Maternal vitamin D concentrations during pregnancy, fetal growth patterns, and risks of adverse birth outcomes.
Maternal vitamin D deficiency during pregnancy may affect fetal outcomes. The objective of this study was to examine whether maternal 25-hydroxyvitamin D [25(OH)D] concentrations in pregnancy affect fetal growth patterns and birth outcomes. This was a population-based prospective cohort in Rotterdam, Netherlands in 7098 mothers and their offspring. We measured 25(OH)D concentrations at a median gestational age of 20.3 wk (range: 18.5-23.3 wk). Vitamin D concentrations were analyzed continuously and in quartiles. Fetal head circumference and body length and weight were estimated by repeated ultrasounds, and preterm birth (gestational age <37 wk) and small size for gestational age (less than the fifth percentile) were determined. Adjusted multivariate regression analyses showed that, compared with mothers with second-trimester 25(OH)D concentrations in the highest quartile, those with 25(OH)D concentrations in the lower quartiles had offspring with third-trimester fetal growth restriction, leading to a smaller head circumference, shorter body length, and lower body weight at birth (all P < 0.05). Mothers who had 25(OH)D concentrations in the lowest quartile had an increased risk of preterm delivery (OR: 1.72; 95% CI: 1.14, 2.60) and children who were small for gestational age (OR: 2.07; 95% CI: 1.33, 3.22). The estimated population attributable risk of 25(OH)D concentrations <50 nmol/L for preterm birth or small size for gestational age were 17.3% and 22.6%, respectively. The observed associations were not based on extreme 25(OH)D deficiency, but presented within the common ranges. Low maternal 25(OH)D concentrations are associated with proportional fetal growth restriction and with an increased risk of preterm birth and small size for gestational age at birth. Further studies are needed to investigate the causality of these associations and the potential for public health interventions.


Overweight and sudden death. Increased ventricular ectopy in cardiopathy of obesity.
Obesity has been documented to be an independent risk factor for sudden death and other cardiovascular mortality. The present study was designed to monitor and quantify cardiac arrhythmias in obese subjects with and without eccentric left ventricular hypertrophy, who were matched with regard to arterial pressure, age, sex, and height with lean subjects. Prevalence of premature ventricular (but not atrial) contractions was 30 times higher in obese patients with eccentric left ventricular hypertrophy compared with lean subjects. Similarly, obese patients with left ventricular hypertrophy scored higher with regard to the classification of Lown and Wolf than those without left ventricular hypertrophy and lean subjects having the same level of arterial pressure. Patients' class in the Lown and Wolf system correlated with ventricular diastolic diameter and left ventricular mass. Thus, heart enlargement of the eccentric type as a consequence of obesity predisposes to excessive ventricular ectopy. Echocardiographic assessment and electrocardiographic monitoring allow us to identify the patients who are at highest risk of more serious arrhythmias or possibly sudden death and to subject them to the most specific preventive and therapeutic measures.


An investigation into the combination of low frequency ultrasound and liposomes on skin permeability.
Antigen application onto skin that has been pre-treated with low frequency ultrasound leads to immunisation, and it was hypothesised that immunisation could be enhanced if antigens were entrapped within liposomes, the latter being known vaccine adjuvants. However, it has been suggested that liposomes can repair skin damage, which could limit antigen permeation and transcutaneous immunisation. The aim of the present work was therefore to investigate the influence of liposome application on subsequent: (i) in vitro antigen permeation through, and (ii) in vivo barrier properties of, ultrasound-treated skin. Sonication was conducted using either phosphate buffered saline (PBS) or an aqueous solution of sodium dodecyl sulphate (SDS) as the coupling medium, and rats were used as the animal models. Liposome application to sonicated skin reduced antigen penetration and transepidermal water loss (TEWL, used as an indication of skin integrity) when the skin had been sonicated using PBS coupling medium. The influence of liposome was evident within 5min of its application, and smaller liposomes were more effective at repairing skin disruption caused by sonication. Such skin repair did not, however, take place when the skin had been sonicated in the presence of SDS (which caused greater skin disruption), and changes in in vitro antigen permeation and in vivo TEWL were negligible. Skin repair by liposomes seems to depend on the extent of the disruption caused by ultrasound application.


Effects of Resistance Training Frequency on Measures of Muscle Hypertrophy: A Systematic Review and Meta-Analysis.
A number of resistance training (RT) program variables can be manipulated to maximize muscular hypertrophy. One variable of primary interest in this regard is RT frequency. Frequency can refer to the number of resistance training sessions performed in a given period of time, as well as to the number of times a specific muscle group is trained over a given period of time. We conducted a systematic review and meta-analysis to determine the effects of resistance training frequency on hypertrophic outcomes. Studies were deemed eligible for inclusion if they met the following criteria: (1) were an experimental trial published in an English-language refereed journal; (2) directly compared different weekly resistance training frequencies in traditional dynamic exercise using coupled concentric and eccentric actions; (3) measured morphologic changes via biopsy, imaging, circumference, and/or densitometry; (4) had a minimum duration of 4 weeks; and (5) used human participants without chronic disease or injury. A total of ten studies were identified that investigated RT frequency in accordance with the criteria outlined. Analysis using binary frequency as a predictor variable revealed a significant impact of training frequency on hypertrophy effect size (P = 0.002), with higher frequency being associated with a greater effect size than lower frequency (0.49 ± 0.08 vs. 0.30 ± 0.07, respectively). Statistical analyses of studies investigating training session frequency when groups are matched for frequency of training per muscle group could not be carried out and reliable estimates could not be generated due to inadequate sample size. When comparing studies that investigated training muscle groups between 1 to 3 days per week on a volume-equated basis, the current body of evidence indicates that frequencies of training twice a week promote superior hypertrophic outcomes to once a week. It can therefore be inferred that the major muscle groups should be trained at least twice a week to maximize muscle growth; whether training a muscle group three times per week is superior to a twice-per-week protocol remains to be determined.


p31 deficiency influences endoplasmic reticulum tubular morphology and cell survival.
p31, the mammalian orthologue of yeast Use1p, is an endoplasmic reticulum (ER)-localized soluble N-ethylmaleimide-sensitive factor attachment protein (SNAP) receptor (SNARE) that forms a complex with other SNAREs, particularly syntaxin 18. However, the role of p31 in ER function remains unknown. To determine the role of p31 in vivo, we generated p31 conditional knockout mice. We found that homozygous deletion of the p31 gene led to early embryonic lethality before embryonic day 8.5. Conditional knockout of p31 in brains and mouse embryonic fibroblasts (MEFs) caused massive apoptosis accompanied by upregulation of ER stress-associated genes. Microscopic analysis showed vesiculation and subsequent enlargement of the ER membrane in p31-deficient cells. This type of drastic disorganization in the ER tubules has not been demonstrated to date. This marked change in ER structure preceded nuclear translocation of the ER stress-related transcription factor C/EBP homologous protein (CHOP), suggesting that ER stress-induced apoptosis resulted from disruption of the ER membrane structure. Taken together, these results suggest that p31 is an essential molecule involved in the maintenance of ER morphology and that its deficiency leads to ER stress-induced apoptosis.


