Estimates of continental ancestry vary widely among individuals with the same mtDNA haplogroup.
The association between a geographical region and an mtDNA haplogroup(s) has provided the basis for using mtDNA haplogroups to infer an individual's place of origin and genetic ancestry. Although it is well known that ancestry inferences using mtDNA haplogroups and those using genome-wide markers are frequently discrepant, little empirical information exists on the magnitude and scope of such discrepancies between multiple mtDNA haplogroups and worldwide populations. We compared genetic-ancestry inferences made by mtDNA-haplogroup membership to those made by autosomal SNPs in ∼940 samples of the Human Genome Diversity Panel and recently admixed populations from the 1000 Genomes Project. Continental-ancestry proportions often varied widely among individuals sharing the same mtDNA haplogroup. For only half of mtDNA haplogroups did the highest average continental-ancestry proportion match the highest continental-ancestry proportion of a majority of individuals with that haplogroup. Prediction of an individual's mtDNA haplogroup from his or her continental-ancestry proportions was often incorrect. Collectively, these results indicate that for most individuals in the worldwide populations sampled, mtDNA-haplogroup membership provides limited information about either continental ancestry or continental region of origin.


An analysis of time of presentation after stroke.
The recent development of potential therapies for acute stroke has focused attention on the time delay between stroke onset and presentation. We used the Duke/Veterans Administration stroke registry to collect data about this delay. Results were analyzed using Fisher's Exact Test and ridit analysis. Data from 457 patients at two hospitals were used. Only 42% (192/457) of patients presented within 24 hours of stroke onset, while 25% (116/457) presented within 48 hours and 33% (149/457) presented after 48 hours. Presentation time varied significantly with stroke type. A majority of patients with infarcts (64% [176/276]), stroke-in-evolution (54% [44/81]), and subarachnoid hemorrhage (54% [25/46]) did not present within 24 hours of stroke onset. Most patients with intracerebral hemorrhage (63% [34 of 54]) did present within 24 hours. Reasons for this delay may include patients' lack of awareness about the symptoms of stroke and lack of recognition of early signs by medical personnel. Because of this delay in presentation, a majority of patients may not be candidates for some therapies for acute stroke.


Imaging findings in patients with clinical anophthalmos.
To review the intracranial and facial imaging features in children with congenital anophthalmos. We retrospectively studied eight children with anophthalmos with respect to intraorbital, intracranial, and craniofacial anomalies (six had CT examinations, including the face, orbits, and brain, and four had MR imaging, including the orbits and brain). Three patients had primary bilateral anophthalmos on CT (n = 1) and MR (n = 3) studies. In these patients, MR images showed hypoplasia of the optic chiasm and posterior visual pathways (n = 3), agenesis (n = 1) or dysgenesis of the corpus callosum (n = 2), and a mass in the tuber cinereum region (n = 1). One patient had incontinentia pigmenti. Five patients had unilateral anophthalmos on CT (n = 5) and MR (n = 1) studies. One of these patients had a contralateral congenital cystic eye and one had contralateral severe microphthalmia and absent optic chiasm. All had craniofacial anomalies that consisted of midline facial clefts (n = 2) and concomitant hemifacial hypoplasia (n = 2). One had a craniosynostosis. All five had normal-appearing brains. Patients with bilateral anophthalmos represent a distinct group from those with unilateral anophthalmos. In our patients, bilateral anophthalmos was associated with absence of the optic chiasm, diminished size of the posterior optic pathways, and agenesis or dysgenesis of the corpus callosum. Patients with unilateral anophthalmos had severe craniofacial anomalies. Imaging of the face is helpful in patients with unilateral anophthalmos.


Pediatric anxiety disorders: management in primary care.
Anxiety disorders are common in children and adolescents, with prevalence rates varying from 6 to 20%. These disorders can result in significant academic, social, and familial impairment. Early identification in pediatric primary care and effective management may help improve outcomes. Self-report measures of pediatric anxiety can supplement the clinical interview and assist in screening children and adolescents for separation anxiety disorder, generalized anxiety disorder, and social phobia. Substantial evidence supports the use of cognitive behavioral therapy and selective serotonin reuptake inhibitors in the treatment of pediatric anxiety disorders. Although treatment with serotonin reuptake inhibitors may lead to a small increase in the risk for suicidal ideation in children and adolescents, the risk benefit ratio for serotonin reuptake inhibitor use in pediatric anxiety disorders is favorable with appropriate monitoring. Although evidence-support treatments have emerged for pediatric anxiety disorders, their effectiveness in pediatric primary care has not been evaluated. Future research should assess the delivery of manual-based cognitive behavioral therapy for anxiety disorders by mental health professionals integrated into the primary care settings, the effectiveness of serotonin reuptake inhibitor prescription by pediatric primary care clinicians, and the use of collaborative models for providing anxiety treatments for children and adolescents in primary care settings.


Psychometric evaluation of daytime sleepiness and nocturnal sleep onset scales in a representative community sample.
The public health importance of daytime sleepiness as a risk factor for accidents, interpersonal problems, and decreased productivity has been recognized. However, epidemiologic research on this topic has been limited by the reliance on laboratory measures (i.e., the Multiple Sleep Latency Test-MSLT). Two scales, daytime sleepiness and nocturnal sleep onset, have been identified from the self-report Sleep-Wake Activity Inventory (SWAI) in a clinic sample and validated against the MSLT. This study evaluates the replicability of the two scales in a population sample and assesses potential thresholds in scale scores that distinguish normal from pathologic levels of daytime sleepiness and difficulty falling asleep. The sample consisted of 2181 subjects 18-45 years old in the Detroit metropolitan area. All sleep characteristic information covered the 2 weeks prior to interview. Split-half sample factor analyses were conducted to assess replicability of the results. Distribution of scale scores and their relation to construct validity variables were used to evaluate possible thresholds. A two-factor model appeared to best account for the variation among the 12 items from the SWAI. The two factors accounted for 50% of the variance in both split-half sample analyses. The revised eight-item daytime sleepiness and two-item nocturnal sleep onset scales showed good and fair internal consistency respectively across both split-half samples. There appeared to be a "natural break" in daytime sleepiness scale scores that was associated with a substantial and consistent change in number of hours slept. No breaks appeared in nocturnal sleep onset scores. This study replicated the results of the clinic-based study and suggested a potentially useful diagnostic threshold for self-report excessive daytime sleepiness. Epidemiology of sleep depends on the ability to move from the laboratory to population surveys in reliable and valid ways. Development of self-report is a step in that direction.


Estimation of the power scintillation probability density function in free-space optical links by use of multicanonical Monte Carlo sampling.
Free-space optics (FSO) can provide cost-effective, high-bandwidth, wireless connections. However, atmospheric turbulence may degrade the performance of FSO links by causing intensity and power scintillations at the receiver. Multicanonical Monte Carlo sampling is used in conjunction with the phase screen method to calculate the statistics, and particularly the probability density function (PDF), of the power fluctuations at an FSO receiver. This allows the efficient calculation of the PDF even for very small values with a limited number of iterations. The obtained PDF can be used to characterize the performance of the system in terms of the error probability.


Strengthening Primary Care Through Family Medicine Around the World Collaborating Toward Promising Practices.
There is a limited evidentiary base on the development of family medicine in different contexts and countries. The lack of evidence impedes our ability to compare and characterize family medicine models and identify areas of success that have led to the effective provision of care. This paper offers a comparative compilation and analysis of the development of family medicine training programs in seven countries: Brazil, Canada, Ethiopia, Haiti, Indonesia, Kenya, and Mali. Using qualitative case studies, this paper examines the process of developing family medicine programs, including enabling strategies and barriers, and shared lessons. An appreciative inquiry framework and complex adaptive systems thinking inform our qualitative study. Committed partnerships, the contribution of champions, health policy, and adaptability were identified as key enablers in all seven case studies. The case studies further reveal that some enablers were more salient in certain contexts as compared to others, and that it is the interaction of enablers that is crucial for understanding how and why initiatives succeeded. The barriers that emerged across the seven case studies include: (1) resistance from other medical specialties, (2) lack of resources and capabilities, (3) difficulty in sustaining support of champions, and (4) challenges in brokering effective partnerships. A key insight from this study is that the implementation of family medicine is nonlinear, dynamic, and complex. The findings of this comparative analysis offer insights and strategies that can inform the design and development of family medicine programs elsewhere.


Bioengineered Approach to the Design of a Fat Graft Based on Mathematical Modeling that Predicts Oxygen Delivery.
Fat grafting is a common procedure in plastic surgery. A major limitation is unpredictable graft retention, in part caused by inadequate oxygen delivery during the early posttransfer period. The authors present a bioengineered approach to the design of a fat graft based on mathematical theory, which can estimate the limitations of oxygen delivery. To simplify the problem, four variables were defined: (1) recipient-site oxygen partial pressure; (2) adipose tissue oxygen permeability; (3) adipose tissue oxygen consumption rate; and (4) fat graft size. Recipient-site oxygen partial pressure and adipose tissue oxygen permeability were estimated from literature, whereas adipose tissue oxygen consumption rate was measured using stirred microchamber technology. Calculations were performed in both spherical and planar geometry to calculate the maximum allowable fat graft size from an oxygen delivery standpoint. As expected, planar geometry is less favorable for oxygenation but represents a realistic configuration for a fat graft. Maximum allowable fat graft thickness is only approximately 1 to 2 mm at external oxygen partial pressures of 10 to 40 mm Hg; any thicker and an anoxic or necrotic core likely develops. Given a reasonably large surface area and assuming several planes of injection, the maximum allowable fat graft volume is tens of milliliters. A systematic bioengineered approach may help better design a fat graft. Applying principles of mass transfer theory can predict whether a fat graft has a favorable chance of surviving from an oxygen delivery standpoint and can direct the development of strategies for improved fat graft oxygenation.


