms from single-celled ancestors -- which occurred several times, independently in different branches of the eukaryotic tree -- is one of the most profound evolutionary transitions in the history of life. These events not only radically changed the course of life on Earth but also created new challenges, including the need for cooperation and communication between cells, and the division of labor among different cell types. However, the genetic changes that accompanied the several origins of multicellularity remain elusive. Recently, the National Human Genome Research Institute (NHGRI) endorsed a multi-taxon genome-sequencing initiative that aims to gain insights into how multicellularity first evolved. This initiative (which we have termed UNICORN) will generate extensive genomic data from some of the closest extant unicellular relatives of both animals and fungi. Here, we introduce this initiative and the biological questions that underpin it, summarize the rationale guiding the choice of organisms and discuss the anticipated benefits to the broader scientific community.


Socioeconomic inequalities in childhood exposure to secondhand smoke before and after smoke-free legislation in three UK countries.
Secondhand smoke (SHS) exposure is higher among lower socioeconomic status (SES) children. Legislation restricting smoking in public places has been associated with reduced childhood SHS exposure and increased smoke-free homes. This paper examines socioeconomic patterning in these changes. Repeated cross-sectional survey of 10 867 schoolchildren in 304 primary schools in Scotland, Wales and Northern Ireland. Children provided saliva for cotinine assay, completing questionnaires before and 12 months after legislation. SHS exposure was highest, and private smoking restrictions least frequently reported, among lower SES children. Proportions of saliva samples containing <0.1 ng/ml (i.e. undetectable) cotinine increased from 31.0 to 41.0%. Although across the whole SES spectrum, there was no evidence of displacement of smoking into the home or increased SHS exposure, socioeconomic inequality in the likelihood of samples containing detectable levels of cotinine increased. Among children from the poorest families, 96.9% of post-legislation samples contained detectable cotinine, compared with 38.2% among the most affluent. Socioeconomic gradients at higher exposure levels remained unchanged. Among children from the poorest families, one in three samples contained >3 ng/ml cotinine. Smoking restrictions in homes and cars increased, although socioeconomic patterning remained. Urgent action is needed to reduce inequalities in SHS exposure. Such action should include emphasis on reducing smoking in cars and homes.


Resveratrol attenuates peripheral and brain inflammation and reduces ischemic brain injury in aged female mice.
Resveratrol is known to improve metabolic dysfunction associated with obesity. Visceral obesity is a sign of aging and is considered a risk factor for ischemic stroke. In this study, we investigated the effects of resveratrol on inflammation in visceral adipose tissue and the brain and its effects on ischemic brain injury in aged female mice. Mice treated with resveratrol (0.1 mg/kg, p.o.) for 10 days showed reduced levels of interleukin-1β and tumor necrosis factor-α, as well as a reduction in the size of adipocytes in visceral adipose tissue. Resveratrol also reduced interleukin-1β and tumor necrosis factor-α protein levels and immunoglobulin G extravasation in the brain. Mice treated with resveratrol demonstrated smaller infarct size, improved neurological function, and blunted peripheral inflammation at 3 days postischemic stroke. These results showed that resveratrol counteracted inflammation in visceral adipose tissue and in the brain and reduced stroke-induced brain injury and peripheral inflammation in aged female mice. Therefore, resveratrol administration can be a valuable strategy for the prevention of age-associated and disease-provoked inflammation in postmenopausal women.


Isokinetic force-power profile of the shoulder joint in males participating in CrossFit training and competing at different levels.
As participants who engage in CrossFit training and competition perform a large volume of high intensity overhead activities, injuries to the shoulder are one of the most common in this sport. Previous research in other sports has indicated that the isokinetic force power profile of the shoulder joint (IPSJ) rotator muscles may assist in the prediction of shoulder injury. Therefore, the objective of this study was to determine the IPSJ in males engaged in CrossFit training at different competitive levels. In a cross-sectional study design, participants (age, 24.1 ± 2.7 years) classified as 'beginner' (n = 6), 'intermediate' (n = 7) or 'advanced' (n = 9) provided informed consent to participate in this study. The IPSJ assessment involved rotational and diagonal movements, including internal and external shoulder rotator muscles, at both 180°.s-1 and 300°.s-1. The variables analysed were peak torque/body mass (%), mean power (W) and the external/internal peak torque/body mass ratio (%). A Kruskal-Wallis test was used to compare the IPSJ of the three groups, with Dunn's test used for post-hoc analysis. The alpha level was set at p < 0.05. The IPSJ showed greater torque and power values in those who competed at the advanced level as compared to those at a lower competitive level (i.e. intermediate, beginner). This was observed mainly for the internal rotation and internal diagonal movements at both 180°.s-1 and 300°.s-1. However, such differences between competitive levels were, in general, absent for the external rotation and external diagonal movements. Moreover, the participants from the advanced competitive level exhibited an imbalance of peak torque between the muscles responsible for the external-internal rotational and external-internal diagonal movements of the shoulder (i.e. peak torque external/internal ratio <66%), particularly in the dominant shoulder. These findings suggest greater development of the shoulder internal rotators and a higher probability of shoulder injury in CrossFit athletes at the advanced competitive level. Based on these results, participants engaged in CrossFit training and competition may wish to increase the volume of training for the shoulder external rotator muscles to complement the large increases in shoulder internal rotator strength that occur as a part of their regular training regimes.


Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells.
The epithelial component of the thymic microenvironment is indispensable for the generation of T lymphocytes. Although the heterogeneity of this epithelium is well documented, little is known about precursor-progeny relationships between distinct thymic epithelial lineages. Here we characterized a thymic epithelial cell subpopulation identified by the cell surface glycoprotein MTS24. These cells contained epithelial progenitor cells that were competent and sufficient to fully reconstitute the complex thymic epithelial microenvironment that supported normal T cell development.