Interdisciplinary studies on Coxiella burnetii: From molecular to cellular, to host, to one health research.
The Q-GAPS (Q fever GermAn interdisciplinary Program for reSearch) consortium was launched in 2017 as a German consortium of more than 20 scientists with exceptional expertise, competence, and substantial knowledge in the field of the Q fever pathogen Coxiella (C.) burnetii. C. burnetii exemplifies as a zoonotic pathogen the challenges of zoonotic disease control and prophylaxis in human, animal, and environmental settings in a One Health approach. An interdisciplinary approach to studying the pathogen is essential to address unresolved questions about the epidemiology, immunology, pathogenesis, surveillance, and control of C. burnetii. In more than five years, Q-GAPS has provided new insights into pathogenicity and interaction with host defense mechanisms. The consortium has also investigated vaccine efficacy and application in animal reservoirs and identified expanded phenotypic and genotypic characteristics of C. burnetii and their epidemiological significance. In addition, conceptual principles for controlling, surveilling, and preventing zoonotic Q fever infections were developed and prepared for specific target groups. All findings have been continuously integrated into a Web-based, interactive, freely accessible knowledge and information platform (www.q-gaps.de), which also contains Q fever guidelines to support public health institutions in controlling and preventing Q fever. In this review, we will summarize our results and show an example of how an interdisciplinary consortium provides knowledge and better tools to control a zoonotic pathogen at the national level.


[Developmental coordination disorder in a child with ADHD; is DCD a DSM-IV diagnosis that is not recognised by child psychiatry?].
A five-year-old boy received treatment for attention deficit hyperactivity disorder (ADHD). In connection with his motor problems he was referred to a rehabilitation centre specialising in the study and treatment of developmental coordination disorder (DCD). When treating a patient with ADHD, doctors should ask regularly about the patient's motor functioning and, if necessary, arrange a referral. In the first instance a young patient should be referred to a paediatric physiotherapist or, if the problems are complex, referral should be to a paediatric rehabilitation doctor. A combination of ADHD and DCD has a poorer prognosis than ADHD alone.


Individual increase in inbreeding allows estimating effective sizes from pedigrees.
We present here a simple approach to obtain reliable estimates of the effective population size in real world populations via the computation of the increase in inbreeding for each individual (delta F(i)) in a given population. The values of delta F(i) are computed as t-root of 1 - (1 - F(i)) where F(i) is the inbreeding coefficient and t is the equivalent complete generations for each individual. The values of delta F computed for a pre-defined reference subset can be averaged and used to estimate effective size. A standard error of this estimate of N(e) can be further computed from the standard deviation of the individual increase in inbreeding. The methodology is demonstrated by applying it to several simulated examples and to a real pedigree in which other methodologies fail when considering reference subpopulations. The main characteristics of the approach and its possible use are discussed both for predictive purposes and for analyzing genealogies.


Assessment of the prognostic and predictive utility of the Breast Cancer Index (BCI): an NCIC CTG MA.14 study.
Biomarkers that can be used to accurately assess the residual risk of disease recurrence in women with hormone receptor-positive breast cancer are clinically valuable. We evaluated the prognostic value of the Breast Cancer Index (BCI), a continuous risk index based on a combination of HOXB13:IL17BR and molecular grade index, in women with early breast cancer treated with either tamoxifen alone or tamoxifen plus octreotide in the NCIC MA.14 phase III clinical trial (ClinicalTrials.gov Identifier NCT00002864; registered 1 November 1999). Gene expression analysis of BCI by real-time polymerase chain reaction was performed blinded to outcome on RNA extracted from archived formalin-fixed, paraffin-embedded tumor samples of 299 patients with both lymph node-negative (LN-) and lymph node-positive (LN+) disease enrolled in the MA.14 trial. Our primary objective was to determine the prognostic performance of BCI based on relapse-free survival (RFS). MA.14 patients experienced similar RFS on both treatment arms. Association of gene expression data with RFS was evaluated in univariate analysis with a stratified log-rank test statistic, depicted with a Kaplan-Meier plot and an adjusted Cox survivor plot. In the multivariate assessment, we used stratified Cox regression. The prognostic performance of an emerging, optimized linear BCI model was also assessed in a post hoc analysis. Of 299 samples, 292 were assessed successfully for BCI for 146 patients accrued in each MA.14 treatment arm. BCI risk groups had a significant univariate association with RFS (stratified log-rank p = 0.005, unstratified log-rank p = 0.007). Adjusted 10-year RFS in BCI low-, intermediate-, and high-risk groups was 87.5 %, 83.9 %, and 74.7 %, respectively. BCI had a significant prognostic effect [hazard ratio (HR) 2.34, 95 % confidence interval (CI) 1.33-4.11; p = 0.004], although not a predictive effect, on RFS in stratified multivariate analysis, adjusted for pathological tumor stage (HR 2.22, 95 % CI 1.22-4.07; p = 0.01). In the post hoc multivariate analysis, higher linear BCI was associated with shorter RFS (p = 0.002). BCI had a strong prognostic effect on RFS in patients with early-stage breast cancer treated with tamoxifen alone or with tamoxifen and octreotide. BCI was prognostic in both LN- and LN+ patients. This retrospective study is an independent validation of the prognostic performance of BCI in a prospective trial.


Role of kidney biomarkers [Kidney injury molecule-1, Calbindin, Interleukin-18 and Monocyte chemoattractant protein-1] in HIV associated pre-eclampsia.
Both HIV infection and pre-eclampsia (PE) are associated with considerable maternal mortality in South Africa. This study was designed to compare the urinary levels of kidney injury molecule-1 (KIM-1), calbindin, interleukin-18 (IL-18), and monocyte chemoattractant protein-1 (MCP-1) in HIV associated normotensive and preeclamptic pregnancies. Following ethical approval and written consent, urine samples were collected from HIV negative (HIV -ve) normotensive pregnant (n = 19), HIV positive (HIV +ve) normotensive pregnant (n = 19), HIV -ve pre-eclamptic (n = 19) and HIV +ve pre-eclamptic (n = 19) women. The concentrations of KIM-1, calbindin, IL-18 and MCP-1 were assessed using the Bioplex technology. In contrast to IL-18 (p > 0.05) and MCP-1 (p > 0.05), the concentrations of KIM-1 (p = 0.02) and calbindin (p = 0.02) were significantly higher in PE compared to normotensive pregnancies, irrespective of HIV status. Based on HIV status, all 4 analytes were similar between HIV+ve and HIV-ve groups. Urinary KIM-1 levels in the HIV -ve pre-eclamptics were significantly higher than those in the HIV -ve women with normal pregnancies (p = 0.007). The maternal hypertension and/or HIV profile has no marked impact on the fetal weight. Our results demonstrate an increase in the urinary level of kidney injury molecule-1 and calbindin in PE, implicating their possible value as biomarkers of kidney injury. We observed no differences in the levels of KIM-1, IL-18, MCP-1 and calbindin based on HIV status. We propose that studies with larger sample sizes using these markers be conducted to establish their use as markers of diagnosing kidney injury in PE.