Drinking Buddies: Who Are They and When Do They Matter?
The present study sought to further examine the role of peers on alcohol use and problems among young adults. In particular, we focused on a specific subset of peers in one's social network mostly for activities related to alcohol use called "drinking buddies." The presence of drinking buddies in one's social network has been shown to predict heavy drinking uniquely over but few studies have focused on potential factors moderating the relationship. Consequently, an aim of present study was to examine the influence of drinking buddies on alcohol outcomes and the extent to which the relationship may be dependent on one's normative perceptions. Another aim was to provide a descriptive examination of drinking buddies. Participants were college students (N = 250; 72.8% women) who completed self-report measures of alcohol use and problems, injunctive norms, descriptive norms, and social network characteristics. Results showed that descriptive norms moderated the relationship between drinking buddies and all alcohol outcomes assessed. Specifically, the influence of drinking buddies was stronger for those who perceived a lower prevalence of peer drinking. Examination of drinking buddies characteristics revealed that these peers tended to be young adults who were moderate social drinkers with whom they felt close and perceived to be available for concrete and emotional support. Several differences emerged between the drinking buddies of heavy versus non-heavy drinkers. The present study contributed to the larger body of work on peer influence and alcohol use by examining a specific subgroup of peers that may promote risky drinking.


The contribution of work and lifestyle factors to socioeconomic inequalities in self-rated health ‒ a systematic review.
Objective This study aimed to systematically review the literature on the contribution of work and lifestyle factors to socioeconomic inequalities in self-rated health among workers. Methods A search for cross-sectional and longitudinal studies assessing the contribution of work and/or lifestyle factors to socioeconomic inequalities in self-rated health among workers was performed in PubMed, PsycINFO and Web of Science in March 2017. Two independent reviewers performed eligibility and risk of bias assessment. The median change in odds ratio between models without and with adjustment for work or lifestyle factors across studies was calculated to quantify the contribution of work and lifestyle factors to health inequalities. A best-evidence synthesis was performed. Results Of those reviewed, 3 high-quality longitudinal and 17 cross-sectional studies consistently reported work factors to explain part (about one-third) of the socioeconomic health inequalities among workers (grade: strong evidence). Most studies separately investigated physical and psychosocial work factors. In contrast with the 12 cross-sectional studies, 2 longitudinal studies reported no separate contribution of physical workload and physical work environment to health inequalities. Regarding psychosocial work factors, lack of job resources (eg, less autonomy) seemed to contribute to health inequalities, whereas job demands (eg, job overload) might not. Furthermore, 2 longitudinal and 4 cross-sectional studies showed that lifestyle factors explain part (about one-fifth) of the health inequalities (grade: strong evidence). Conclusions The large contribution of work factors to socioeconomic health inequalities emphasizes the need for future longitudinal studies to assess which specific work factors contribute to health inequalities.


S100P regulates the collective invasion of pancreatic cancer cells into the lymphatic endothelial monolayer.
Lymph node metastasis is an independent prognostic factor in pancreatic cancer. However, the mechanisms of lymph node colonization are unknown. As a mechanism of lymphatic metastasis, it has been reported for other types of cancer that spheroids from tumor cells cause circular chemorepellent‑induced defects (CCIDs) in lymphatic endothelial monolayers. In pancreatic cancer, such mechanisms of metastasis have not been elucidated. The present study evaluated the involvement of this new mechanism of metastasis in pancreatic cancer and investigated the associated factors. In human pancreatic cancer tissue, it was observed that clusters of cancer cells penetrated the wall of lymphatic ducts around the primary tumor. An in vitro co‑culture system was then used to analyze the mechanisms of tumor cell‑mediated disruption of lymphatic vessels. Time‑lapse microscopic imaging revealed that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. CCID formation ability differed depending on the cell line. Neither aggregation of spheroids nor adhesion to lymphatic endothelial cells (LECs) exhibited a significant correlation with this phenomenon. The addition of supernatant from cultured cancer cells enhanced CCID formation. Microarray analysis revealed that the expression of S100 calcium binding protein P (S100P) was significantly increased when LECs were treated with supernatant from cultured cancer cells. Addition of a S100P antagonist significantly suppressed the migration of LECs and CCID formation. The present findings demonstrated that spheroids from pancreatic cancer cells caused circular defects in lymphatic endothelial monolayers. These CCIDs in pancreatic cancer were partly regulated by S100P, suggesting that S100P may be a promising target to inhibit lymph node metastasis.


Neonatal exposure to ketamine disrupts developmental synapse unsilencing and predisposes adult mice for stressor-evoked anxiety.
Accumulating evidence suggests long-lasting impairments in brain development and cognition caused by neonatal exposure to general anesthetics. To date, very little is known about potential abnormal psychiatric manifestations attributable to neonatal anesthesia. In this study, we used ketamine to induce anesthesia in neonatal mice. By applying mild stressors one day before behavioral tests, we found that adult mice exhibit significant anxiety-like behaviors that were indistinguishable at basal level. Recruitment of AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) type glutamate receptors into silent synapses is a prominent cellular process during neonatal neurodevelopment. We found that exposure to ketamine significantly disrupted synapse unsilencing, and impaired the expression of unsilencing-mediated long-term potentiation (LTP). Pharmacologically enhancement of neural activities by AMPAkine drug CX546 [1-(1,4-benzodioxan-6-ylcarbonyl) piperidine] effectively rescued disrupted developmental synapse unsilencing and LTP at neonatal age, and prevented stressor-evoked anxiety-like behaviors in adult mice. Together, our results indicate that neonatal exposure to ketamine may predispose individuals for psychiatric conditions via disrupting synapse unsilencing, and potentiation of neural activities during the anesthesia-recovery period may be an effective approach to manage adverse effects on brain development. This article is part of the special issue on 'Stress, Addiction and Plasticity'.


Risk prediction models of breast cancer: a systematic review of model performances.
The number of risk prediction models has been increasingly developed, for estimating about breast cancer in individual women. However, those model performances are questionable. We therefore have conducted a study with the aim to systematically review previous risk prediction models. The results from this review help to identify the most reliable model and indicate the strengths and weaknesses of each model for guiding future model development. We searched MEDLINE (PubMed) from 1949 and EMBASE (Ovid) from 1974 until October 2010. Observational studies which constructed models using regression methods were selected. Information about model development and performance were extracted. Twenty-five out of 453 studies were eligible. Of these, 18 developed prediction models and 7 validated existing prediction models. Up to 13 variables were included in the models and sample sizes for each study ranged from 550 to 2,404,636. Internal validation was performed in four models, while five models had external validation. Gail and Rosner and Colditz models were the significant models which were subsequently modified by other scholars. Calibration performance of most models was fair to good (expected/observe ratio: 0.87-1.12), but discriminatory accuracy was poor to fair both in internal validation (concordance statistics: 0.53-0.66) and in external validation (concordance statistics: 0.56-0.63). Most models yielded relatively poor discrimination in both internal and external validation. This poor discriminatory accuracy of existing models might be because of a lack of knowledge about risk factors, heterogeneous subtypes of breast cancer, and different distributions of risk factors across populations. In addition the concordance statistic itself is insensitive to measure the improvement of discrimination. Therefore, the new method such as net reclassification index should be considered to evaluate the improvement of the performance of a new develop model.


Remodeling of coronary vessels during aging in purebred beagles.
We compared six young (1 year) and six senescent (11 years) purebred beagles to determine the effects of aging on the coronary microvasculature. The hearts were perfusion-fixed in vitro, and myocardial specimens were subjected to microscopic image analysis. Absolute left ventricular mass increased by 55% with age, while cardiocyte cross-sectional area increased by 10% and 30% in the midmyocardium and endomyocardium, respectively. Although capillary numerical density was lower in the senescent dogs (16% in midmyocardium and 19% in endomyocardium), volume density was similar in the two groups because capillary diameter increased significantly with age in both regions. Capillary length density was reduced by 27% with age in the endomyocardium of the old beagles. Wall/lumen ratios of arterioles of three size classes (less than or equal to 15, 16-25, and 26-50 microns) were found to be nearly identical for the two age groups. Mean arteriolar diameter increased within the smallest size class in both ventricular regions. In contrast, a twofold or greater increase in wall thickness with age occurred in the left anterior descending coronary artery and its first branch, which was mainly due to expansion of the medial interstitium. The connective tissue fraction of the myocardium was significantly higher in the senescent than in the young in the epimyocardium and midmyocardium but not in the endomyocardium. These data provide evidence for three conclusions regarding aging of coronary vessels in beagles. First, a decline in capillary length density is limited to the endomyocardium.(ABSTRACT TRUNCATED AT 250 WORDS)


Targeting blood pressure in people with diabetes mellitus.
Hypertension is a strong risk factor for cardiovascular (CV)-related morbidity and mortality, and its treatment has been shown to be beneficial. Hypertension is common in people with diabetes mellitus, and the combination of these conditions markedly increases CV risk in comparison with individuals with neither condition. Although there is increasing clarity as to blood pressure (BP) targets in numerous conditions, the target in people with diabetes remains unclear, and, as a result, many clinical practice guidelines differ on the optimal BP goal. The ACCORD (Action to Control Cardiovascular Risk in Diabetes) trial did not demonstrate benefit when systolic BP (SBP) was lowered to less than 120 mmHg compared with a target of less than 140 mmHg. This was in contrast to the recent SPRINT trial (Systolic Blood Pressure Intervention Trial), which demonstrated the superiority of a target SBP of less than 120 mmHg in reducing CV events. However, people with diabetes mellitus were excluded. Recent meta-analyses have suggested that lowering BP in patients with diabetes mellitus should be reserved for a baseline SBP greater than 140 mmHg, targeting an SBP of between 130 and 140 mmHg. Lower targets may reduce the risk of stroke but may also be harmful with respect to other important CV outcomes. The methodological limitations of these meta-analyses highlight the need for a large randomized controlled trial comparing lower and standard BP targets in people with diabetes mellitus.


Controlling the fluorescence of ordinary oxazine dyes for single-molecule switching and superresolution microscopy.
Fluorescent molecular switches have widespread potential for use as sensors, material applications in electro-optical data storages and displays, and superresolution fluorescence microscopy. We demonstrate that adjustment of fluorophore properties and environmental conditions allows the use of ordinary fluorescent dyes as efficient single-molecule switches that report sensitively on their local redox condition. Adding or removing reductant or oxidant, switches the fluorescence of oxazine dyes between stable fluorescent and nonfluorescent states. At low oxygen concentrations, the off-state that we ascribe to a radical anion is thermally stable with a lifetime in the minutes range. The molecular switches show a remarkable reliability with intriguing fatigue resistance at the single-molecule level: Depending on the switching rate, between 400 and 3,000 switching cycles are observed before irreversible photodestruction occurs. A detailed picture of the underlying photoinduced and redox reactions is elaborated. In the presence of both reductant and oxidant, continuous switching is manifested by "blinking" with independently controllable on- and off-state lifetimes in both deoxygenated and oxygenated environments. This "continuous switching mode" is advantageously used for imaging actin filament and actin filament bundles in fixed cells with subdiffraction-limited resolution.