Behavioral interventions for improving dual-method contraceptive use.
Dual-method contraception refers to using condoms as well as another modern method of contraception. The latter (usually non-barrier) method is commonly hormonal (e.g., oral contraceptives) or a non-hormonal intrauterine device. Use of two methods can better prevent pregnancy and the transmission of HIV and other sexually transmitted infections (STIs) compared to single-method use. Unprotected sex increases risk for disease, disability, and mortality in many areas due to the prevalence and incidence of HIV/STI. Millions of women, especially in lower-resource areas, also have an unmet need for protection against unintended pregnancy. We examined comparative studies of behavioral interventions for improving use of dual methods of contraception. Dual-method use refers to using condoms as well as another modern contraceptive method. Our intent was to identify effective interventions for preventing pregnancy as well as HIV/STI transmission. Through January 2014, we searched MEDLINE, CENTRAL, POPLINE, EMBASE, COPAC, and Open Grey. In addition, we searched ClinicalTrials.gov and ICTRP for current trials and trials with relevant data or reports. We examined reference lists of pertinent papers, including review articles, for additional reports. Studies could be either randomized or non-randomized. They examined a behavioral intervention with an educational or counseling component to encourage or improve the use of dual methods, i.e., condoms and another modern contraceptive. The intervention had to address preventing pregnancy as well as the transmission of HIV/STI. The program or service could be targeted to individuals, couples, or communities. The comparison condition could be another behavioral intervention to improve contraceptive use, usual care, other health education, or no intervention.Studies had to report use of dual methods, i.e., condoms plus another modern contraceptive method. We focused on the investigator's assessment of consistent dual-method use or use at last sex. Outcomes had to be measured at least three months after the behavioral intervention began. Two authors evaluated abstracts for eligibility and extracted data from included studies. For the dichotomous outcomes, the Mantel-Haenszel odds ratio (OR) with 95% CI was calculated using a fixed-effect model. Where studies used adjusted analysis, we presented the results as reported by the investigators. No meta-analysis was conducted due to differences in interventions and outcome measures. We identified four studies that met the inclusion criteria: three randomized controlled trials and a pilot study for one of the included trials. The interventions differed markedly: computer-delivered, individually tailored sessions; phone counseling added to clinic counseling; and case management plus a peer-leadership program. The latter study, which addressed multiple risks, showed an effect on contraceptive use. Compared to the control group, the intervention group was more likely to report consistent dual-method use, i.e., oral contraceptives and condoms. The reported relative risk was 1.58 at 12 months (95% CI 1.03 to 2.43) and 1.36 at 24 months (95% CI 1.01 to 1.85). The related pilot study showed more reporting of consistent dual-method use for the intervention group compared to the control group (reported P value = 0.06); the investigators used a higher alpha (P < 0.10) for this pilot study. The other two trials did not show any significant difference between the study groups in reported dual-method use or in test results for pregnancy or STIs at 12 or 24 months. We found few behavioral interventions for improving dual-method contraceptive use and little evidence of effectiveness. A multifaceted program showed some effect but only had self-reported outcomes. Two trials were more applicable to clinical settings and had objective outcomes measures, but neither showed any effect. The included studies had adequate information on intervention fidelity and sufficient follow-up periods for change to occur. However, the overall quality of evidence was considered low. Two trials had design limitations and two had high losses to follow up, as often occurs in contraceptive trials. Good quality studies are still needed of carefully designed and implemented programs or services.


Limits to post-fire vegetation recovery under climate change.
Record-breaking fire seasons in many regions across the globe raise important questions about plant community responses to shifting fire regimes (i.e., changing fire frequency, severity and seasonality). Here, we examine the impacts of climate-driven shifts in fire regimes on vegetation communities, and likely responses to fire coinciding with severe drought, heatwaves and/or insect outbreaks. We present scenario-based conceptual models on how overlapping disturbance events and shifting fire regimes interact differently to limit post-fire resprouting and recruitment capacity. We demonstrate that, although many communities will remain resilient to changing fire regimes in the short-term, longer-term changes to vegetation structure, demography and species composition are likely, with a range of subsequent effects on ecosystem function. Resprouting species are likely to be most resilient to changing fire regimes. However, even these species are susceptible if exposed to repeated short-interval fire in combination with other stressors. Post-fire recruitment is highly vulnerable to increased fire frequency, particularly as climatic limitations on propagule availability intensify. Prediction of community responses to fire under climate change will be greatly improved by addressing knowledge gaps on how overlapping disturbances and climate change-induced shifts in fire regime affect post-fire resprouting, recruitment, growth rates, and species-level adaptation capacity.


Analysis of emotionality and locomotion in radio-frequency electromagnetic radiation exposed rats.
In the current study the modulatory role of mobile phone radio-frequency electromagnetic radiation (RF-EMR) on emotionality and locomotion was evaluated in adolescent rats. Male albino Wistar rats (6-8 weeks old) were randomly assigned into the following groups having 12 animals in each group. Group I (Control): they remained in the home cage throughout the experimental period. Group II (Sham exposed): they were exposed to mobile phone in switch-off mode for 28 days, and Group III (RF-EMR exposed): they were exposed to RF-EMR (900 MHz) from an active GSM (Global system for mobile communications) mobile phone with a peak power density of 146.60 μW/cm(2) for 28 days. On 29th day, the animals were tested for emotionality and locomotion. Elevated plus maze (EPM) test revealed that, percentage of entries into the open arm, percentage of time spent on the open arm and distance travelled on the open arm were significantly reduced in the RF-EMR exposed rats. Rearing frequency and grooming frequency were also decreased in the RF-EMR exposed rats. Defecation boli count during the EPM test was more with the RF-EMR group. No statistically significant difference was found in total distance travelled, total arm entries, percentage of closed arm entries and parallelism index in the RF-EMR exposed rats compared to controls. Results indicate that mobile phone radiation could affect the emotionality of rats without affecting the general locomotion.