The association among antioxidant enzymes, autoantibodies, and disease severity score in systemic lupus erythematosus: comparison of neuropsychiatric and nonneuropsychiatric groups.
Antioxidative capacity plays an important role in the severity of systemic lupus erythematosus (SLE), which is characterized by autoantibodies. This study aimed to determine the relationship among autoantibody titers, antioxidative stress reserve, and severity of SLE. The autoantibody titers, clinical markers, antioxidant enzyme levels, and disease activity index (SLEDAI-2k) of 32 SLE patients and 16 healthy controls were compared. We also compared both the neuropsychiatric (NPSLE) and nonneuropsychiatric (non-NPSLE) groups. Superoxide dismutase in red blood cells was significantly lower in the SLE than in the control group. CRP levels are significant higher in SLE patients than in control group (P = 0.034). Among the autoantibodies, anti-U1RNP (P = 0.008), a-Sm (P = 0.027), and anti-ribosomal p (P = 0.028) significantly negatively correlated with glutathione levels. There has no significant correlation between SLE disease activity indexes (SLEDAI) and levels of C3, C4, and antioxidant enzymes. Erythrocyte superoxide dismutase is significantly lower in both NPSLE and non-NPSLE groups. SLE patients have both higher CRP and autoantibodies level and decreased superoxide dismutase level than the healthy control group.


Formation of human hepatocytes by human hematopoietic stem cells in sheep.
We took advantage of the proliferative and permissive environment of the developing preimmune fetus to develop a noninjury large animal model in sheep, in which the transplantation of defined populations of human hematopoietic stem cells resulted in the establishment of human hematopoiesis and led to the formation of significant numbers of long-lasting, functional human liver cells, with some animals exhibiting levels as high as 20% of donor (human) hepatocytes 11 months after transplantation. A direct correlation was found between hepatocyte activity and phenotype of transplanted cells, cell dose administered, source of cells used on a cell-per-cell basis (bone marrow, cord blood, mobilized peripheral blood), and time after transplantation. Human hepatocytes generated in this model retained functional properties of normal hepatocytes, constituted hepatic functional units with the presence of human endothelial and biliary duct cells, and secreted human albumin that was detected in circulation. Transplanting populations of hematopoietic stem cells can efficiently generate significant numbers of functional hepatic cells in this noninjury large animal model and thus could be a means of ameliorating or curing genetic diseases in which a deficiency of liver cells or their products threatens the life of the fetus or newborn.


Comparative enhancing effects of phenobarbital, amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane on 2-acetylaminofluorene-induced hepatic tumorigenesis in the rat.
Earlier studies showed that phenobarbital feeding enhanced hepatic tumorigenesis in rats previously fed 2-acetylaminofluorene for a brief period. As part of an investigation of the mechanism of this enhancement, the present study evaluated the relative enhancing abilities of amobarbital, diphenylhydantoin, and dichlorodiphenyltrichloroethane (DDT), agents that resemble phenobarbital to varying degrees in their effects on liver structure and metabolism. A comparison of hepatic tumor yields in rats fed 2-acetylaminofluorene, followed by the test substance (sequential treatment), showed that amobarbital and diphenylhydantoin had no enhancing activity, whereas the enhancing effect of DDT was similar to that of phenobarbital. These results show that the sequential treatment technique readily distinguishes among substances differing in enhancing ability and should prove useful in screening additional substances for this activity. The comparative biochemical effects of these substances in the liver can then be correlated with their relative enhancing abilities to provide information on the molecular events specifically associated with enhancement. Such correlations were initiated in this study by comparing the effects of the four test substances on liver weight and DNA synthesis. The results showed that the enhancers, phenobarbital and DDT, each stimulated liver DNA synthesis and increased liver weight, whereas the nonenhancers, amobarbital and diphenylhydantoin, had neither effect. Phenobarbital and DDT both increased the early tumor incidence rate and maintained an increment in tumor incidence over that in the other treatment groups throughout the experiment, although it is not clear whether this increment would persist indefinitely. In addition, although the spectrum of tumor types observed ranged from highly differentiated to poorly differentiated in all treatment groups, DDT and phenobarbital selectively increased the incidence of highly differentiated tumors throughout most of the experiment.


Treating Individuals With Eating Disorders: Part 1.
According to the American Psychiatric Association, eating disorders (EDs) are characterized by a persistent disturbance of eating or eating-related behaviors that result in altered consumption or absorption of food and that significantly impair physical health and/or psychosocial functioning. EDs are chronic psychiatric illnesses and are notoriously difficult to treat. The etiology of eating disorders is unknown and thought to be a complex interplay among biological predisposition, environmental and sociocultural factors, neurobiological influences, and psychological factors. Moreover, prevalence of eating disorders is increasing despite variation in prevalence estimates across studies. Nurses are well-positioned to implement appropriate screening for and comprehensive assessment of EDs as well as offer patient-centered treatment options including referrals when indicated. As the first in a two-part series, this article provides an overview of the clinical characteristics of EDs and key areas for assessment and diagnostic considerations. The follow-up article in this series will focus on pharmacological treatment strategies. [Journal of Psychosocial Nursing and Mental Health Services, 58(3), 7-13.].


[Controversies in the prostate surgical anatomy. A literature review].
Radical prostatectomy technique has improved in the last years based on accumulated surgical experience and new anatomical findings. We think it is time to update anatomical concepts to standardized the criteria formentioning structures related with radical prostatectomy With the followings key words: "cavernosal nerves, prostatectomy, anatomy, neurovascular bundle" we search in Medline/PubMed database selecting papers fulfilling the search criteria. The prostate does not have a true capsule but rather an incomplete fibromuscular band as an intrinsic part of the gland. Periprostatic fascia seems to be a different structure from this fibromuscular band. Histologically Denonvilliers's fascia is formed by two thin layers that cannot be separated during surgery. The longitudinal smooth muscle fibres located beneath the posterior bladder neck corresponds to the posterior longitudinal fascia of the detrusor muscle. Cavernosal nerves are located between the two layers of the endopelvic fascia, the inner layer could be named periprostatic fascia and the outer, levator ani fascia. Cavernosal nerves merged from the pelvic plexus running within a neurovascular bundle around the prostate that could be found as a singular bundle or spread all around the anterolateral surface of this gland. There are overlapping terms to designate the pelvic fascia, therefore it could be useful for Urologists to standardized them.