Temperature retrieval from Rayleigh-Brillouin scattering profiles measured in air.
In order to investigate the performance of two different algorithms for retrieving temperature from Rayleigh-Brillouin (RB) line shapes, RB scattering measurements have been performed in air at a wavelength of 403 nm, for a temperature range from 257 K to 330 K, and atmospherically relevant pressures from 871 hPa to 1013 hPa. One algorithm, based on the Tenti S6 line shape model, shows very good accordance with the reference temperature. In particular, the absolute difference is always less than 2 K. A linear correlation yields a slope of 1.01 ± 0.02 and thus clearly demonstrates the reliability of the retrieval procedure. The second algorithm, based on an analytical line shape model, shows larger discrepancies of up to 9.9 K and is thus not useful at its present stage. The possible reasons for these discrepancies and improvements of the analytical model are discussed. The obtained outcomes are additionally verified with previously performed RB measurements in air, at 366 nm, temperatures from 255 K to 338 K and pressures from 643 hPa to 826 hPa [Appl. Opt. 52, 4640 (2013)]. The presented results are of relevance for future lidar studies that might utilize RB scattering for retrieving atmospheric temperature profiles with high accuracy.


High-throughput mycobacterial interspersed repetitive-unit-variable-number tandem-repeat genotyping for Mycobacterium tuberculosis epidemiological studies.
The emergence of drug-resistant forms of tuberculosis (TB) represents a major public health concern. Understanding the transmission routes of the disease is a key factor for its control and for the implementation of efficient interventions. Mycobacterial interspersed repetitive-unit-variable-number tandem-repeat (MIRU-VNTR) marker typing is a well-described method for lineage identification and transmission tracking. However, the conventional manual genotyping technique is cumbersome and time-consuming and entails many risks for errors, thus hindering its implementation and dissemination. We describe here a new approach using the QIAxcel system, an automated high-throughput capillary electrophoresis system that also carries out allele calling. This automated method was assessed on 1,824 amplicons from 82 TB isolates and tested with sets of markers of 15 or 24 loci. Overall allele-calling concordance between the methods from 140 to 1,317 bp was 98.9%. DNA concentrations and repeatability and reproducibility performances showed no biases in allele calling. Furthermore, turnaround time using this automated system was reduced by 81% compared to the conventional manual agarose gel method. In sum, this new automated method facilitates MIRU-VNTR genotyping and provides reliable results. Therefore, it is well suited for field genotyping. The implementation of this method will help to achieve accurate and cost-effective epidemiological studies, especially in countries with a high prevalence of TB, where the high number of strains complicates the surveillance of circulating lineages and requires efficient interventions to be carried out in an urgent manner.


From drought to deluge: how information overload saturated absorption capacity in a disrupted health sector.
Provision of technical assistance is a common form of support to health sectors emerging from prolonged conflicts. But what actions signal that the Ministry of Health (MoH) is, or is not, actively analysing and digesting the output of this assistance? Where are the boundaries between doing with and doing for? This article presents a qualitative description of an early post-conflict policy process in southern Sudan, which represented an opportunity to test these boundaries. The methodology of provision of technical assistance to the MoH in the formulation of a human resource plan is reviewed. Initial objectives are compared with the results accomplished. Shortcomings are discussed and recommendations for technical assistance programmes in similar contexts are provided. Between October 2005 and May 2006, World Health Organization advisers supported the MoH in conducting a human resources assessment to lay the grounds for a human resources development plan. The study employed three consultants, ten data collectors and entailed questionnaires, field visits, interviews and a review of literature. The survey shed new important evidence on the human resources situation in southern Sudan, both in quantitative and qualitative terms, and formulated specific recommendations. The formulation of the human resources plan, however, took another direction, apparently unrelated to the findings of the survey. Various factors contributed to the scope and methodology of the survey being inappropriate to the reality of southern Sudan. In the presence of systemic capacity gaps, including uncertain governance and precarious management systems, the benefit of one-off comprehensive surveys is likely to be negligible. Inaction is not always rooted in the lack of information, as too often assumed; this case study exposes the limits of a rationalistic approach to policy formulation and planning in the field of human resources for health. An alternative approach that entails incremental steps to institutional capacity building is suggested.


Lipoprotein-associated phospholipase A(2) and risk of coronary disease, stroke, and mortality: collaborative analysis of 32 prospective studies.
Lipoprotein-associated phospholipase A(2) (Lp-PLA(2)), an inflammatory enzyme expressed in atherosclerotic plaques, is a therapeutic target being assessed in trials of vascular disease prevention. We investigated associations of circulating Lp-PLA(2) mass and activity with risk of coronary heart disease, stroke, and mortality under different circumstances. With use of individual records from 79 036 participants in 32 prospective studies (yielding 17 722 incident fatal or non-fatal outcomes during 474 976 person-years at risk), we did a meta-analysis of within-study regressions to calculate risk ratios (RRs) per 1 SD higher value of Lp-PLA(2) or other risk factor. The primary outcome was coronary heart disease. Lp-PLA(2) activity and mass were associated with each other (r=0.51, 95% CI 0.47-0.56) and proatherogenic lipids. We noted roughly log-linear associations of Lp-PLA(2) activity and mass with risk of coronary heart disease and vascular death. RRs, adjusted for conventional risk factors, were: 1.10 (95% CI 1.05-1.16) with Lp-PLA(2) activity and 1.11 (1.07-1.16) with Lp-PLA(2) mass for coronary heart disease; 1.08 (0.97-1.20) and 1.14 (1.02-1.27) for ischaemic stroke; 1.16 (1.09-1.24) and 1.13 (1.05-1.22) for vascular mortality; and 1.10 (1.04-1.17) and 1.10 (1.03-1.18) for non-vascular mortality, respectively. RRs with Lp-PLA(2) did not differ significantly in people with and without initial stable vascular disease, apart from for vascular death with Lp-PLA(2) mass. Adjusted RRs for coronary heart disease were 1.10 (1.02-1.18) with non-HDL cholesterol and 1.10 (1.00-1.21) with systolic blood pressure. Lp-PLA(2) activity and mass each show continuous associations with risk of coronary heart disease, similar in magnitude to that with non-HDL cholesterol or systolic blood pressure in this population. Associations of Lp-PLA(2) mass and activity are not exclusive to vascular outcomes, and the vascular associations depend at least partly on lipids. UK Medical Research Council, GlaxoSmithKline, and British Heart Foundation.


Viral kinetics in untreated versus treated acute HIV infection in prospective cohort studies in Thailand.
The extent of viral replication during acute HIV infection (AHI) influences HIV disease progression. However, information comparing viral load (VL) kinetics with and without antiretroviral therapy (ART) in AHI is limited. The knowledge gained could inform preventive strategies aimed at reducing VL during AHI and therapeutic strategies to alter the viral kinetics that may enhance the likelihood of achieving HIV remission. The analysis utilized VL data captured during the first year of HIV infection from two studies in Thailand: the RV217 study (untreated AHI, 30 participants and 412 visits) and the RV254 study (treated AHI, 235 participants and 2803 visits). Fiebig stages were I/II (HIV RNA+, HIV IgM-) and Fiebig III/IV (HIV IgM+, Western blot-/indeterminate). Data were modelled utilizing spline effects within a linear mixed model, with a random intercept and slope to allow for between-subject variability and adjustment for the differences in variability between studies. The number of knots in the quadratic spline basis functions was determined by comparing models with differing numbers of knots via the Akaike Information Criterion. Models were fit using PROC GLIMMIX in SAS v9.3. At enrolment, there were 24 Fiebig I/II and 6 Fiebig III/IV individuals in the untreated group and 137 Fiebig I/II and 98 Fiebig III/IV individuals in the treated group. Overall, the median age was 27.5 years old, most were male (89%), and CRF01_AE was the most common HIV clade (76%). By day 12 (4 days after ART in RV254), the untreated group had a 2.7-fold higher predicted mean VL level compared to those treated (predicted log VL 6.19 for RV217 and 5.76 for RV254, p = 0.05). These differences increased to 135-fold by day 30 (predicted log VL 4.89 for RV217 and 2.76 for RV254) and 1148-fold by day 120 (predicted log VL 4.68 for RV217 and 1.63 for RV254) (p < 0.0001 for both) until both curves were similarly flat at about day 150 (p = 0.17 between days 150 and 160). The VL trajectories were significantly different between Fiebig I/II and Fiebig III/IV participants when comparing the two groups and within the treated group (p < 0.001 for both). Initiating ART in AHI dramatically changed the trajectory of VL very early in the course of infection that could have implications for reducing transmission potential and enhancing responses to future HIV remission strategies. There is an urgency of initiating ART when acute infection is identified. New and inexpensive strategies to engage and test individuals at high risk for HIV as well as immediate treatment access will be needed to improve the treatment of acute infection globally. NCT00796146 and NCT00796263.


Development of real time PCR to detect Toxoplasma gondii and Borrelia burgdorferi infections in postal samples.
Most of the samples sent to reference laboratories are delivered by post. Thus, diagnostic PCR tests on blood samples have to be performed using methods which are optimised and validated for such conditions. There is a low probability that the organisms Toxoplasma gondii and Borrelia burgdorferi will be present. To confirm that robotic extraction methods followed by real time PCR will detect as little as one organism/test sample in postal specimens. Human blood samples spiked with decreasing numbers of each organism (range 10(5)-1/per extract) were extracted using two commercial kits on a Qiagen BioRobot EZ1 Workstation. Extracts of whole blood and blood fractions were tested by real time PCR. The effect of storage of blood for 1-6 days at room temperature was also investigated. Maximum sensitivity (1 organism/test sample) was achieved for T gondii with either extraction method; the sensitivity for B burgdorferi was between 1 and 10 organisms/test. Whole blood was the most suitable sample to extract, as both organisms were as likely to be detectable in the red cell as the white cell fraction. Sensitivity was not reduced by storing spiked samples at room temperature for up to 6 days. Inhibitory effects on PCR were not a significant problem provided that samples were extracted using the blood extraction kit. Using appropriate robotic extraction methods, both T gondii and B burgdorferi can be detected by real time PCR with near maximum possible sensitivity in whole blood samples. Blood samples can be transferred to reference laboratories by post without loss of sensitivity over the likely transit period.