Effect of intrauterine device use on cervical shedding of HIV-1 DNA.
Hormonal contraception has been associated with an increased prevalence of cervical shedding of HIV-1 DNA among infected women. We conducted this study to evaluate the effect of the use of an intrauterine device (IUD) on the detection of HIV-1 DNA in cervical secretions. A prospective study of HIV-1-seropositive women undergoing IUD insertion at two public family planning clinics in Nairobi, Kenya. Cervical swab samples were collected before IUD insertion and approximately 4 months thereafter for the detection of HIV-1-infected cells using polymerase chain reaction (PCR) amplification of HIV-1 gag DNA sequences. Ninety-eight women were enrolled and followed after IUD insertion. The prevalence of HIV-1 DNA cervical shedding was 50% at baseline and 43% at follow-up [odds ratio (OR) 0.8, 95% confidence interval (CI) 0.5-1.2]. There was no statistically significant difference between the baseline and follow-up shedding rates in a multivariate model that controlled for previous hormonal contraceptive use, condom use, cervical ectopy, friable cervix, cervical infections at an interim visit, and CD4 lymphocyte levels (OR 0.6, 95% CI 0.3-1.1). The insertion of an IUD did not significantly alter the prevalence of cervical shedding of HIV-1-infected cells. The use of IUDs, in conjunction with condoms, may be an appropriate method of contraception for HIV-1-infected women from the standpoint of potential infectivity to the male partner through exposure to genital HIV-1.


Modified FDR controlling procedure for multi-stage analyses.
Multiple testing has become an integral component in genomic analyses involving microarray experiments where a large number of hypotheses are tested simultaneously. However, before applying more computationally intensive methods, it is often desirable to complete an initial truncation of the variable set using a simpler and faster supervised method such as univariate regression. Once such a truncation is completed, multiple testing methods applied to any subsequent analysis no longer control the appropriate Type I error rates. Here we propose a modified marginal Benjamini & Hochberg step-up FDR controlling procedure for multi-stage analyses (FDR-MSA), which correctly controls Type I error in terms of the entire variable set when only a subset of the initial set of variables is tested. The method is presented with respect to a variable importance application. As the initial subset size increases, we observe convergence to the standard Benjamini & Hochberg step-up FDR controlling multiple testing procedures. We demonstrate the power and Type I error control through simulation and application to the Golub Leukemia data from 1999.


COVID-19 pandemic and remote teaching: transition and transformation in nursing education.
Remote teaching (RT) was the only option left to educators to continue education with public policy of lockdowns and social distancing during COVID-19 pandemic. RT is the online mode of instructional delivery. Globally it has become mandatory for all nurse educators to switch to RT mode. Many factors have been identified for effective implementation of RT, of which the major elements are choice of online teaching mode, pedagogy to choose the platform or technology, faculty preparedness, and the learner motivation and expectations. The dire need to meet the educational objectives demanded sudden transition to online mode. The paradigm shifts to RT brought many challenges and pragmatic guidance for teachers and institutions Remote teaching is flexible, student centered and feasible with opportunities to develop technically empowered faculty and coherent digital education strategies. However, tackling threats like academic integrity, inequity in accessibility and limited faculty preparedness necessitates attention. RT being flexible tool is weakened by low self-motivated students and low connectivity with digital inequity and security issues. The challenges opened opportunity to enhance faculty technical competency and learning management system.


Choroid plexus size in young children with Sturge-Weber syndrome.
To assess the size of the choroid plexus in young children with unilateral and bilateral Sturge-Weber syndrome. Subjects included 15 children 4 years old or younger with Sturge-Weber syndrome. Eleven cases were unilateral and four were bilateral. Unilateral or bilateral involvement was determined by the distribution of abnormal leptomeningeal enhancement on MR images. The diameters of the choroid plexus were measured on contrast-enhanced axial MR images. The choroid plexus of the affected and unaffected sides in these cases were compared with those of 15 age-matched children without Sturge-Weber syndrome who were being examined for seizures. Our results show a wide variation in the size of the choroid plexus in children with Sturge-Weber syndrome; however, plexus associated with a hemisphere affected by Sturge-Weber syndrome were significantly larger than those on the unaffected side and in the age-matched control group. The size of the choroid plexus was positively correlated with the extent of leptomeningeal involvement as demonstrated by abnormal contrast enhancement. The choroid plexus is enlarged early in the course of Sturge-Weber syndrome in both unilateral and bilateral cases. There is a positive correlation between choroid plexus size and extent of leptomeningeal involvement in children with Sturge-Weber syndrome.


The use of platelet-rich plasma in the nonsurgical management of sports injuries: hype or hope?
Interest in platelet-rich plasma (PRP) has skyrocketed over the last decade, with a growing body of research contributing to both excitement and skepticism regarding its use. Despite mixed opinions in the medical field, interest from the public has fueled increased utilization of PRP for musculoskeletal conditions, particularly those that are difficult to treat such as chronic, degenerative tendinopathy and osteoarthritis. PRP's reputation as a "natural healer" and stories in the lay press featuring the use of PRP by professional athletes and celebrities has created a lucrative market for PRP even absent insurance reimbursement, casting further doubt regarding motivation for use by some practitioners. Research of PRP is clouded by the fact that PRP is a heterogeneous term representing a variety of different platelet preparations and there are many variables in technique and postprocedure rehabilitation, all of which may have significant effects on outcome. This article discusses definitions and classification of PRP, reviews rationale and evidence for use of PRP in chronic tendon injuries and osteoarthritis, and looks at future directions.


Over 75% incident-photon-to-current efficiency without solid electrodes.
The efficiency of photoelectrochemical reactions is conventionally defined in terms of the ratio between the current responses arising from the collection of carriers at electrical contacts and the incident photon flux at a given wavelength, i.e. the incident-photon-to-current-efficiency (IPCE). IPCE values are determined by a variety of factors such as the absorption constant of the active layer, bulk and surface recombination of photogenerated carriers, as well as their characteristic diffusion length. These parameters are particularly crucial in nanostructured photoelectrodes, which commonly display low carrier mobility. In this article, we examine the photoelectrochemical responses of a mesoporous TiO2 film in which the IPCE is enhanced by fast extraction of carriers via chemical reactions. TiO2 films are spontaneously formed by destabilisation of colloidal particles at the polarisable interface between two immiscible electrolyte solutions. The photocurrent arises from hole-transfer to redox species confined to the organic electrolyte, which is coupled to the transfer of electrons to oxygen in the aqueous electrolyte. The dynamic photocurrent responses demonstrate that no coupled ion transfer is involved in the process. The interplay of different interfacial length scales, molecularly sharp liquid/liquid boundary and mesoporous TiO2 film, promotes efficiencies above 75% (without correction for reflection losses). This is a significant step change in values reported for these interfaces (below 1%), which are usually limited to sub-monolayer coverage of photoactive molecular or nanoscopic materials.