[Auricular vagal stimulation in the treatment of patients with left ventricular dysfunction].
We assessed effect of enhancement of parasympathetic activity by indirect vagal stimulation via sensitive n. vagus-r. auricularis terminals on dynamics of clinical conditions, ejection fraction and global longitudinal left ventricle deformation in patients with chronic cardiac insufficiency (CCI). This comparative placebo-controlled parallel study 3 months in duration included 70 patients with chronic coronary heart disease, signs of IIl-IV FC CCI, and sinus rhythm. Auricular electric vagal stimulation (AEVS) was performed using a device for electric stimulation of sensitive vagus terminals (patent No 2327492 of 27.06.2008). The complex of clinical and instrumental studies included 6 min walk test, echocardiography, and speckle tracking imaging before, immediately and 3 months after AEVS. A course of AEVS improved clinical conditions in 58 (92.06%) of the 63 patients due to one-grade or greater decrease of CCI FC and increase of the walking distance. This effect persisted till month 3. It was absent in 5 (8.33%) patients. Improvement of clinical conditions with the decrease of CCI FC was accompanied by increase of left ventricular ejection fraction due to diminished end-systolic volume. The ejection fraction did not change in 4 patients with HR over 80/min. All patients with lowered HR after AEVS showed improved LV contractility in the longitudinal direction.


Two Artificial Tears Outbreak-Associated Cases of Extensively Drug-Resistant Pseudomonas aeruginosa Detected Through Whole Genome Sequencing-Based Surveillance.
We describe 2 cases of extensively drug-resistant Pseudomonas aeruginosa infection caused by a strain of public health concern, as it was recently associated with a nationwide outbreak of contaminated artificial tears. Both cases were detected through database review of genomes in the Enhanced Detection System for Hospital-Associated Transmission (EDS-HAT), a routine genome sequencing-based surveillance program. We generated a high-quality reference genome for the outbreak strain from an isolate from our center and examined the mobile elements encoding blaVIM-80 and bla-GES-9 carbapenemases. We used publicly available Pseudomonas aeruginosa genomes to explore the genetic relatedness and antimicrobial resistance genes of the outbreak strain.


HYPERBARIC EXPOSURE OF MICE TO PRESSURES OF 60 TO 90 ATMOSPHERES.
Albino mice breathing helium-oxygen mixtures remained in good condition for periods of 1 to 13 hours at pressure-equivalent depths of 396 to 914 meters of sea water. They were successfully decompressed to normal atmospheric pressure in less than 5 hours. There were no immediate or delayed adverse effects that could be attributed to the hyperbaric helium-oxygen environment. An occasional death was attributable to hypoxia or the decompression procedure.


Effects of miR-221 on the apoptosis of non-small cell lung cancer cells by lncRNA HOTAIR.
The aim of this study was to investigate the effects of miR-221 on the proliferation of non-small cell lung cancer (NSCLC) cells through long non-coding RNA (lncRNA) HOX transcript antisense RNA (HO-TAIR), and to explore the possible underlying mechanism. Reverse Transcription-Polymerase Chain Reaction (RT-PCR) was applied to detect the expression level of HOTAIR in 38 NSCLC patients. The correlations of HOTAIR expression with clinic-pathological features, as well as the correlation between HOTAIR expression and miR-221 expression was analyzed by RT-PCR. Furthermore, NSCLC cell lines were cultured in vitro, and the expressions of HOTAIR and miR-221 in NSCLC cells were also detected. A549 cells were transfected with miR-221 mimics, miR-221 inhibitors, HOTAIR-small interfering RNAs (siRNAs) and plasmid cytomegalovirus deoxyribonucleic acid (pcDNA)3.1-HOTAIR. The interaction between miR-221 and HOTAIR in transfected cells was analyzed via RT-PCR and Northern blotting. Ultimately, flow cytometry was adopted to analyze the effects of miR-221 on the apoptosis of NSCLC cells through HOTAIR. The expression of HOTAIR in tissues of clinical patients only exhibited a correlation with the stage of cancer. The expressions of HOTAIR in patients with stage I and II were remarkably lower than those with stage III and IV. Additionally, the expression of HOTAIR was negatively correlated with the expression of miR-221 (r=-0.7651, p<0.0001). Further studies revealed that there was a negatively regulatory interaction between miR-221 expression and HOTAIR expression. Apoptosis assay results manifested that miR-221 significantly promoted the apoptosis of NSCLC cells by negatively regulating HOTAIR expression. MiR-221 promotes the apoptosis of NSCLC cells through negative regulation of lncRNA HOTAIR, which can be used in the treatment of NSCLC.


Assessing the interaction between depressive symptoms and alcohol use prior to antiretroviral therapy on viral suppression among people living with HIV in Rural Uganda.
Although there is evidence of individual associations between depressive symptoms and hazardous alcohol use with suboptimal antiretroviral therapy (ART) adherence among people living with HIV (PLWH), few studies have established how the two risk factors may interact to predict viral suppression. We conducted secondary data analyses with two cohorts of Ugandan PLWH (N = 657) to investigate the hypothesized interaction between depressive symptoms (Center for Epidemiological Studies Depression Scale) and hazardous alcohol use (Alcohol Use Disorder Identification Test -Consumption and/or Phosphatidylethanol biomarker) prior to ART initiation with viral suppression (<550 copies/ml). We were unable to detect an interaction between depressive symptoms and hazardous alcohol use prior to ART initiation with viral suppression in the first two years (M = 19.9 months) after ART initiation (p = 0.75). There was also no evidence of a main effect association for depressive symptoms (Adjusted Odds Ratio [AOR] = 0.88, 95% Confidence Interval [CI]: 0.50, 1.55) or hazardous alcohol use (AOR = 1.37, 95% CI: 0.80, 2.33). PLWH with depressive symptoms and/or hazardous alcohol use appear to exhibit similar levels of viral suppression as others in care; further work is needed to determine effects on HIV testing and treatment engagement.


Beyond the ABCs of CKC and SCC. Do centromeres orchestrate sister chromatid cohesion or vice versa?
The centromere-kinetochore complex is a highly specialized chromatin domain that both mediates and monitors chromosome-spindle interactions responsible for accurate partitioning of sister chromatids to daughter cells. Centromeres are distinguished from adjacent chromatin by specific patterns of histone modification and the presence of a centromere-specific histone H3 variant (e.g. CENP-A). Centromere-proximal regions usually correspond to sites of avid and persistent sister chromatid cohesion mediated by the conserved cohesin complex. In budding yeast, there is a substantial body of evidence indicating centromeres direct formation and/or stabilization of centromere-proximal cohesion. In other organisms, the dependency of cohesion on centromere function is not as clear. Indeed, it appears that pericentromeric heterochromatin recruits cohesion proteins independent of centromere function. Nonetheless, aspects of centromere function are impaired in the absence of sister chromatid cohesion, suggesting the two are interdependent. Here we review the nature of centromeric chromatin, the dynamics and regulation of sister chromatid cohesion, and the relationship between the two.