Color-center production and recovery in electron-irradiated magnesium aluminate spinel and ceria.
Single crystals of magnesium aluminate spinel (MgAl2O4) with (1 0 0) or (1 1 0) orientations and cerium dioxide or ceria (CeO2) were irradiated by 1.0 MeV and 2.5 MeV electrons in a high-fluence range. Point-defect production was studied by off-line UV-visible optical spectroscopy after irradiation. For spinel, regardless of both crystal orientation and electron energy, two characteristic broad bands centered at photon energies of 5.4 eV and 4.9 eV were assigned to F and F(+) centers (neutral and singly ionized oxygen vacancies), respectively, on the basis of available literature data. No clear differences in color-center formation were observed for the two crystal orientations. Using calculations from displacement cross sections by elastic collisions, these results are consistent with a very large threshold displacement energy (200 eV) for oxygen atoms at room temperature. A third very broad band centered at 3.7 eV might be attributed either to an oxygen hole center (V-type center) or an F2 dimer center (oxygen di-vacancy). The onset of recovery of these color centers took place at 200 °C with almost full bleaching at 600 °C. Activation energies (~0.3-0.4 eV) for defect recovery were deduced from the isochronal annealing data by using a first-order kinetics analysis. For ceria, a sub-band-gap absorption feature, which peaked at ~3.1 eV, was recorded for 2.5 MeV electron irradiation only. Assuming a ballistic process, we suggest that the latter defect might result from cerium atom displacement on the basis of computed cross sections.


The polymerase domain of Streptococcus pneumoniae DNA polymerase I. High expression, purification and characterization.
The 3'-terminal two-thirds of the Streptococcus pneumoniae polA gene was cloned in an Escherichia coli genefusion vector with inducible expression. The resulting recombinant plasmid (pSM10) directs the hyperproduction of a polypeptide of 70.6 kDa corresponding to the C-terminal fragment of pneumococcal DNA polymerase I. Induced cells synthesized catalytically active protein to the extent of 7% of the total soluble protein in the cells. The polymerase fragment was purified to greater than 90% homogeneity with a yield of 1.5 mg pure protein/l culture. The protein has DNA polymerase activity, but no exonuclease activity. The enzyme requires a divalent cation (MgCl2 or MnCl2) for polymerization of DNA. Comparison of the mutant and wild-type pneumococcal polymerases shows that the construction did not affect the enzymatic affinity for the various substrates. The mutant protein, like its parent DNA polymerase I, exhibited an intermediate level of activity with primed single-stranded DNA. At high molar ratio of enzyme/DNA substrate, the polymerase fragment catalyzes strand displacement and switching after completing the replication of a primed single-stranded M13 DNA molecule.


Achieving Equity in Physical Activity Participation: ACSM Experience and Next Steps.
There is clear and consistent evidence that regular physical activity is an important component of healthy lifestyles and fundamental to promoting health and preventing disease. Despite the known benefits of physical activity participation, many people in the United States remain inactive. More specifically, physical activity behavior is socially patterned with lower participation rates among women; racial/ethnic minorities; sexual minority youth; individuals with less education; persons with physical, mental, and cognitive disabilities; individuals >65 yr of age; and those living in the southeast region of the United States. Many health-related outcomes follow a pattern that is similar to physical activity participation. In response to the problem of inequities in physical activity and overall health in the United States, the American College of Sports Medicine (ACSM) has developed a national roadmap that supports achieving health equity through a physically active lifestyle. The actionable, integrated pathways that provide the foundation of ACSM's roadmap include the following: 1) communication-raising awareness of the issue and magnitude of health inequities and conveying the power of physical activity in promoting health equity; 2) education-developing educational resources to improve cultural competency for health care providers and fitness professionals as well as developing new community-based programs for lay health workers; 3) collaboration-building partnerships and programs that integrate existing infrastructures and leverage institutional knowledge, reach, and voices of public, private, and community organizations; and 4) evaluation-ensuring that ACSM attains measurable progress in reducing physical activity disparities to promote health equity. This article provides a conceptual overview of these four pathways of ACSM's roadmap, an understanding of the challenges and advantages of implementing these components, and the organizational and economic benefits of achieving health equity.


Prevalence of accelerated coronary artery disease in heart transplant survivors. Comparison of cyclosporine and azathioprine regimens.
Rapid development of diffuse, occlusive coronary artery disease in the cardiac allograft has emerged as a major limiting factor for long-term survival after transplantation. Prior multivariate analyses have failed to identify any strong predictors of this disease. We retrospectively reviewed serial annual coronary angiograms to assess the prevalence of transplant coronary artery disease. A total of 103 patients treated initially with azathioprine-based therapy were compared with a later cohort of 78 patients for whom cyclosporine was the basis of immunosuppressive therapy. The percent of patients free of angiographically visible transplant coronary artery disease at 1 year was 89% for the azathioprine group versus 86% for the cyclosporine group. At 3 years, 74% of the azathioprine group versus 63% of the cyclosporine group were free of visible disease (p = NS). By the fifth postoperative year, 58% of azathioprine-treated and 50% of cyclosporine-treated patients were free of transplant coronary artery disease (p = NS). The mean number of rejection episodes in the first year after transplantation was 2.0 for cyclosporine patients versus 2.5 for azathioprine patients. The azathioprine and cyclosporine patients were compared with respect to a variety of baseline and clinical follow-up measurements that might influence the development of coronary artery disease. Patients in the cyclosporine group had higher blood pressure (135/94 versus 123/85 mm Hg, p less than 0.001) and were receiving lower maintenance prednisone doses. This study demonstrates that improved cyclosporine immunosuppression does not decrease the time-related prevalence of transplant coronary artery disease.


Origin of the bacterial SET domain genes: vertical or horizontal?
The presence of Supressor of variegation-Enhanser of zeste-Trithorax (SET) domain genes in bacteria is a current paradigm for lateral genetic exchange between eukaryotes and prokaryotes. Because a major function of SET domain proteins is the chemical modification of chromatin and bacteria do not have chromatin, there is no apparent functional requirement for the existence of bacterial SET domain genes. Consequently, their finding in only a small fraction of pathogenic and symbiotic bacteria was taken as evidence that bacteria have obtained the SET domain genes from their hosts. Furthermore, it was proposed that the products of the genes would, most likely, be involved in bacteria-host interactions. The broadened scope of sequenced bacterial genomes to include also free-living and environmental species provided a larger sample to analyze the bacterial SET domain genes. By phylogenetic analysis, examination of individual chromosomal regions for signs of insertion, and evaluating the chromosomal versus SET domain genes' GC contents, we provide evidence that SET domain genes have existed in the bacterial domain of life independently of eukaryotes. The bacterial genes have undergone an evolution of their own unconnected to the evolution of the eukaryotic SET domain genes. Initial finding of SET domain genes in predominantly pathogenic and symbiotic bacteria resulted, most probably, from a biased sample. However, a lateral transfer of SET domain genes may have occurred between some bacteria and a family of Archaea. A model for the evolution and distribution of SET domain genes in bacteria is proposed.


The Mediterranean Diet And Cardioprotection: Historical Overview And Current Research.
Ancient Greece was the cradle of the Mediterranean food tradition, characterized by the Mediterranean "eternal trinity" wheat - olive oil - wine, the very essence of the country's traditional agricultural and dietary regime, enriched by a culture of sharing and commensality. This food model, subsequently adopted and spread by the Romans, was rediscovered at the end of the Second World War by two American researchers, Leland Allbaugh and Ancel Keys. With the famous Seven Countries Study, Keys demonstrated for the first time that populations practicing a Mediterranean diet - such as the Greeks and southern Italians - showed low mortality rates from ischemic heart disease compared to the peoples of Northern Europe and North America. Since then, numerous subsequent epidemiological studies and randomized clinical trials have confirmed the beneficial effects of the Mediterranean diet both in primary and secondary prevention of cardiovascular diseases. This review will focus on the origins of the Mediterranean diet from its roots and its relationship to cardiovascular disease, with a brief overview of the nutritional mechanisms that influence atherosclerosis.


Calcium response in single osteocytes to locally applied mechanical stimulus: differences in cell process and cell body.
It is proposed that osteocytes embedded in the bone matrix have the ability to sense deformation and/or damage to the matrix and to feed these mechanical signals back to the adaptive bone remodeling process. When osteoblasts differentiate into osteocytes during the bone formation process, they change their morphology to a stellate form with many slender processes. This characteristic cell shape may underlie the differences in mechanosensitivity between the cell processes and cell body. To elucidate the mechanism of cellular response to mechanical stimulus in osteocytes, we investigated the site-dependent response to quantitatively controlled local mechanical stimulus in single osteocytes isolated from chick embryos, using the technique of calcium imaging. A mechanical stimulus was applied to a single osteocyte using a glass microneedle targeting a microparticle adhered to the cell membrane by modification with a monoclonal antibody OB7.3. Application of the local deformation induced calcium transients in the vicinity of the stimulated point and caused diffusive wave propagation of the calcium transient to the entire intracellular region. The rate of cell response to the stimulus was higher when applied to the cell processes than when applied to the cell body. In addition, a large deformation was necessary at the cell body to induce calcium transients, whereas a relatively small deformation was sufficient at the cell processes, suggesting that the mechanosensitivity of the cell processes was higher than that of the cell body. These results suggest that the cell shape with slender processes contributes to the site-dependent mechanosensitivity in osteocytes.