Health team for the elderly: a feasibility study for preventive home visits.
The aim was to describe the development, utilization and feasibility of a model of preventive home visits, in an urban and a rural municipality in Norway. Older people >65 years will rise significantly in coming years. Increased age is associated with risk of disability, illness and need for public health services. Preventive home visits is assumed to help older people to maintain their functional level longer, delaying disease and thus delaying the need for health care. Descriptive explorative design describing the development, utilization and feasibility of preventive home visits in two different settings. All 77-year-old persons living at home in an urban municipality and all 75 years and older in a rural municipality were invited to participate. A questionnaire including a substantial number of tests concerning; fall, nutrition, polypharmacy and cognitive impairment was used by Health Team Nurses as base for a risk assessment. Pilot studies were conducted to validate the questionnaire including an inter-rater reliability study of the risk assessment tool. A multiprofessional team, Health Team for the Elderly met each week to evaluate risk assessments and make recommendations to be sent to each respective general practitioner. Data were analysed using descriptive and inferential statistics. In total, 167 persons (109 from the urban municipality and 58 from the rural municipality) participated, corresponding to 60% of the approached individuals. The mean time for the visits was 108 minutes (SD 20). Missing data were identified for; Do you feel safe in your municipality (17.5%) and Are you looking forward to ageing (11.4%). In total, 36 persons (21.7%) were identified with increased risk for developing illness. We suggest that a structured model of preventive home visits and collaboration between highly specialized health care professionals are important factors for reliable health promoting risk assessments of elderly home dwellers.


Piloting a Remission Strategy in Type 2 Diabetes: Results of a Randomized Controlled Trial.
Medical strategies targeting remission of type 2 diabetes have not been systematically studied. This trial assessed the feasibility, safety, and potential to induce remission of a short-term intensive metabolic strategy. A randomized, parallel, open-label pilot trial with 83 participants followed for 52 weeks. Ambulatory care. Patients with type 2 diabetes of up to 3 years in duration. Participants were randomized to: (1) an 8-week intensive metabolic intervention, (2) a 16-week intensive metabolic intervention, or (3) standard diabetes care. During the intensive intervention period, weight loss and normoglycemia were targeted using lifestyle approaches and treatment with metformin, acarbose, and insulin glargine. Diabetes drugs were then discontinued in the intervention groups and participants were followed for hyperglycemic relapse. On-treatment normoglycemia. At 8 weeks, 50.0% of the 8-week intervention group vs 3.6% of controls achieved normoglycemia on therapy [relative risk (RR), 14.0; 95% confidence interval (CI), 1.97 to 99.38), and at 16 weeks, these percentages were 70.4% in the 16-week group and 3.6% in controls (RR, 19.7; 95% CI, 2.83 to 137.13). Twelve weeks after completion of the intervention, 21.4% of the 8-week group compared with 10.7% of controls (RR, 2.00; 95% CI, 0.55 to 7.22) and 40.7% of the 16-week group compared with 14.3% of controls (RR, 2.85; 95% CI, 1.03 to 7.87) met hemoglobin A1C criteria for complete or partial diabetes remission. A short course of intensive lifestyle and drug therapy achieves on-treatment normoglycemia and promotes sustained weight loss. It may also achieve prolonged, drug-free diabetes remission and strongly supports ongoing studies of novel medical regimens targeting remission.


Sex-specific genetic predictors of Alzheimer's disease biomarkers.
Cerebrospinal fluid (CSF) levels of amyloid-β 42 (Aβ42) and tau have been evaluated as endophenotypes in Alzheimer's disease (AD) genetic studies. Although there are sex differences in AD risk, sex differences have not been evaluated in genetic studies of AD endophenotypes. We performed sex-stratified and sex interaction genetic analyses of CSF biomarkers to identify sex-specific associations. Data came from a previous genome-wide association study (GWAS) of CSF Aβ42 and tau (1527 males, 1509 females). We evaluated sex interactions at previous loci, performed sex-stratified GWAS to identify sex-specific associations, and evaluated sex interactions at sex-specific GWAS loci. We then evaluated sex-specific associations between prefrontal cortex (PFC) gene expression at relevant loci and autopsy measures of plaques and tangles using data from the Religious Orders Study and Rush Memory and Aging Project. In Aβ42, we observed sex interactions at one previous and one novel locus: rs316341 within SERPINB1 (p = 0.04) and rs13115400 near LINC00290 (p = 0.002). These loci showed stronger associations among females (β = - 0.03, p = 4.25 × 10-8; β = 0.03, p = 3.97 × 10-8) than males (β = - 0.02, p = 0.009; β = 0.01, p = 0.20). Higher levels of expression of SERPINB1, SERPINB6, and SERPINB9 in PFC was associated with higher levels of amyloidosis among females (corrected p values < 0.02) but not males (p > 0.38). In total tau, we observed a sex interaction at a previous locus, rs1393060 proximal to GMNC (p = 0.004), driven by a stronger association among females (β = 0.05, p = 4.57 × 10-10) compared to males (β = 0.02, p = 0.03). There was also a sex-specific association between rs1393060 and tangle density at autopsy (pfemale = 0.047; pmale = 0.96), and higher levels of expression of two genes within this locus were associated with lower tangle density among females (OSTN p = 0.006; CLDN16 p = 0.002) but not males (p ≥ 0.32). Results suggest a female-specific role for SERPINB1 in amyloidosis and for OSTN and CLDN16 in tau pathology. Sex-specific genetic analyses may improve understanding of AD's genetic architecture.