DNA Topoisomerase II modulates acetyl-regulation of cohesin-mediated chromosome dynamics.
Cohesin is one of three multi-protein structural maintenance of chromosome (SMC) complexes that regulate eukaryotic chromosome dynamics. It forms a ring-shaped structure that embraces sister chromatids through interphase to promote their pairing. In preparation for mitosis, most cohesin is stripped from the chromosome arms in prophase by a poorly defined process that is associated with cohesin phosphorylation. In the fission yeast Schizosaccharomyces pombe this prophase pathway is dependent on the cohesin-related Smc5/6 complex, and this requirement is heightened in Smc5/6 hypomorphs by DNA damage, replication stress and Topoisomerase II (Top2) dysfunction. Cohesin interacts with chromosomes immediately upon mitotic exit and becomes cohesive coincident with DNA replication. Cohesiveness is promoted by acetylation of the Smc3 subunit by an acetyltransferase, known as Eso1 in the S. pombe, which counteracts the anti-cohesive function(s) of the cohesin regulators Pds5 and Wpl1. We recently showed that Eso1 and Smc5/6 antagonize each other, and concurrent inactivation restores sister chromatid separation following genotoxic stress. Here, we have investigated the relationship between Top2 and Eso1 in successful completion of mitosis. We observe that partial inactivation of both results in a synthetic lethal mitotic block, but this is not overcome by deleting pds5 or wpl1. However, analysis of both acetyl-blocking and mimetic mutations in Smc3 indicates that the cycling of cohesin acetyl-regulation is more important than acetyl-status per se, highlighting the non-linear nature of the cohesin cycle.


Developing and evaluating prediction models in rehabilitation populations.
This article presents a 3-part framework for developing and evaluating prediction models in rehabilitation populations. First, a process for developing and refining prognostic research questions and the scientific approach to prediction models is presented. Primary components of the scientific approach include the study design and sampling of patients, outcome measurement, selecting predictor variable(s), minimizing methodologic sources of bias, assuring a sufficient sample size for statistical power, and selecting an appropriate statistical model. Examples focus on prediction modeling using samples of rehabilitation patients. Second, a brief overview for statistically building and validating multivariable prediction models is provided, which includes the following 7 steps: data inspection, coding of predictors, model specification, model estimation, model performance, model validation, and model presentation. Third, we propose a set of primary considerations for evaluating prediction model studies using specific quality indicators as criteria to help stakeholders evaluate the quality of a prediction model study. Lastly, we offer perspectives on the future development and use of rehabilitation prediction models.


Lysosomal acid lipase: at the crossroads of normal and atherogenic cholesterol metabolism.
Unregulated cellular uptake of apolipoprotein B-containing lipoproteins in the arterial intima leads to the formation of foam cells in atherosclerosis. Lysosomal acid lipase (LAL) plays a crucial role in both lipoprotein lipid catabolism and excess lipid accumulation as it is the primary enzyme that hydrolyzes cholesteryl esters derived from both low density lipoprotein (LDL) and modified forms of LDL. Evidence suggests that as atherosclerosis progresses, accumulation of excess free cholesterol in lysosomes leads to impairment of LAL activity, resulting in accumulation of cholesteryl esters in the lysosome as well as the cytosol in foam cells. Impaired metabolism and release of cholesterol from lysosomes can lead to downstream defects in ATP-binding cassette transporter A1 regulation, needed to offload excess cholesterol from plaque foam cells. This review focuses on the role LAL plays in normal cholesterol metabolism and how the associated changes in its enzymatic activity may ultimately contribute to atherosclerosis progression.


Long-acting beta2-agonists for chronic obstructive pulmonary disease.
Chronic obstructive pulmonary disease (COPD) is characterised by airflow limitation which is only partially reversible. Long acting beta2-agonists, effective in the management of asthma,are also recommended for COPD management so it is important to establish whether these drugs are effective in reducing COPD symptoms in view of the potential side effect and cost burden. To determine the effectiveness of long acting beta2-adrenoceptor agonists in improving lung function and quality of life and reducing dyspnoea in patients with COPD. A search was carried out using the Cochrane Airways Group register. Bibliographies of identified RCTs were searched for additional relevant RCTs. Authors of identified RCTs were contacted for other published and unpublished studies. In addition, unpublished studies were also obtained from the pharmaceutical companies that manufacture long acting beta2- adrenoceptor agonists. All randomised controlled trials over four weeks in duration comparing treatment with long-acting beta2-adrenoceptor agonists (salmeterol and formoterol) with placebo in patients with stable non-reversible COPD. Outcome measures included forced expiratory volume in one second (FEV1), peak expiratory flow rate (PEFR), symptom scores, six minute walk distance, quality of life scores, Borg scores for dyspnoea and rescue bronchodilator use. Data extraction and study quality assessment was performed independently by two reviewers. Where further or missing data were required, authors of studies were contacted. Thirty three abstracts were identified as potentially relevant. Of these, four randomised controlled trials (RCTs) were included in this review. Two were parallel group studies of 16 week duration and two were cross-over studies with four week treatment arms. All four RCTs assessed the efficacy of salmeterol in COPD. In a 16 week study of salmeterol 50 mcg and 100 mcg twice daily treatment, a significant increase in FEV1 was seen in both treatment groups. The weighted mean difference (WMD) for the increase in FEV1 for the 50 mcg group was 0.10 litre (95% CI: 0.05;0. 15) and in the 100 mcg group the WMD was 0.12 litre (95% CI: 0.06; 0. 17 ). In the two cross-over studies of four weeks treatment, salmeterol 50 mcg twice daily treatment did not show significant increases in FEV1 (WMD = 0.04 litre, 95% CI: -0.06; 0.15). Similarly, morning and night time PEFR was not significantly improved with salmeterol treatment. In a 16 week study, disease-specific quality of life, measured using the St. George's Respiratory Questionnaire (SGRQ), showed a significant improvement after 50 mcg twice daily, but not after 100 mcg twice daily. This improvement exceeded the threshold for a clinically significant change with this questionnaire. General health status, as measured by the Medical Outcomes Short Form 36, did not improve in any of the eight components with either salmeterol dose. No significant difference was demonstrated in the mean change from baseline in the six minute walk distance (WMD = 1.9 metres, 95% CI: -15.4;19.3). Breathlessness was reduced in one study in patients receiving salmeterol 50 mcg twice daily group. Significantly more patients in this group had Borg scores for breathlessness less than three (a score of three indicating moderate dyspnoea) compared to the placebo treated group (Peto Odds Ratio = 0.60, 95% CI: 0.40; 0.88). Neither dose of salmeterol influenced the incidence of COPD exacerbations, (50 mcg: Peto Odds Ratio = 0.74, 95% CI: 0.47, 1.15) and (100 mcg: Peto Odds Ratio = 0.98, 95% CI: 0.64, 1.52). Treatment of patients with COPD with long acting beta2-agonists produces only small increases in FEV1. In one study, a dose of salmeterol 50 mcg twice daily produced a reduction in breathlessness and a clinically significant improvement in quality of life. (ABSTRACT TRUNCATED)