The influence of emotional words on sentence processing: electrophysiological and behavioral evidence.
Whereas most previous studies on emotion in language have focussed on single words, we investigated the influence of the emotional valence of a word on the syntactic and semantic processes unfolding during sentence comprehension, by means of event-related brain potentials (ERP). Experiment 1 assessed how positive, negative, and neutral adjectives that could be either syntactically correct or incorrect (violation of number agreement) modulate syntax-sensitive ERP components. The amplitude of the left anterior negativity (LAN) to morphosyntactic violations increased in negative and decreased in positive words in comparison to neutral words. In Experiment 2, the same sentences were presented but positive, negative, and neutral adjectives could be either semantically correct or anomalous given the sentence context. The N400 to semantic anomalies was not significantly affected by the valence of the violating word. However, positive words in a sentence seemed to influence semantic correctness decisions, also triggering an apparent N400 reduction irrespective of the correctness value of the word. Later linguistic processes, as reflected in the P600 component, were unaffected in either experiment. Overall, our results indicate that emotional valence in a word impacts the syntactic and semantic processing of sentences, with differential effects as a function of valence and domain.


A novel pro-angiogenic function for interferon-γ-secreting natural killer cells.
To explore the function of natural killer (NK) cells in inflammatory angiogenesis in mice. To study ocular angiogenic responses we used the cornea BFGF micropellet and the laser-induced choroidal neovascularization (CNV) mouse models (C57BL/6). To deplete NK cells in these models, we injected an anti-NK1.1 antibody or an isotype antibody as a control. Corneas or choroids were immunohistochemically stained for blood vessels (CD31), macrophages (F4/80), or CNV (isolectin-IB4). Vascular endothelial growth factors (VEGF), IFN-γ, or TNF-α levels were measured by real-time quantitative PCR (qPCR) or flow cytometry. A coculture assay of macrophages, NK cells, and human umbilical vein endothelial cells (HUVECs) was analyzed morphometrically to examine the ability of NK cells to induce angiogenesis in vitro. Our data demonstrate that in vivo depletion of NK cells leads to a significant reduction of corneal angiogenesis and CNV. Furthermore, NK cell depletion reduces macrophage infiltration into the cornea and mRNA expression levels of VEGF-A, VEGF-C, and VEGFR3 at day 7 after micropellet insertion. In the laser-induced CNV model, our data show that NK cell depletion leads to decreased areas of CNV and significantly reduced mRNA expression of VEGFs and IFN-γ in the choroid. An in vitro coculture assay shows an IFN-γ-dependent increase in VEGF expression levels, thereby increasing endothelial cell proliferation. Our findings demonstrate a novel pro-angiogenic function for NK cells, indicating that IFN-γ-secreting NK cells can induce angiogenesis by promoting enhanced VEGF expression by macrophages.


What controls the distribution of tropical forest and savanna?
Forest and savanna biomes dominate the tropics, yet factors controlling their distribution remain poorly understood. Climate is clearly important, but extensive savannas in some high rainfall areas suggest a decoupling of climate and vegetation. In some situations edaphic factors are important, with forest often associated with high nutrient availability. Fire also plays a key role in limiting forest, with fire exclusion often causing a switch from savanna to forest. These observations can be captured by a broad conceptual model with two components: (1) forest and savanna are alternative stable states, maintained by tree cover-fire feedbacks, (2) the interaction between tree growth rates and fire frequency limits forest development; any factor that increases growth (e.g. elevated availability of water, nutrients, CO(2)), or decreases fire frequency, will favour canopy closure. This model is consistent with the range of environmental variables correlated with forest distribution, and with the current trend of forest expansion, likely driven by increasing CO(2) concentrations. Resolving the drivers of forest and savanna distribution has moved beyond simple correlative studies that are unlikely to establish ultimate causation. Experiments using Dynamic Global Vegetation Models, parameterised with measurements from each continent, provide an important tool for understanding the controls of these systems.


Vascular coupling induces synchronization, quasiperiodicity, and chaos in a nephron tree.
The paper presents a study of synchronization phenomena in a system of 22 nephrons supplied with blood from a common cortical radial artery. The nephrons are assumed to interact via hemodynamic and vascularly propagated coupling, both mediated by vascular connections. Using anatomic and physiological criteria, the nephrons are divided into groups: cortical nephrons and medullary nephrons with short, intermediate and long Henle loops. Within each of these groups the delay parameters of the internal feedback regulation are given a random component to represent the internephron variability. For parameters that generate simple limit cycle dynamics in the pressure and flow regulation of single nephrons, the ensemble of coupled nephrons showed steady state, quasiperiodic or chaotic dynamics, depending on the interaction strengths and the arterial blood pressure. When the solutions were either quasiperiodic or chaotic, cortical nephrons synchronized to a single frequency, but the longer medullary nephrons formed two clusters with different frequencies. Under no physiologically realistic combination of parameters did all nephrons assume a common frequency. Our results suggest a greater variability in the nephron dynamics than is apparent from measurements performed on cortical nephrons only. This variability may explain the development of chaotic dynamics in tubular pressure records from hypertensive rats.


The slice overlay assay: a versatile tool to study the influence of extracellular signals on neuronal development.
We have developed a technique that allows characterization and identification of extracellular signals that regulate various aspects of neuronal differentiation. In this in vitro assay, dissociated cells isolated from the developing cerebral wall are labeled and cultured over organotypic cortical slices. We have used this slice overlay assay to identify some of the extracellular cues that regulate differentiation and patterning of axons and dendrites in the cerebral cortex. This assay can be easily adapted to identify factors that control other aspects of neuronal development, such as proliferation and survival, and can also be used to evaluate the role of extracellular signals in the development of nonneural tissues.


Liver stiffness measurement as a predictive tool of clinically significant portal hypertension in patients with compensated hepatitis C virus or alcohol-related cirrhosis.
Hepatic venous pressure gradient (HVPG) is the gold standard for assessing the presence and the severity of portal hypertension (PHT). Liver stiffness measurement (LSM) is a non-invasive method for liver fibrosis assessment. To assess the relationship between LSM and HVPG in patients with compensated cirrhosis related to hepatitis C virus (HCV) or alcohol and to define the performance and the best cut-off of LSM for the diagnosis of PHT in these patients. Between January 2004 and September 2006, we studied all the consecutive patients with compensated HCV or alcohol-related-cirrhosis referred for transjugular liver biopsy with HVPG measurement and LSM performed the same day. Ninety-two patients were eligible, 44 had HCV related-cirrhosis and 48 alcoholic cirrhosis. LSM was positively correlated to HVPG in both groups. The area under the receiver operating characteristic curve for the diagnosis of significant PHT was 0.76 +/- 0.07 in HCV patients (best cut-off at 20.5 kPa) and 0.94 +/- 0.03 (best cut-off at 34.9 kPa) in alcoholic patients. Liver stiffness measurement and HVPG were significantly correlated in patients with compensated cirrhosis because of HCV infection or alcohol. LSM could predict significant PHT in both these groups of patients with a higher cut-off and a better performance in alcoholic patients.


Colloidal liquid crystals in rectangular confinement: theory and experiment.
We theoretically and experimentally study nematic liquid crystal equilibria within shallow rectangular wells. We model the wells within a two-dimensional Oseen-Frank framework, with strong tangent anchoring, and obtain explicit analytical expressions for the director fields and energies of the 'diagonal' and 'rotated' solutions reported in the literature. These expressions separate the leading-order defect energies from the bulk distortion energy for both families of solutions. The continuum Oseen-Frank study is complemented by a microscopic mean-field approach. We numerically minimize the mean-field functional, including the effects of weak anchoring, variable order and random initial conditions. In particular, these simulations suggest the existence of higher-energy metastable states with internal defects. We compare our theoretical results to experimental director profiles, obtained using two types of filamentous virus particles, wild-type fd-virus and a modified stiffer variant (Y21M), which display nematic ordering in rectangular chambers, as found by confocal scanning laser microscopy. We combine our analytical energy expressions with experimentally recorded frequencies of the different equilibrium states to obtain explicit estimates for the extrapolation length, defined to be the ratio of the nematic elastic constant to the anchoring coefficient, of the fd-virus.


Recovering Religious Voice and Imagination: A Response to Nolan's Case Study "He Needs to Talk!".
In Nolan's case study, "He Needs to Talk!": A Chaplain's Response to Nonreligious Spiritual Care," he asks an important question: "What is distinctive about the chaplain's role in working with nonreligious people?" This is a compelling question for chaplains working in a society where individuals are increasingly defining themselves as NOT religious. In this response, I will analyze how our current religious context, in which we feel over-responsible for an existential quest without a language to express our dilemma, creates a unique role for chaplaincy with the nonreligious. I will apply this context to Nolan's case study providing examples of how the care provided can support nonreligious individuals to find language to express their religious dilemmas and to foster a moral imagination that counters over-responsibility. Finally, I will suggest that case studies provide thick qualitative descriptions of care that help to reveal what chaplains do while countering stereotypical and thin accounts of religion.


Time for a change of practice: the real-world value of testing for neuronal autoantibodies in acute first-episode psychosis.
It is time that all patients with acute-onset psychosis are screened for autoimmune encephalitis, that lumbar puncture becomes a routine psychiatric investigation and that immunotherapy is available in indicated cases. We call for a culture change in the management of psychosis by psychiatry. None.


Stimulation of gastrin release by bombesin and canine gastrin-releasing peptides. Studies with isolated canine G cells in primary culture.
Bombesin, a polypeptide derived from frog skin, has been shown to stimulate gastrin release from the gastric antrum in vivo and in vitro. To elucidate the mechanisms of this effect, we developed a method to culture isolated and enriched G cells from canine stomach. After digestion of antral mucosa with collagenase and EDTA, dispersed cells were fractionated by counterflow elutriation then cultured on a collagen support. Bombesin and three molecular forms of canine gastrin-releasing peptides all stimulated gastrin release from G cells in a dose-dependent manner. The effect of bombesin was suppressed by somatostatin and potentiated by dibutyryl cyclic AMP (10(-3) M) but not by carbachol (10(-6) M). Extracellular calcium depletion attenuated the stimulation of gastrin release by bombesin but not by forskolin. These findings suggest that the bombesin family peptides directly activate G cells through calcium-dependent mechanisms to cause gastrin release.