Malignant vascular tumors of the serous membranes mimicking mesothelioma. A report of 14 cases.
Malignant endothelial neoplasms involving the serous membranes are rare, and only a few cases have been documented. We report 14 patients with epithelioid hemangioendothelioma (EHE) or epithelioid angiosarcoma (EA) diffusely involving the pleural, peritoneal, or pericardial cavities, resulting in a picture closely resembling mesothelioma. The mean age at diagnosis was 52 (range, 34-85). The patients included two women and one man with peritoneal tumors, eight men with pleural tumors, and three men with pericardial tumors. A shared histological appearance was a diffuse sheet-like and clustered pattern of tumor growth with variable degrees of vascular differentiation. A tubulopapillary growth pattern, often seen in mesothelioma, was prominent in four cases. Nine cases showed a variable number of spindle cells, some neoplastic, others reactive, focally producing a biphasic growth pattern, further suggesting mesothelioma. Initial interpretations included mesothelioma, adenocarcinoma, and, in one case with prominent spindle-cell components, leiomyosarcoma. Immunohistochemically, strong vimentin staining and negative or weak to moderate cytokeratin staining were observed in all 14 cases. The tumor cells coexpressed at least two of the four endothelial markers used in the study (CD31, CD34, von Willebrand factor, and Ulex europaeus agglutinin-I [UEA-I)]. Detection of abortive vessel formation was facilitated by staining for collagen type IV. Markers of mesothelial, epithelial, muscular, and neuronal differentiation were all negative in the subset of cases studied. As a control group, 39 mesotheliomas and more than 60 adenocarcinomas of various origins were studied using the same antibody panel. This group revealed strong keratin staining, moderate or negative vimentin staining, and no expression of any of the endothelial-lineage markers, with the exception of positive staining for UEA-I in occasional adenocarcinomas. Clinically, these endothelial tumors were highly aggressive; 12 patients presented with disseminated disease, and most died within months of the initial presentation. These findings indicate that, although uncommon, EHE/EA should be included in the differential diagnosis of serous membrane neoplasms with histological and clinical features of malignant mesothelioma. The diagnosis of an endothelial neoplasm can be suspected by the presence of abortive vessel formation and by the strong expression of vimentin, with absent or low-level expression of cytokeratin. The demonstration of immunoreactivity for two or more endothelial-associated markers is essential in confirming the diagnosis.


Variability of weaning age in mountain gorillas (Gorilla beringei beringei).
Weaning is a key life history milestone for mammals that represents both the end of nutritional investment from the perspective of mothers and the start of complete nutritional independence for the infants. The age at weaning may vary depending on ecological, social, and demographic factors experienced by the mother and infant. Bwindi mountain gorillas live in different environmental conditions and have longer interbirth intervals than their counterparts in the Virunga Volcanoes, yet other life history characteristics of this population remain less well known. We use long-term data from Bwindi Impenetrable National Park, Uganda to examine factors related to weaning age. We analyzed data on infants born in four mountain gorilla groups in Bwindi to quantify their age of weaning (defined as last nipple contact) and to test if the sex of offspring, parity, and dominance rank of mother influences age of weaning. We also compared the age at weaning and time to conception after resumption of mating in Bwindi and Virunga gorillas. Bwindi gorillas were weaned at an average age of 57.5 months. No difference was found between age of weaning for primiparous and multiparous mothers, nor did maternal dominance rank influence age of weaning, but sons were weaned at a later age than daughters. The majority of Bwindi mothers were still suckling when they resumed mating and mothers generally conceived before they weaned their previous offspring. The age of weaning was significantly later in Bwindi than in Virunga gorillas. After mothers resumed mating, the time to conceiving the next offspring was not significantly longer for Bwindi females than Virungas females (6 vs. 4 months). Later weaning age for sons than daughters is similar to findings of other studies of great apes. Bwindi mountain gorillas are weaned at approximately the same age as western gorillas and chimpanzees, which is more than a year later than Virunga mountain gorillas. The results of this study suggest that variation in ecological conditions of populations living in close geographic proximity can result in variation in life history patterns, which has implications for understanding the evolution of the unique life history patterns of humans.


A profile of anaesthesia trainees in Hong Kong.
To examine the demographics, professional background, progress, and aspirations of anaesthesia trainees in Hong Kong. Anonymous questionnaire consisting of 56 items grouped into the areas of demographics, and anaesthetic and postanaesthetic training. Eight of the items were open questions. Descriptive analyses were undertaken for the closed items. Hong Kong College of Anaesthesiologists, Hong Kong. All trainees. Demographic data, aspects of training, supervision, working environment, career aspirations, job satisfaction, and morale. The response rate was 77%. The various problems highlighted by respondents included the need for more input and feedback into individual training programmes, the lack of senior support, and the need for more relevant and examination-orientated courses and workshops. Unsatisfactory aspects of the specialty reported were the lack of control over work routines, relationships with surgeons, boredom, and the poor public image of the specialty. Eighty-four percent of respondents reported having reasonable to good job satisfaction. Ongoing benefits could be derived from enhancing communication between trainees and the Hong Kong College of Anaesthesiologists, through appropriate channels for trainee feedback.


The autonomy of public health facilities in decentralised contexts: insights from applying a complexity lens in Kenya.
The financing of public health facilities influences their performance. A key feature that defines health facility financing is the degree of financial autonomy. Understanding the factors that influence public health facility financial autonomy is pertinent to developing strategies to addressing challenges that arise from constrained autonomy. In this paper, we apply a complexity lens to draw on a body of research that we have conducted in Kenya over the past decade, from the onset of devolution reforms, to unpack the determinants of public health facility financial autonomy in a context of decentralisation and provide suggestions for pertinent considerations when designing interventions to address financial autonomy challenges. We find that the factors that affect public health facility autonomy are not only structural, but also procedural, and political and interact in complex ways. These factors include; the public finance management (PFM) laws, sense-making by actors in the health system, political interests in control over resources, subnational level PFM capacity, PFM implementation bottlenecks and broader operational autonomy. Drawing from this analysis, we recommend that efforts at resolving public health facility financial autonomy include: PFM capacity development for subnational levels of government in decentralised settings, the use of a political lens that recognises interests and seeks to align incentives in engagement and solution finding for health facility financial autonomy, the audit of PFM processes to establish and resolve implementation bottlenecks that impinge on public health facility autonomy, and the resolution of operational autonomy to as a facilitator of financial autonomy.