Feral genetically modified herbicide tolerant oilseed rape from seed import spills: are concerns scientifically justified?
One of the concerns surrounding the import (for food and feed uses or processing) of genetically modified herbicide tolerant (GMHT) oilseed rape is that, through seed spillage, the herbicide tolerance (HT) trait will escape into agricultural or semi-natural habitats, causing environmental or economic problems. Based on these concerns, three EU countries have invoked national safeguard clauses to ban the marketing of specific GMHT oilseed rape events on their territory. However, the scientific basis for the environmental and economic concerns posed by feral GMHT oilseed rape resulting from seed import spills is debatable. While oilseed rape has characteristics such as secondary dormancy and small seed size that enable it to persist and be redistributed in the landscape, the presence of ferals is not in itself an environmental or economic problem. Crucially, feral oilseed rape has not become invasive outside cultivated and ruderal habitats, and HT traits are not likely to result in increased invasiveness. Feral GMHT oilseed rape has the potential to introduce HT traits to volunteer weeds in agricultural fields, but would only be amplified if the herbicides to which HT volunteers are tolerant were used routinely in the field. However, this worst-case scenario is most unlikely, as seed import spills are mostly confined to port areas. Economic concerns revolve around the potential for feral GMHT oilseed rape to contribute to GM admixtures in non-GM crops. Since feral plants derived from cultivation (as distinct from import) occur at too low a frequency to affect the coexistence threshold of 0.9% in the EU, it can be concluded that feral GMHT plants resulting from seed import spills will have little relevance as a potential source of pollen or seed for GM admixture. This paper concludes that feral oilseed rape in Europe should not be routinely managed, and certainly not in semi-natural habitats, as the benefits of such action would not outweigh the negative effects of management.


Diagnosis and treatment of femoroacetabular impingement in Legg-Calvé-Perthes disease.
Residual hip deformities secondary to Legg-Calvé-Perthes disease (LCPD) include growth disturbance of the proximal femoral physis with nonspherical femoral head, overriding greater trochanter with short femoral neck and secondary remodeling of the acetabulum. These deformities can change the mechanical function of the hip joint and contribute to femoroacetabular impingement. All these deformities need to be recognized and its contribution to the patient's symptoms understood before a treatment strategy can be planned. Safe surgical dislocation of the hip allows for complete inspection of the hip joint and dynamic assessment of femoroacetabular contact during hip motion. The goals of this paper are to review the pathophysiology, clinical presentation, imaging findings, and the management of femoroacetabular impingement in patients with LCPD. We sought to present our treatment philosophy for patients who were diagnosed and treated for LCPD as a child and present with femoroacetabular impingement as adolescents and young adults.


Serum Expression of ESM-1, HMWA, and AGEs and Its Relationship with Disease Severity in Patients with Gestational Hypertension.
The research is to investigate the expression and the relationship between serum endothelial cell-specific molecular molecule-1 (ESM-1), high molecular weight adiponectin (HMWA), and late glycosylation terminal product (AGEs) in patients with gestational hypertension. 75 patients with pregnant hypertension who were treated in our hospital from June 2019 to June 2020 were selected as the case group, and 70 healthy pregnant women with pregnancy examination at the same period in our hospital were selected as the control group to analyze the changes in serum ESM-1, HMWA, and AGEs levels and the correlation with the degree of illness and their predictive value. Serum ESM-1 and AGEs were significantly higher in the case group than in the control group. Serum HMWA was significantly lower than that in the control group (P < 0.05). The gestational hypertensive serum ESM-1 and AGEs was significantly lower than in patients with mild preeclampsia and severe preeclampsia. Serum HMWA was significantly higher than in patients with mild preeclampsia and severe preeclampsia. Serum ESM-1 and AGEs of mild preeclampsia were significantly lower than in patients with severe preeclampsia. Serum HMWA was significantly higher than in patients with severe preeclampsia (P < 0.05). The result of correlation analysis shows a positive correlation between serum ESM-1 and AGEs (P < 0.05). A negative correlation was observed between HMWA and the degree of illness (P < 0.05). Serum ESM-1, HMWA, and AGEs are abnormally expressed in gestational hypertension, are closely related to the degree of condition, and have important clinical significance for condition control.


Confirmation of ureteric patency during cystoscopy using phenazopyridine HCl: a low-cost approach.
To describe the use of oral phenazopyridine (Pyridium) prior to pelvic surgery to facilitate intraoperative confirmation of ureteric patency. We performed a chart review of women given phenazopyridine preoperatively prior to pelvic surgery in a tertiary care centre between July 2004 and June 2005. The primary outcome was the cystoscopic observation of bilateral ureteric urine efflux. Secondary outcomes included the visualization of bladder mucosa during cystoscopy, postoperative complications, and urinary tract injury diagnosed postoperatively (i.e., missed intraoperatively). Pelvic reconstructive surgery requiring intraoperative cystoscopy was performed in 124 women. Bilateral ureteric patency and bladder mucosal integrity was confirmed in all cases. Phenazopyridine was well tolerated by all patients, and its use was unequivocally documented in 32 subjects whose chart was reviewed to determine postoperative course. Bladder mucosal appearance was unaltered. Dye continued to be excreted during prolonged procedures. Postoperatively, no ureteric injuries were subsequently diagnosed in any patients. The cost per patient of phenazopyridine ($0.29) is substantially lower than indigo carmine ($34.50). Preoperative oral phenazopyridine is an inexpensive and safe dye that assists effectively in the confirmation of ureteric patency when cystoscopy is planned during pelvic surgery.


Septicaemia caused by cysteine-requiring isolates of Escherichia coli.
The clinical and bacteriological findings in five cases of septicaemia with cysteine-requiring isolates of Escherichia coli are reported. Infections with these nutritionally-dependent organisms have been found previously in the urinary tract only, associated usually with chronic rather than acute conditions. The urinary tract was considered to be the source of the septicaemia in our patients and that site should be investigated when such strains are isolated from blood cultures. When first isolated the organisms characteristically form small translucent colonies on media deficient in appropriate growth factors. Their nutritional requirement for cysteine can be determined by a simple auxanographic technique, thereby enabling the appropriate supplementation of media necessary for reliable identification and antibiotic-sensitivity testing.