The mixed evidence for brief intervention in emergency departments, trauma care centers, and inpatient hospital settings: what should we do?
This qualitative review is based on a symposia presented at the 2009 annual conference of the Research Society on Alcoholism (Baird et al., 2009; Field et al., 2009; Monti et al., 2009; Saitz et al., 2009a). The purpose is to describe the mixed evidence supporting brief interventions in the emergency department, trauma care, and in-patient medical care settings; examine potential moderators of treatment outcome in light of the mixed evidence; and identify methods to move the research and practice of brief interventions beyond their current state. By drawing upon existing reviews and selected individual studies, we provide examples that reflect the current complexity of research in this area and propose steps for advancing the field. Emergency departments, inpatient hospital settings, and trauma care settings represent three unique contexts within which brief interventions have been tested. While the general efficacy of brief alcohol interventions in these settings has been recognized, the evidence is increasingly mixed. Recent studies investigating potential moderators of treatment outcomes suggest that a more sophisticated approach to evaluating the effectiveness of brief interventions across varying patient populations is needed to further understand its effectiveness. Current dissemination efforts represent a significant advance in broadening the base of treatment for alcohol problems by providing an evidence-based intervention in health care settings and should not be curtailed. However, additional research is required to enhance treatment outcomes, refine current practice guidelines, and continue to bridge the gap between science and practice. Given the current state of research, a multisetting clinical trial is recommended to account for potential contextual differences while controlling for study design.


A Comparative Study of Assay Performance of Commercial Hepatitis E Virus Enzyme-Linked Immunosorbent Assay Kits in Australian Blood Donor Samples.
Hepatitis E virus (HEV) is transfusion-transmissible and therefore poses a risk to blood transfusion safety. Seroprevalence studies are useful for estimating disease burden and determining risk factors. Considerable variability in the sensitivity of HEV antibody detection assays exists. This study aimed to compare the performances of commercially available HEV enzyme-linked immunosorbent assays (ELISA) in Australian blood donor samples. Plasma samples that tested positive (n = 194) or negative (n = 200) for HEV IgG (Wantai HEV IgG ELISA) were selected. Of the 194 HEV IgG positive samples, 4 were positive for HEV IgM (Wantai HEV IgM ELISA). All samples were tested with the MP Diagnostics: HEV IgG ELISA, total (IgG, IgM, and IgA) HEV antibody ELISA, and HEV IgM ELISA. Of the 194 Wantai HEV IgG positive samples, 92 (47%) tested positive with the MP Diagnostics HEV IgG ELISA (κ = 0.47) and 126 (65%) with MP Diagnostics total HEV antibody assay (κ = 0.65). There was poor agreement between Wantai and MP Diagnostics HEV IgM assays. This study demonstrated poor agreement between the assays tested. These observations are consistent with previous reports demonstrating significant variability between HEV ELISAs, highlighting that results of HEV serology should be interpreted with caution.


Individual correlation of morphology, muscle mechanics, and locomotion in a salamander.
Measurements were made on locomotor performance (burst run and swim speed, run and swim endurance), morphology (body, tail, and hindlimb length, body mass), and skeletal muscle mechanics (isometric: twitch and tetanic tension, rates of force development and relaxation; isotonic: maximal velocity of shortening and power output) in a size range of individual salamanders (Ambystoma tigrinum nebulosum) at 10 and 20 degrees C. The size dependence of each factor was determined, and the interindividual correlations among factors were measured after removal of size effects. Locomotor performance is positively related to body size: larger animals are faster and have higher endurance. Isometric tensions (standardized for muscle cross-sectional area) and isotonic properties are mass independent; rates of isometric force development and relaxation are negatively related to body mass. Locomotor performance capacities are not intercorrelated among individuals. Isometric force and rates of force development are highly intercorrelated as are maximal shortening velocity and power output. Several statistical techniques failed to uncover correlations among sets of variables (performance, morphology, muscle mechanics): neither fast individuals nor individuals with high endurance necessarily have relatively fast muscles or long limbs or tails after the effects of body size have been removed.


Anthropometry and bone mineral density in treated and untreated hyperphenylalaninemia.
Despite recent improvements in the composition of the diet, lower mineral bone density and overweight tendencies are incoherently described in patients with phenylketonuria (PKU). The impact of dietary factors and plasma phenylalanine levels on growth, BMI, body composition, and bone mineral density was investigated in our cohort of patients with hyperphenylalaninemia (HPA) with or without dietary treatment. The anthropometric, metabolic, BMI and other nutritional indicators and bone mineral density were compared between the group of 96 treated patients with PKU (58 classic PKU (cPKU) and 38 patients with moderate-mild PKU defined as non-classic PKU (non-cPKU)) and the untreated group of 62 patients with benign HPA. Having compared the treated and untreated groups, there were normal outcomes and no statistically significant differences in BMI, body composition, and bone mineral density. Lower body height standard deviation scores were observed in the treated as compared to the untreated group (P < 0.001), but the difference was not significant when analyzing patients older than 18 years; however, cPKU adults were shorter compared to non-cPKU treated adults (P = 0.012). Interestingly, the whole-body fat was statistically higher in non-cPKU as compared to cPKU patients. In conclusion, the dietary treatment ensured adequate nutrition without significant consequences in BMI, body composition, and bone mineral density. A low protein diet may have delayed the growth in childhood, but the treated patients gained a normal final height. Mild untreated hyperphenylalaninemia characteristic for benign HPA had no negative physiological effect on bone mineral density.


Transgenerational Effects of Early Life Starvation on Growth, Reproduction, and Stress Resistance in Caenorhabditis elegans.
Starvation during early development can have lasting effects that influence organismal fitness and disease risk. We characterized the long-term phenotypic consequences of starvation during early larval development in Caenorhabditis elegans to determine potential fitness effects and develop it as a model for mechanistic studies. We varied the amount of time that larvae were developmentally arrested by starvation after hatching ("L1 arrest"). Worms recovering from extended starvation grew slowly, taking longer to become reproductive, and were smaller as adults. Fecundity was also reduced, with the smallest individuals most severely affected. Feeding behavior was impaired, possibly contributing to deficits in growth and reproduction. Previously starved larvae were more sensitive to subsequent starvation, suggesting decreased fitness even in poor conditions. We discovered that smaller larvae are more resistant to heat, but this correlation does not require passage through L1 arrest. The progeny of starved animals were also adversely affected: Embryo quality was diminished, incidence of males was increased, progeny were smaller, and their brood size was reduced. However, the progeny and grandprogeny of starved larvae were more resistant to starvation. In addition, the progeny, grandprogeny, and great-grandprogeny were more resistant to heat, suggesting epigenetic inheritance of acquired resistance to starvation and heat. Notably, such resistance was inherited exclusively from individuals most severely affected by starvation in the first generation, suggesting an evolutionary bet-hedging strategy. In summary, our results demonstrate that starvation affects a variety of life-history traits in the exposed animals and their descendants, some presumably reflecting fitness costs but others potentially adaptive.


Near-death experience in survivors of cardiac arrest: a prospective study in the Netherlands.
Some people report a near-death experience (NDE) after a life-threatening crisis. We aimed to establish the cause of this experience and assess factors that affected its frequency, depth, and content. In a prospective study, we included 344 consecutive cardiac patients who were successfully resuscitated after cardiac arrest in ten Dutch hospitals. We compared demographic, medical, pharmacological, and psychological data between patients who reported NDE and patients who did not (controls) after resuscitation. In a longitudinal study of life changes after NDE, we compared the groups 2 and 8 years later. 62 patients (18%) reported NDE, of whom 41 (12%) described a core experience. Occurrence of the experience was not associated with duration of cardiac arrest or unconsciousness, medication, or fear of death before cardiac arrest. Frequency of NDE was affected by how we defined NDE, the prospective nature of the research in older cardiac patients, age, surviving cardiac arrest in first myocardial infarction, more than one cardiopulmonary resuscitation (CPR) during stay in hospital, previous NDE, and memory problems after prolonged CPR. Depth of the experience was affected by sex, surviving CPR outside hospital, and fear before cardiac arrest. Significantly more patients who had an NDE, especially a deep experience, died within 30 days of CPR (p<0.0001). The process of transformation after NDE took several years, and differed from those of patients who survived cardiac arrest without NDE. We do not know why so few cardiac patients report NDE after CPR, although age plays a part. With a purely physiological explanation such as cerebral anoxia for the experience, most patients who have been clinically dead should report one.


Signal amplification using functional nanomaterials for biosensing.
Signal amplification based on biofunctional nanomaterials has recently attracted considerable attention due to the need for ultrasensitive bioassays and the trend towards miniaturized assays. The biofunctional nanomaterials can not only produce a synergic effect among catalytic activity, conductivity and biocompatibility to accelerate the signal transduction, but also provide amplified recognition events by high loading of signal tags, leading to a highly sensitive and specific biosensing. Most importantly, nanoscaled materials are in direct contact with the environment, which permits them to act as chemical and biological sensors in single-molecule detection of biomolecules. In this tutorial review, we will focus on recent significant advances in signal amplification strategies combining the cross-disciplines of chemistry, biology, and materials science, and highlight some elegant applications of biofunctional nanomaterials as excellent electronic or optical signal tags in ultrasensitive bioanalysis. The biofunctional nanomaterials-based biosensing opens a series of concepts for basic research and offers new tools for detection of trace amounts of a wide variety of analytes in clinical, environmental, and industrial applications.