Effects of exercise on depressive symptoms in adults with arthritis and other rheumatic disease: a systematic review of meta-analyses.
Depression is a major public health problem among adults with arthritis and other rheumatic disease. The purpose of this study was to conduct a systematic review of previous meta-analyses addressing the effects of exercise (aerobic, strength or both) on depressive symptoms in adults with osteoarthritis, rheumatoid arthritis, fibromyalgia and systemic lupus erythematous. Previous meta-analyses of randomized controlled trials were included by searching nine electronic databases and cross-referencing. Methodological quality was assessed using the Assessment of Multiple Systematic Reviews (AMSTAR) Instrument. Random-effects models that included the standardized mean difference (SMD) and 95% confidence intervals (CIs) were reported. The alpha value for statistical significance was set at p ≤ 0.05. The U3 index, number needed to treat (NNT) and number of US people who could benefit were also calculated. Of the 95 citations initially identified, two aggregate data meta-analyses representing 6 and 19 effect sizes in as many as 870 fibromyalgia participants were included. Methodological quality was 91% and 82%, respectively. Exercise minus control group reductions in depressive symptoms were found for both meta-analyses (SMD, -0.61, 95% CI, -0.99 to -0.23, p = 0.002; SMD, -0.32, 95% CI, -0.53 to -0.12, p = 0.002). Percentile improvements (U3) were equivalent to 22.9 and 12.6. The number needed to treat was 6 and 9 with an estimated 0.83 and 0.56 million US people with fibromyalgia potentially benefitting. Exercise improves depressive symptoms in adults with fibromyalgia. However, a need exists for additional meta-analytic work on this topic.


Role of glutamate in neuron-glia metabolic coupling.
The coupling between synaptic activity and glucose utilization (neurometabolic coupling) is a central physiologic principle of brain function that has provided the basis for 2-deoxyglucose-based functional imaging with positron emission tomography. Approximately 10 y ago we provided experimental evidence that indicated a central role of glutamate signaling on astrocytes in neurometabolic coupling. The basic mechanism in neurometabolic coupling is the glutamate-stimulated aerobic glycolysis in astrocytes, such that the sodium-coupled reuptake of glutamate by astrocytes and the ensuing activation of the Na(+)-K(+) ATPase triggers glucose uptake and its glycolytic processing, which results in the release of lactate from astrocytes. Lactate can then contribute to the activity-dependent fueling of the neuronal energy demands associated with synaptic transmission. Analyses of this coupling have been extended in vivo and have defined the methods of coupling for inhibitory neurotransmission as well as its spatial extent in relation to the propagation of metabolic signals within the astrocytic syncytium. On the basis of a large body of experimental evidence, we proposed an operational model, "the astrocyte-neuron lactate shuttle." A series of results obtained by independent laboratories have provided further support for this model. This body of evidence provides a molecular and cellular basis for interpreting data that are obtained with functional brain imaging studies.


Modeling Criminal Careers as Departures from a Unimodal Population Age-Crime Curve: The Case of Marijuana Use.
A major aim of longitudinal analyses of life course data is to describe the within- and between-individual variability in a behavioral outcome, such as crime. Statistical analyses of such data typically draw on mixture and mixed-effects growth models. In this work, we present a functional analytic point of view and develop an alternative method that models individual crime trajectories as departures from a population age-crime curve. Drawing on empirical and theoretical claims in criminology, we assume a unimodal population age-crime curve and allow individual expected crime trajectories to differ by their levels of offending and patterns of temporal misalignment. We extend Bayesian hierarchical curve registration methods to accommodate count data and to incorporate influence of baseline covariates on individual behavioral trajectories. Analyzing self-reported counts of yearly marijuana use from the Denver Youth Survey, we examine the influence of race and gender categories on differences in levels and timing of marijuana smoking. We find that our approach offers a flexible model for longitudinal crime trajectories and allows for a rich array of inferences of interest to criminologists and drug abuse researchers.


Inhibition of in vitro intracellular growth of Trypanosoma cruzi by dicationic compounds.
Dicationic compounds, which are derivatives of pentamidine, are being developed for use as antiprotozoal drugs. These compounds bind to the minor groove of DNA and are thought to inhibit DNA-dependent enzymes and thereby prevent cellular replication by protozoans. The objective of this study was to test the ability of a group of these compounds to inhibit the intracellular and extracellular reproduction of Trypanosoma cruzi in vitro. At present, there are few drugs in use capable of inhibiting the intracellular stages of this parasite, and therefore compounds with this ability would be of value. Cultures of mouse fibroblasts were infected and treated with doses of dicationic compounds, and the numbers of parasites released at the end of the 5- to 7-day growth cycle were determined. Five of the compounds tested were found to be effective at inhibiting T. cruzi growth at doses that were not toxic to the host cells. The compound found most effective (DB709) inhibited parasite release at the low concentration of 0.8 ng/ ml, justifying further study. These results suggest that dicationic compounds may have potential as chemotherapy against T. cruzi infection.


Silaproline helical mimetics selectively form an all-trans PPII helix.
The polyproline II helix (PPII) is increasingly recognized as an important element in peptide and protein structures. The discovery of pertinent PPII peptidomimetics is of great interest to tune physical properties of the targeted structure. A series of silaproline oligomers from dimer to pentamer were synthesized. CD studies, NMR spectroscopy and molecular modeling revealed that the ribbon preferentially populates the polyproline type II secondary structure in both [D]chloroform and [D4 ]MeOH. The characteristics of this new lipophilic PPII-like helix were determined.