Causal associations between genetically determined common psychiatric disorders and the risk of falls: evidence from Mendelian randomization.
The causal associations between psychiatric disorders and falls risk remains uncertain. Consequently, this study aimed to explore the causal relationship between genetically determined three common psychiatric disorders and the risk of falls based on Mendelian randomization (MR). The genome-wide association study (GWAS) data for schizophrenia (SCZ) (N = 320,404), major depressive disorder (MDD) (N = 480,359), and Alzheimer's disease (AD) (N = 63,926) were obtained as exposures. The GWAS data for falls risk (N = 451,179) was obtained as outcome. Univariate Mendelian randomization (UVMR) was used to evaluate the direct causal relationship between SCZ, MDD, AD, and risk of falls. Inverse variance weighting (IVW) was used as the primary analysis method. Sensitivity analysis was performed to assess the validity of the casualty. Multivariate Mendelian randomization (MVMR) analysis was conducted after adjusting body mass index and smoking initiation. Mediating MR was conducted to calculate the mediating effects of potential intermediaries. UVMR analysis showed that SCZ (OR 1.02, 95% CI 1.01-1.04, p = 8.03E-03) and MDD (OR 1.15, 95% CI 1.08-1.22, p = 1.38E-05) were positively associated with the risk of falls. Sensitivity analysis results were reliable and robust. MVMR results indicated that the relationship between MDD and SCZ and falls risk remained significant. Mediating MR results demonstrated that smoking initiation mediated partial causal effect of SCZ (0.65%, P = 0.03) and MDD (14.82%, P = 2.02E-03) on risk of falls. This study provides genetic evidence for a causal relationship of individuals with SCZ and MDD on an increased risk of falls. Healthcare providers should be aware of the risk of falls in MDD and SCZ patients and develop strategies accordingly.


Assessing risk and prioritizing referral for self-harm: when and why is my judgement different from yours?
This study investigated individual differences in the use of risk factors when making risk assessments for self-harm. Clinical judgement analysis using 35 hypothetical case scenarios was used to determine how case characteristics influence risk assessment for self-harm by mental health professionals. Seven practitioners made four risk/priority assessment judgements for each case, and individual models of judgement for risk and priority were constructed by regressing 10 case variables onto these sets of judgements. All but two of the variables (potential risk factors) examined were related to risk and/or priority judgements. Risk assessors applied cues to make assessments consistently-broadly consistent with practice guidelines-although precise cue application varied between professionals. The findings demonstrate the potential for ambiguity in risk assessment (terms such as 'low' or 'high' risk had variable interpretation) and that it can be important to specify whether risk is to be assessed for the initiation, continuation, re-occurrence, or escalation of an event or condition. The study shows the importance of clear practice guidelines (not all risk factors were used as might be anticipated from practice guidelines) and illustrates how clinical judgement analysis can be used to understand and enhance the reliability of professional judgement. The process by which risk assessment is undertaken can be reliably statistically modelled to allow an in-depth examination of an individual practitioner or comparisons between practitioners, which can be used to support efforts to improve assessment reliability. Senior practitioners may be more consistent in applying information to clinical judgements of self-harm. Apparent agreement over a categorical judgement of risk may mask an underlying disagreement over numerical probabilities. The term 'low risk' may be particularly subject to variability in its interpretation. The term 'risk' can be ambiguous, reflecting the probability of occurrence for some practitioners and the severity of its occurrence for others, a problem that may be compounded if it is unclear exactly which event is being assessed (e.g., risk of initiating the behaviour versus risk of re-occurrence).


Dual role of the actin cytoskeleton in regulating cell adhesion mediated by the integrin lymphocyte function-associated molecule-1.
Intracellular signals are required to activate the leukocyte-specific adhesion receptor lymphocyte function-associated molecule-1 (LFA-1; CD11a/CD18) to bind its ligand, intracellular adhesion molecule-1 (ICAM-1). In this study, we investigated the role of the cytoskeleton in LFA-1 activation and demonstrate that filamentous actin (F-actin) can both enhance and inhibit LFA-1-mediated adhesion, depending on the distribution of LFA-1 on the cell surface. We observed that LFA-1 is already clustered on the cell surface of interleukin-2/phytohemagglutinin-activated lymphocytes. These cells bind strongly ICAM-1 and disruption of the actin cytoskeleton inhibits adhesion. In contrast to interleukin-2/phytohemagglutinin-activated peripheral blood lymphocytes, resting lymphocytes, which display a homogenous cell surface distribution of LFA-1, respond poorly to intracellular signals to bind ICAM-1, unless the actin cytoskeleton is disrupted. On resting peripheral blood lymphocytes, uncoupling of LFA-1 from the actin cytoskeleton induces clustering of LFA-1 and this, along with induction of a high-affinity form of LFA-1, via "inside-out" signaling, results in enhanced binding to ICAM-1, which is dependent on intact intermediate filaments, microtubules, and metabolic energy. We hypothesize that linkage of LFA-1 to cytoskeletal elements prevents movement of LFA-1 over the cell surface, thus inhibiting clustering and strong ligand binding. Release from these cytoskeletal elements allows lateral movement and activation of LFA-1, resulting in ligand binding and "outside-in" signaling, that subsequently stimulates actin polymerization and stabilizes cell adhesion.


Tobacco smoking and oral cancer: a meta-analysis.
Several epidemiological studies suggest that tobacco smoking increases the risk of oral cancer. No systematic review, however, has been reported to examine how consistent the evidence is across the studies. We undertook a meta-analysis of epidemiological studies investigating the magnitude relationship between tobacco smoking and oral cancer. Primary studies were identified through a computerized literature search of Medline. Articles abstracted were all epidemiological studies published as original articles in English during 1990-2007 provided the summary estimates of odds ratios (OR) of tobacco smoking for oral cancer compared to that of non-smokers. A total of 15 case-control studies were used for this meta-analysis. Summary of OR was calculated based on random effects model. The combined odds ratio for tobacco smoking related to oral cancer was 4.65 (95%CI, 3.19-6.77). Also, the highest combined odds ratio was belong to America continents (OR= 7.65; 95%CI, 5.11-11.45) and the lowest was in Asia (OR= 1.88; 95%CI, 0.95-3.71). There was heterogeneity in the pooled OR estimate across the studies. Our results clearly indicate that tobacco smokers are at increased risk of oral cancer. The cancer risk can be reduced by controlling of tobacco smoking in different countries.