The Segond fracture occurs at the site of lowest sub-entheseal trabecular bone volume fraction on the tibial plateau.
In a series of human cadaveric experiments, Dr. Paul Segond first described the avulsion injury occurring at the anterolateral tibial plateau that later took his name. The fracture is thought to arise as a consequence of excessive tibia internal rotation which often also elicits damage to other connective tissue of the knee. The exact mechanism behind the avulsion is, however, unclear. A number of ligamentous structures have been proposed in separate studies to insert into the Segond fragment. Suggestions include the iliotibial band (ITB), biceps femoris and the controversial 'anterolateral ligament' (ALL). Despite increasing knowledge of tibial plateau bony microarchitecture in both healthy and disease states, no studies have yet, to our knowledge, considered the role of tibial sub-entheseal bone structure in pathogenesis of the Segond fracture. The goal of this study was thus to elucidate the differences in trabecular properties at regions across the tibial plateau in order to provide an explanation for the susceptibility of the anterolateral region to avulsion injury. Twenty human tibial plateaus from cadaveric donors were dissected and imaged using a Nikon-XTH225-μCT scanner with <80 μm isotropic voxel size. Scans were reconstructed using MicroView 3D Image Viewer and Analysis Tool. Subsequent virtual biopsy at ten anatomically defined regions of interest (ROI) generated estimates of bone volume fraction ('bone volume divided by total volume' (BV/TV)). The overall mean BV/TV value across all 20 tibiae and all 10 ROIs was 0.271. Univariate repeated-measurements ANOVA demonstrated that BV/TV values differed between ROIs. BV/TV values at the Segond site (Sα, Sβ or Sγ) were lower than all other ROIs at 0.195, 0.192 and 0.193, respectively. This suggests that, notwithstanding inter- and intra-specimen variation, the Segond site tends to have a lower trabecular bone volume fraction than entheseal sites elsewhere on the tibia. Since BV/TV correlates with tensile and torsional strength, the lower BV/TV at the Segond site could equate to a region of local weakness in certain individuals which predisposes them to an avulsion injury following the application of force from excessive internal rotation. The low BV/TV recorded at the Segond site also challenges the idea that the fracture occurs due to pull from a discrete 'anterolateral ligament', as the tension exerted focally would be expected to elicit a hypertrophic response in line with Frost's Mechanostat hypothesis. Our data would instead agree with the aforementioned reports of the fibrous band at the Segond site being part of a broader insertion of an 'anterolateral complex'.


Ectopic expression of KNOTTED1-like homeobox protein induces expression of cytokinin biosynthesis genes in rice.
Some phytohormones such as gibberellins (GAs) and cytokinins (CKs) are potential targets of the KNOTTED1-like homeobox (KNOX) protein. To enhance our understanding of KNOX protein function in plant development, we identified rice (Oryza sativa) genes for adenosine phosphate isopentenyltransferase (IPT), which catalyzes the rate-limiting step of CK biosynthesis. Molecular and biochemical studies revealed that there are eight IPT genes, OsIPT1 to OsIPT8, in the rice genome, including a pseudogene, OsIPT6. Overexpression of OsIPTs in transgenic rice inhibited root development and promoted axillary bud growth, indicating that OsIPTs are functional in vivo. Phenotypes of OsIPT overexpressers resembled those of KNOX-overproducing transgenic rice, although OsIPT overexpressers did not form roots or ectopic meristems, both of which are observed in KNOX overproducers. Expression of two OsIPT genes, OsIPT2 and OsIPT3, was up-regulated in response to the induction of KNOX protein function with similar kinetics to those of down-regulation of GA 20-oxidase genes, target genes of KNOX proteins in dicots. However, expression of these two OsIPT genes was not regulated in a feedback manner. These results suggest that OsIPT2 and OsIPT3 have unique roles in the developmental process, which is controlled by KNOX proteins, rather than in the maintenance of bioactive CK levels in rice. On the basis of these findings, we concluded that KNOX protein simultaneously decreases GA biosynthesis and increases de novo CK biosynthesis through the induction of OsIPT2 and OsIPT3 expression, and the resulting high-CK and low-GA condition is required for formation and maintenance of the meristem.


Why do high school seniors drink? Implications for a targeted approach to intervention.
The transition from high school to college provides a potentially critical window to intervene and reduce risky behavior among adolescents. Understanding the motivations (e.g., social, coping, enhancement) behind high school seniors' alcohol use could provide one important avenue to reducing risky drinking behaviors. In the present study, latent class analysis was used to examine the relationship between different patterns of drinking motivations and behaviors in a sample of 12th graders (N = 1,877) from the 2004 Monitoring the Future survey. Unlike previous variable-centered analyses, this person-centered approach identifies types of motivations that cluster together within individuals and relates membership in these profiles to drinking behaviors. Results suggest four profiles of drinking motivations for both boys and girls, including Experimenters, Thrill-seekers, Multi-reasoners, and Relaxers. Early initiation of alcohol use, past year drunkenness, and drinking before 4 P.M. were associated with greater odds of membership in the Multi-reasoners class as compared to the Experimenters class. Although the strength of these relationships varied for boys and girls, findings were similar across gender suggesting that the riskiest drinking behavior was related to membership in the Multi-reasoners class. These findings can be used to inform prevention programming. Specifically, targeted interventions that tailor program content to the distinct drinking motivation profiles described above may prove to be effective in reducing risky drinking behavior among high school seniors.


Differentiating Variations in Thumb Position From Recordings of the Surface Electromyogram in Adults Performing Static Grips, a Proof of Concept Study.
Hand gesture and grip formations are produced by the muscle synergies arising between extrinsic and intrinsic hand muscles and many functional hand movements involve repositioning of the thumb relative to other digits. In this study we explored whether changes in thumb posture in able-body volunteers can be identified and classified from the modulation of forearm muscle surface-electromyography (sEMG) alone without reference to activity from the intrinsic musculature. In this proof-of-concept study, our goal was to determine if there is scope to develop prosthetic hand control systems that may incorporate myoelectric thumb-position control. Healthy volunteers performed a controlled-isometric grip task with their thumb held in four different opposing-postures. Grip force during task performance was maintained at 30% maximal-voluntary-force and sEMG signals from the forearm were recorded using 2D high-density sEMG (HD-sEMG arrays). Correlations between sEMG amplitude and root-mean squared estimates with variation in thumb-position were investigated using principal-component analysis and self-organizing feature maps. Results demonstrate that forearm muscle sEMG patterns possess classifiable parameters that correlate with variations in static thumb position (accuracy of 88.25 ± 0.5% anterior; 91.25 ± 2.5% posterior musculature of the forearm sites). Of importance, this suggests that in transradial amputees, despite the loss of access to the intrinsic muscles that control thumb action, an acceptable level of control over a thumb component within myoelectric devices may be achievable. Accordingly, further work exploring the potential to provide myoelectric control over the thumb within a prosthetic hand is warranted.


Effects of mechanical stress and carvedilol in lamin A/C-deficient dilated cardiomyopathy.
Mutations in the LMNA gene, which encodes the nuclear lamina proteins lamin A and lamin C, are the most common cause of familial dilated cardiomyopathy (DCM). Mechanical stress-induced apoptosis has been proposed as the mechanism underpinning DCM in lamin A/C-deficient hearts, but supporting in vivo evidence has been lacking. Our aim was to study interventions to modify mechanical stress in heterozygous Lmna knockout (Lmna(+/-)) mice. Cardiac structure and function were evaluated before and after exercise training, thoracic aortic constriction, and carvedilol treatment. Lmna(+/-) mice develop adult-onset DCM with relatively more severe disease in males. Lmna(+/-) cardiomyocytes show altered nuclear morphology and perinuclear desmin organization, with enhanced responses to hypo-osmotic stress indicative of cytoskeletal instability. Despite these structural defects that provide a template for mechanical stress-induced damage, young Lmna(+/-) mice subjected to 6 weeks of moderate or strenuous exercise training did not show induction of apoptosis or accelerated DCM. In contrast, regular moderate exercise attenuated DCM development in male Lmna(+/-) mice. Sustained pressure overload generated by thoracic aortic constriction depressed ventricular contraction in young wild-type and Lmna(+/-) mice with no sex or genotype differences in the time-course or severity of response. Treatment of male Lmna(+/-) mice from 12 to 40 weeks with the beta-blocker, carvedilol, prevented the dilatation and contractile dysfunction that was observed in placebo-treated mice. These data suggest that factors other than mechanical stress-induced apoptosis contribute to DCM and provide the first demonstration that regular moderate exercise and carvedilol can modify disease progression in lamin A/C-deficient hearts.


Could mindfulness decrease anger, hostility, and aggression by decreasing rumination?
Research suggests that rumination increases anger and aggression. Mindfulness, or present-focused and intentional awareness, may counteract rumination. Using structural equation modeling, we examined the relations between mindfulness, rumination, and aggression. In a pair of studies, we found a pattern of correlations consistent with rumination partially mediating a causal link between mindfulness and hostility, anger, and verbal aggression. The pattern was not consistent with rumination mediating the association between mindfulness and physical aggression. Although it is impossible with the current nonexperimental data to test causal mediation, these correlations support the idea that mindfulness could reduce rumination, which in turn could reduce aggression. These results suggest that longitudinal work and experimental manipulations mindfulness would be worthwhile approaches for further study of rumination and aggression. We discuss possible implications of these results.


New triterpenoids from the stem bark of Hypodaphnis zenkeri.
A new pentacyclic triterpenoid and three new derivatives based on the taraxer-14-ene skeleton with a C-28 attached a carboxylic acid group have been isolated from the stem bark of Hypodaphnis zenkeri, together with six known compounds. The new product was identified as 2α,3α-dihydroxytaraxer-14-en-28-oic acid (1). Its derivatives, 2α,3α-diacetyltaraxer-14-en-28-oic acid (2), 2α,3α-di-O-carbonyl-2α,3α-dihydroxytaraxer-14-en-28-oic acid (3) and 2α,3α-dipropionyltaraxer-14-en-28-oic acid (4) were obtained by semisynthesis. The known compounds were identified as 3β-hydroxytaraxer-14-en-28-oic acid or aleuritolic acid (5) (McPhail, A.T., McPhail, D.R., Wani, M.C., Wall, M.E. & A.W., Nicholas, A.W. (1989). Identity of maprounic acid with aleuritolic acid. Revision of the structure of maprounic acid: X-ray crystal structure of p-bromobenzyl acetylmaprounate. Journal Natural Products, 52, 212), 3α-hydroxytaraxer-14-en-28-oic acid or isoaleuritolic acid (6), 3α-acetyltaraxer-14-en-28-oic acid acetate or aleuritolic acid acetate (7) (Chaudhuri, S.K., Fullas, F., Brown, D.M., Wani, M.C., Wall, M.E., Cai, L., … Kinghorn, A.D. (1995). Isolation and structural elucidation of pentacyclic triterpenoids from Maprounea africana. Journal of Natural Products, 58, 1-9), 3-oxo-taraxer-14-ene or taraxerone (8) β-sitosterol (9) and stigmasterol (10) (Kamboj & Saluja, 2011), together with fatty acids. Their structures were established on the basis of spectroscopic studies and chemical transformations.