Modeling of the pH dependence of the binding of WIN 35,428 to the dopamine transporter in rat striatal membranes: is the bioactive form positively charged or neutral?
Cocaine and its phenyltropane analogs, including 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane can exist in either the cationic or the neutral form, with the proportion of each form determined by the pKA and ambient pH. It is unknown which form is the active form for binding to the dopamine transporter. Our study examines the following models for the pH dependency of [3H]2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane binding to the dopamine transporter in rat striatal membranes: 1) pH does not affect the binding affinity of the ligand for the dopamine transporter, and the observed binding is a function only of the concentration of the active form; and 2) pH affects the binding affinity of the ligand for the transporter, and changes in this affinity as well as in the concentration of the active form of the ligand in the medium contribute to the observed binding changes upon varying pH. For each model, predictions are formulated for the case that either the cation, neutral base, or both are the active form, and these predictions are compared with the experimental data obtained over a pH range of 6 to 9.5. Observations for 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane, which can be both in the cationic and neutral form, are compared with those for cocaine methiodide, which is permanently cationic, and benzocaine, which is permanently neutral. Consonant with all data is a simple model in which the cationic and neutral form have similar binding activity and binding changes as a function of pH are caused by changes at the level of the transporter rather than the ligand.


Study of the actions of human recombinant erythropoietin on rat renal haemodynamics.
1. Studies were undertaken to examine the effect of acute and chronic administration of human recombinant erythropoietin on kidney cortical and papillary perfusion in the anaesthetized rat using laser-Doppler flowmetry. 2. Thirty minutes after erythropoietin (50 and 150 units/kg intravenously), blood pressure, cortical perfusion and papillary perfusion were unchanged. 3. In animals treated chronically with erythropoietin over 7 days (three doses of 150 units/kg subcutaneously) blood pressure was similar to that of vehicle-treated animals, whereas cortical perfusion and papillary perfusion were reduced by 23% and 20%, respectively (both P < 0.05), and the packed cell volume (51.1 +/- 0.7%) was significantly (P < 0.01) greater than in vehicle-treated animals (46.2 +/- 0.6%). 4. Bolus doses of vasopressin and phenylephrine increased blood pressure (by between 10% and 40%) and decreased cortical and papillary perfusion (by between 10% and 20%), while angiotensin II caused similar increases in blood pressure and decreases in cortical perfusion but not papillary perfusion. The magnitude and pattern of these responses were comparable after both acute and chronic administration of erythropoietin. 5. Erythropoietin given acutely at therapeutic levels has a marginal effect on cortical and papillary perfusion. However, the chronic treatment indicated that there was a sustained reduction in both cortical and papillary perfusion, reflecting a vasoconstriction. This reduction in renal haemodynamics could contribute to the increase in blood pressure observed when this hormone is administered in man.


'Hep C's like the common cold': understanding barriers along the HCV care continuum among young people who inject drugs.
New highly effective medications are available to treat the hepatitis C virus (HCV). However, little is known about HCV treatment knowledge and readiness among young people who inject drugs (PWID), or factors that may contribute to treatment uptake and adherence in this treatment era. Using a framework for understanding healthcare utilization, we examined perspectives and experiences of young PWID tied to the HCV care continuum in Boston, Massachusetts, to inform future strategies. We conducted 24 in-depth interviews with active and recent PWID aged 22-30 years living with HCV in Boston, February-August 2016. At the time of the interviews, no participants had been prescribed or had taken the new direct acting antivirals. We developed a codebook deductively from the interview guide and coded and analyzed the data into themes using a consensus-based process. The following five themes emerged, which captured PWID's knowledge of and experiences with HCV along the care continuum through social determinants of engagement in care, as well as illness level: (1) deservingness of HCV treatment and stigma, (2) dissatisfaction with provider interactions, (3) perceived lack of referral to treatment and care continuity, (4) disincentives around HCV treatment for PWID; and (5) perceived need for treatment. Young PWID living with HCV face unique barriers to HCV testing, counseling, and treatment. Breakdowns in the HCV care continuum may have adverse effects on HCV-treatment readiness and willingness. Improved public health and practice approaches are needed to address these barriers to effectively engage young PWID in care.


Chondroitin sulfate for corneal preservation at 4 degrees C. Evaluation by electron microscopy.
We tested three new corneal preservation media in which the dextran in McCarey-Kaufman (M-K) medium was replaced by three preparations of chondroitin sulfate (CS): 1.5% CS, 5.0% CS, and 2.0% modified CS (K-Sol). One cornea from each of 36 pairs of corneas was placed in M-K medium and the opposite cornea was placed in one of the CS media. Endothelial preservation was evaluated by electron microscopy after storage at 4 degrees C for 1, 3, 5, 7, 10, and 14 days. We judged cellular preservation in a masked manner from the electron micrographs according to a morphologic grading system. Preservation in 1.5% CS solution was similar to that in M-K medium. Both 5.0% CS and K-Sol gave better endothelial preservation than M-K medium. The best preservation appeared to be in K-Sol, in which only 3% of the endothelial cells were disrupted after 14 days of storage at 4 degrees C.


Detection of circulating cancer cells using electrocatalytic gold nanoparticles.
A rapid cancer cell detection and quantification assay, based on the electrocatalytic properties of gold nanoparticles towards the hydrogen evolution reaction, is described. The selective labeling of cancer cells is performed in suspension, allowing a fast interaction between the gold nanoparticle labels and the target proteins expressed at the cell membrane. The subsequent electrochemical detection is accomplished with small volumes of sample and user-friendly equipment through a simple electrochemical method that generates a fast electrochemical response used for the quantification of nanoparticle-labeled cancer cells. The system establishes a selective cell-detection assay capable of detecting 4 × 10(3) cancer cells in suspension that can be extended to several other cells detection scenarios.


Identification of novel restriction endonuclease-like fold families among hypothetical proteins.
Restriction endonucleases and other nucleic acid cleaving enzymes form a large and extremely diverse superfamily that display little sequence similarity despite retaining a common core fold responsible for cleavage. The lack of significant sequence similarity between protein families makes homology inference a challenging task and hinders new family identification with traditional sequence-based approaches. Using the consensus fold recognition method Meta-BASIC that combines sequence profiles with predicted protein secondary structure, we identify nine new restriction endonuclease-like fold families among previously uncharacterized proteins and predict these proteins to cleave nucleic acid substrates. Application of transitive searches combined with gene neighborhood analysis allow us to confidently link these unknown families to a number of known restriction endonuclease-like structures and thus assign folds to the uncharacterized proteins. Finally, our method identifies a novel restriction endonuclease-like domain in the C-terminus of RecC that is not detected with structure-based searches of the existing PDB database.


Intake of fatty acids and risk of coronary heart disease in a cohort of Finnish men. The Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study.
The relation of intakes of specific fatty acids and the risk of coronary heart disease was examined in a cohort of 21,930 smoking men aged 50-69 years who were initially free of diagnosed cardiovascular disease. All men participated in the Finnish Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study and completed a detailed and validated dietary questionnaire at baseline. After 6.1 years of follow-up from 1985-1988, the authors documented 1,399 major coronary events and 635 coronary deaths. After controlling for age, supplement group, several coronary risk factors, total energy, and fiber intake, the authors observed a significant positive association between the intake of trans-fatty acids and the risk of coronary death. For men in the top quintile of trans-fatty acid intake (median = 6.2 g/day), the multivariate relative risk of coronary death was 1.39 (95% confidence interval (CI) 1.09-1.78) (p for trend = 0.004) as compared with men in the lowest quintile of intake (median = 1.3 g/day). The intake of omega-3 fatty acids from fish was also directly related to the risk of coronary death in the multivariate model adjusting also for trans-saturated and cis-monounsaturated fatty acids (relative risk (RR) = 1.30, 95% CI 1.01-1.67) (p for trend = 0.06 for men in the highest quintile of intake compared with the lowest). There was no association between intakes of saturated or cis-monounsaturated fatty acids, linoleic or linolenic acid, or dietary cholesterol and the risk of coronary deaths. All the associations were similar but somewhat weaker for all major coronary events.


Vagal afferent is involved in short-pulse gastric electrical stimulation in rats.
This study investigated the effect of gastric electrical stimulation (GES) on vagal activity and its possible vagal afferent-mediated mechanisms. Sixty rats implanted with gastric serosal electrodes were divided into six groups (control, vehicle, local capsaicin, perivagal capsaicin, systemic capsaicin, and vagotomy). GES with six sets of parameters was performed in the control group; and GES with one set of effective parameters was performed in the other five groups. Spectral analysis of heart rate variability was used to assess vagal activity. Regular gastric slow waves were recorded in the control rats with a frequency of 4.8 cycles/min. Vagotomy significantly reduced the frequency of the gastric slow wave but did not induce dysrhythmia. Capsaicin did not alter the gastric slow wave. Short-pulse (300-microsec) GES significantly increased vagal activity at a frequency four times the intrinsic slow-wave frequency. Stimulation at a lower frequency or with a long pulse (300 msec) had no effect on vagal activity. Vagotomy or capsaicin administered perivagally, systemically, or locally abolished the effect of GES on the vagal activity. GES with short but not long pulses is capable of altering vagal activity. This effect is mediated by capsaicin-sensitive vagal afferent fibers.


Aerobic exercise reduces blood pressure in resistant hypertension.
Regular physical exercise is broadly recommended by current European and American hypertension guidelines. It remains elusive, however, whether exercise leads to a reduction of blood pressure in resistant hypertension as well. The present randomized controlled trial examines the cardiovascular effects of aerobic exercise on resistant hypertension. Resistant hypertension was defined as a blood pressure ≥140/90 mm Hg in spite of 3 antihypertensive agents or a blood pressure controlled by ≥4 antihypertensive agents. Fifty subjects with resistant hypertension were randomly assigned to participate or not to participate in an 8- to 12-week treadmill exercise program (target lactate, 2.0±0.5 mmol/L). Blood pressure was assessed by 24-hour monitoring. Arterial compliance and cardiac index were measured by pulse wave analysis. The training program was well tolerated by all of the patients. Exercise significantly decreased systolic and diastolic daytime ambulatory blood pressure by 6±12 and 3±7 mm Hg, respectively (P=0.03 each). Regular exercise reduced blood pressure on exertion and increased physical performance as assessed by maximal oxygen uptake and lactate curves. Arterial compliance and cardiac index remained unchanged. Physical exercise is able to decrease blood pressure even in subjects with low responsiveness to medical treatment. It should be included in the therapeutic approach to resistant hypertension.


The renin-angiotensin system during acute myocardial ischemia in dogs.
We used the technique of high-performance liquid chromatography combined with radioimmunoassay to establish the profile of angiotensin peptides in the periphery and across the circulation of the dog's heart. Data were obtained before and after blockade of angiotensin converting enzyme, and after acute myocardial ischemia produced by occlusion of the left anterior descending coronary artery. Baseline values of plasma renin activity and immunoreactive angiotensin II were higher in the aortic root than in the coronary sinus but concentrations of angiotensin I and angiotensin-(1-7) were similar. In untreated animals, coronary occlusion produced significant increases in renin activity and arterial and venous levels of angiotensin I and angiotensin II. Inhibition of converting enzyme with benazeprilat (CGS-14,831) increased baseline circulating levels of angiotensin I, whereas angiotensin II and its carboxyl terminal fragments were reduced markedly. Baseline plasma levels of angiotensin-(1-7) and its fragments did not change. Myocardial ischemia in benazeprilat-treated dogs increased plasma renin activity and circulating levels of angiotensin I. Concentrations of angiotensin II and angiotensin-(1-7) did not change either in peripheral blood or across the coronary circulation. These results indicate that angiotensin peptides can be formed endogenously by enzymatic pathways alternate to converting enzyme. Furthermore, these data provide the basis for a further understanding of the role of the renin-angiotensin system after myocardial ischemia.