A DNA binding motif coordinating synthesis and degradation in proofreading DNA polymerases.
The functional significance of the conserved motif 'YxGG/A', located between the 3'-5' exonuclease and polymerization domains of eukaryotic-type DNA polymerases, has been studied by site-directed mutagenesis in phi29 DNA polymerase. Single substitutions at this region were obtained, and 11 phi29 DNA polymerase mutant derivatives were overproduced in Escherichia coli and purified to homogeneity. Nine mutants showed an altered polymerase/3'-5' exonuclease balance on a template/primer DNA structure, giving rise to three different mutant phenotypes: (i) favored polymerization (high pol/exo ratio); (ii) favored exonucleolysis (low pol/exo ratio); and (iii) favored exonucleolysis and null polymerization. Interestingly, these three different phenotypes could be obtained by mutating a single amino acid at the 'YxGG/A' motif. All different phenotypes could be directly related to defects in DNA binding at a particular active site. Thus, a high pol/exo ratio was related to a poor stability at the 3'-5' exonuclease active site. On the contrary, a low pol/exo ratio or null polymerization capacity was related to a poor stability at the polymerization active site and either a normal or an increased accessibility to the exonuclease active site. These results allow us to propose that this motif, located in the connecting region between the N-terminal and C-terminal domains, has a primary role in DNA binding, playing a critical role in the coordination or cross-talk between synthesis and degradation.


RACK1 regulates G1/S progression by suppressing Src kinase activity.
Cancer genes exert their greatest influence on the cell cycle by targeting regulators of a critical checkpoint in late G(1). Once cells pass this checkpoint, they are fated to replicate DNA and divide. Cancer cells subvert controls at work at this restriction point and remain in cycle. Previously, we showed that RACK1 inhibits the oncogenic Src tyrosine kinase and NIH 3T3 cell growth. RACK1 inhibits cell growth, in part, by prolonging G(0)/G(1). Here we show that RACK1 overexpression induces a partial G(1) arrest by suppressing Src activity at the G(1) checkpoint. RACK1 works through Src to inhibit Vav2, Rho GTPases, Stat3, and Myc. Consequently, cyclin D1 and cyclin-dependent kinases 4 and 2 (CDK4 and CDK2, respectively) are suppressed, CDK inhibitor p27 and retinoblastoma protein are activated, E2F1 is sequestered, and G(1)/S progression is delayed. Conversely, downregulation of RACK1 by short interference RNA activates Src-mediated signaling, induces Myc and cyclin D1, and accelerates G(1)/S progression. RACK1 suppresses Src- but not mitogen-activated protein kinase-dependent platelet-derived growth factor signaling. We also show that Stat3 is required for Rac1 induction of Myc. Our results reveal a novel mechanism of cell cycle control in late G(1) that works via an endogenous inhibitor of the Src kinase.


Clinical consequences of diet-induced dysbiosis.
Various disease states are associated with an imbalance of protective and pathogenic bacteria in the gut, termed dysbiosis. Current evidence reveals that dietary factors affect the microbial ecosystem in the gut. Changes to community structure of the intestinal microbiota are not without consequence considering the wide effects that the microbes have on both local and systemic immunity. The goal of this review is to give insight into the importance of gut microbiota in disease development and the possible therapeutic interventions in clinical settings. We introduce the complex tripartite relationship between diet, microbes and the gut epithelium. This is followed by a summary of clinical evidence of diet-induced dysbiosis as a contributing factor in the development of gastrointestinal diseases like inflammatory bowel disease, irritable bowel syndrome and colorectal cancer, as well as systemic diseases like obesity, diabetes, atherosclerosis and nonalcoholic fatty liver disease. Finally, the current dietary and microbial interventions to promote a healthy microbial profile will be reviewed.


Superficial femoral popliteal vein: An anatomic study.
The superficial femoral popliteal vein (SFPV) has been used as an alternative conduit for both arterial and venous reconstructive surgery. Its popularity continues to grow, despite concern about the potential for venous morbidity after harvest. The purpose of this study was to determine an anatomic "safe" length of SFPV for harvest, assuming that the preservation of at least one valve and one significant collateral vein in the remaining popliteal vein (PV) segment can minimize venous morbidity. Forty-four SFPVs were harvested from 39 cadaveric specimens. The length of both the superficial femoral vein (SFV) and PV was measured, and the number and location of valves and significant side branches (more than 2 mm in diameter) of the PV were measured. The Student two-tailed t test was used as a means of comparing vein lengths between the sexes. Correlation coefficients were determined for the effect of patient height on vein length, stratified by means of sex. Vein length (SFV mean, 24.4 +/- 4 cm; PV mean, 18.8 +/- 4 cm) varied with sex (male SFV mean, 28.1 +/- 5 cm; male PV mean, 21. 5 +/- 3 cm; female SFV mean, 22.6 +/- 4 cm; female PV mean, 18.4 +/- 3 cm; P =.01). Valve number (mean, 1.8 +/- 0.5) and location and collateral vein number (mean, 5 +/- 1.8) and location were variable and independent of height or sex. An anatomic "safe" length of SFPV for harvest to minimize venous morbidity would include all the SFV and 12 cm of PV in 95% of women and 15 cm of PV in 95% of men. We found that the male sex was a significant determinant for a longer safe length of vein that can be harvested.


Minimal pre-mRNA substrates with natural and converted sites for full-round U insertion and U deletion RNA editing in trypanosomes.
Trypanosome RNA editing by uridylate insertion or deletion cycles is a mitochondrial mRNA maturation process catalyzed by multisubunit complexes. A full-round of editing entails three consecutive steps directed by partially complementary guide RNAs: pre-mRNA cleavage, U addition or removal, and ligation. The structural and functional composition of editing complexes is intensively studied, but their molecular interactions in and around editing sites are not completely understood. In this study, we performed a systematic analysis of distal RNA requirements for full-round insertion and deletion by purified editosomes. We define minimal substrates for efficient editing of A6 and CYb model transcripts, and established a new substrate, RPS12. Important differences were observed in the composition of substrates for insertion and deletion. Furthermore, we also showed for the first time that natural sites can be artificially converted in both directions: from deletion to insertion or from insertion to deletion. Our site conversions enabled a direct comparison of the two editing kinds at common sites during substrate minimization and demonstrate that all basic determinants directing the editosome to carry out full-round insertion or deletion reside within each editing site. Surprisingly, we were able to engineer a deletion site into CYb, which exclusively undergoes insertion in nature.


Exertional Heat Stroke: Pathophysiology, Epidemiology, Diagnosis, Treatment, and Prevention.
Temperature increases due to climate changes and operations expected to be conducted in hot environments make heat-related injuries a major medical concern for the military. The most serious of heat-related injuries is exertional heat stroke (EHS). EHS generally occurs when health individual perform physical activity in hot environments and the balance between body heat production and heat dissipation is upset resulting in excessive body heat storage. Blood flow to the skin is increased to assist in dissipating heat while gut blood flow is considerably reduced, and this increases the permeability of the gastrointestinal mucosa. Toxic materials from gut bacteria leak through the gastrointestinal mucosa into the central circulation triggering an inflammatory response, disseminated intravascular coagulation (DIC), multiorgan failure, and vascular collapse. In addition, high heat directly damages cellular proteins resulting in cellular death. In the United States military, the overall incidence of clinically diagnosed heat stroke from 1998 to 2017 was (mean ± standard deviation) 2.7 ± 0.5 cases/10,000 Soldier-years and outpatient rates rose over this period. The cornerstone of EHS diagnosis is recognition of central nervous dysfunction (ataxia, loss of balance, convulsions, irrational behavior, unusual behavior, inappropriate comments, collapse, and loss of consciousness) and a body core temperature (obtained with a rectal thermometer) usually >40.5°C (105°F). The gold standard treatment is whole body cold water immersion. In the field where water immersion is not available it may be necessary to use ice packs or very cold, wet towels placed over as much of the body as possible before transportation of the victim to higher levels of medical care. The key to prevention of EHS and other heat-related injuries is proper heat acclimation, understanding work/rest cycles, proper hydration during activity, and assuring that physical activity is matched to the Soldiers' fitness levels. Also, certain dietary supplements (DSs) may have effects on energy expenditure, gastrointestinal function, and thermoregulation that should be considered and understood. In many cases over-motivation is a major risk factor. Commanders and trainers should be alert to any change in the Soldier's behavior. Proper attention to these factors should considerably reduce the incidence of EHS.


Opposed-view dark-field digital holographic microscopy.
Scattering and absorption belong to the major problems in imaging the internal layers of a biological specimen. Due to the structural inhomogeneity of the specimen, the distribution of the structures in the upper layers of a given internal structure of interest is different from the lower layers that may result in different interception of scattered light, falling into the angular aperture of the microscope objective, from the object in each imaging view. Therefore, different spatial frequencies of the scattered light can be acquired from different (top and bottom) views. We have arranged an opposed-view dark-field digital holographic microscope (DHM) to collect the scattered light concurrently from both views with the aim to increase the contrast of internal structures and improve the signal-to-noise ratio. Implementing a DHM system gives the possibility to implement digital refocusing process and obtain multilayer images from each side without a depth scan of the object. The method is explained and the results are presented exemplary for a Drosophila embryo.


Butyrate in Human Milk: Associations with Milk Microbiota, Milk Intake Volume, and Infant Growth.
Butyrate in human milk (HM) has been suggested to reduce excessive weight and adipo-sity gains during infancy. However, HM butyrate's origins, determinants, and its influencing mechanism on weight gain are not completely understood. These were studied in the prospective longitudinal Cambridge Baby Growth and Breastfeeding Study (CBGS-BF), in which infants (n = 59) were exclusively breastfed for at least 6 weeks. Infant growth (birth, 2 weeks, 6 weeks, 3 months, 6 months, and 12 months) and HM butyrate concentrations (2 weeks, 6 weeks, 3 months, and 6 months) were measured. At age 6 weeks, HM intake volume was measured by deuterium-labelled water technique and HM microbiota by 16S sequencing. Cross-sectionally at 6 weeks, HM butyrate was associated with HM microbiota composition (p = 0.036) although no association with the abundance of typical butyrate producers was detected. In longitudinal analyses across all time points, HM butyrate concentrations were overall negatively associated with infant weight and adiposity, and associations were stronger at younger infant ages. HM butyrate concentration was also inversely correlated with HM intake volume, supporting a possible mechanism whereby butyrate might reduce infant growth via appetite regulation and modulation of HM intake.