[Fatty-acid composition of staphylococci induced by antibiotic AL-87 as a marker of their resistance or sensitivity to the given antibiotic].
Three strains of S. aureus isolated from patients were studied and it was shown that their population was heterogenous with respect to antibiotic AL-87: it contained both the antibiotic sensitive and the antibiotic resistant species in different ratios. The fatty acid composition induced by low concentrations of the antibiotic (subbacteriostatic for the sensitive microorganism) characterized by predominance of branched chain fatty acids in the antibiotic sensitive microorganisms and straight chain fatty acids in the antibiotic resistant microorganisms may serve a marker of sensitivity or resistance. Therefore, the data are indicative of the presence of genetic information in staphylococci determining their resistance to antibiotic AL-87 not yet used in medical practice.


Herpes zoster in lupus nephritis: experience on 292 patients followed up for 15 years.
To evaluate the prevalence, incidence, and predictors of herpes zoster (HZ) development in lupus nephritis (LN). This retrospective study included 292 LN patients to determine HZ incidence during the last decades and its correlation with LN activity. LN patients with HZ were matched with LN patients without HZ in a 1:2 ratio based on sex, age, year of LN diagnosis, and LN histological class at kidney biopsy to assess HZ risk factors. Statistical tests included t-test, U-test, and Fisher's test. Univariate and multivariate logistic regression analyses were conducted to identify potential risk factors. HZ occurred after LN diagnosis in 66 patients (prevalence 22.6%) with an average of 8.7 years (range 0.2-28.4 years). Although with the potential limitations of the retrospective nature and the extensive duration of the study, the incidence of HZ was 15.6/1,000 person-years, increasing from 6.9 before 1980 to 16.0 in the 1990s and 43.9 after 2010. HZ onset was unrelated to LN activity. LN was active in 43% of cases and quiescent in the other 57% of cases at HZ diagnosis. The percentage of patients who developed lupus flares during the year after HZ (18.9%) was not different from that which occurred during the year before HZ (17.2%, p = 0.804). After excluding confounding factors through matching, the univariate analysis suggested that cyclosporin during induction therapy (p = 0.011) and higher cumulative doses of glucocorticoids (GCs; >50 g, p = 0.004), cyclophosphamide (CYC; >5 g, p = 0.001), and mycophenolate mofetil (MMF > 1,000 g, p = 0.007) predisposed patients to HZ. Univariate and multivariate analyses revealed a protective role of azathioprine (p = 0.008) and methylprednisolone pulses (p = 0.010) during induction therapy. HZ occurs unpredictably throughout the course of LN, underscoring the importance of continuous monitoring for these patients. In addition, the incidence of HZ seems to have increased in recent decades. Induction therapy with azathioprine and methylprednisolone pulses appears to provide protection, while higher cumulative doses of GCs, CYC, and MMF increase susceptibility.


Cerebrospinal fluid biomarkers for neuropsychological symptoms in early stage of late-onset Alzheimer's disease.
In addition to testing blood, cerebrospinal fluid (CSF) has been analyzed in the search for biomarkers. The aim of this study was to identify biomarkers in CSF for neuropsychological symptoms in early-stage late-onset Alzheimer's disease (LOAD). CSF levels of beta-amyloid 1-42 (Aβ42), F2-isoprostanes (F2-IsoPs) and F4-neuroprostanes (F4-NPs) were assayed in nine patients with mild Alzheimer's disease (AD), nine patients with amnestic mild cognitive impairment (a-MCI) and nine individuals with normal mental function. The three groups underwent neuropsychological testing. CSF levels of F2-IsoPs and F4-NPs did not significantly differ among the three groups. Aβ42 in CSF was significantly higher in the control group compared with the mild AD group (p < 0.001) and a-MCI group (p = 0.03). There was a significant positive correlation between the level of F2-IsoPs and Aβ42 in the a-MCI group and between the level of F2-IsoPs and F4-NPs in the mild AD group. In comparisons between the mild AD group and a-MCI group combined, the cognitive impairment (CI) group, with the control group, the median levels of F2-IsoPs and F4-NPs were significantly higher in the CI group and median level of Aβ42 was significantly lower in the CI group. Both the levels of F2-IsoPs and Aβ42 were significantly negatively correlated with paranoid and delusional ideation and total score for the Behavioral Pathology in Alzheimer's Disease Scale (BEHAVE-AD). The findings suggest CSF levels of Aβ42 and F2-IsoPs are associated with the severity of neuropsychological symptoms.


TP53INP2 modulates the malignant progression of colorectal cancer by reducing the inactive form of β-catenin.
TP53INP2 (tumor protein p53-inducible nuclear protein 2), known as an autophagy protein, is essential for regulating transcription and starvation-induced autophagy, which plays a crucial role in the oncogenesis and progression of various cancers. The present study aims to investigate the expression pattern, function and prognostic value of TP53INP2 in colorectal cancer (CRC). Here, we report that low expression of TP53INP2 correlates with poor survival in CRC patients. TP53INP2 was significantly downregulated in CRC tissues compared with adjacent tissues. As the malignancy of CRC progresses, the expression level of TP53INP2 gradually decreased. Knockdown of TP53INP2 promoted CRC cell proliferation and tumor growth in mice. Mechanistically, TP53INP2 deficiency decreased phosphorylation of β-catenin on S33, S37, and T41, resulting in increased accumulation of β-catenin and enhanced nuclear translocation and transcriptional activity. Moreover, we further demonstrated that TP53INP2 sequestered TIM50, thereby inhibiting its activation of β-catenin. Taken together, our findings indicate that the downregulation of TP53INP2 promotes CRC progression by activating β-catenin and suggest that TP53INP2 may be a candidate therapeutic target for CRC.


Supplemental dietary folic acid has no effect on chromosome damage in erythrocyte progenitor cells of mice.
Folate deficiency can cause chromosome damage, which could result from reduced de novo thymidylate synthesis or DNA hypomethylation. High folic acid intake has been hypothesized to inhibit folate-dependent one-carbon metabolism, which could also lead to DNA damage. A large proportion of the general population may have high folic acid intakes. In this study, 2 experiments were conducted to examine the effects of folate on chromosome damage. First, male mice were fed folic acid-deficient (D) (0 mg folic acid/kg diet), control (C) (2 mg/kg), or folic acid-supplemented (S) (6 mg folic acid/kg diet) diets from weaning to maturity. Second, female mice were fed the D, C, or S diet throughout pregnancy, lactation, and breeding for 3 generations; male mice from the F3 generation were fed the same diet as their mothers from weaning, producing D, C, and S F3 male mice. RBC micronucleus frequencies, a measure of chromosome damage or aneuploidy, were determined for both experimental groups. In mice fed diets from weaning to maturity, erythrocyte micronucleus frequency was 24% greater in D compared with C mice. F3 mice fed diet D had 260% and 174% greater reticulocyte and erythrocyte micronucleus frequencies compared with F3 C mice, respectively. The S diets did not affect micronucleus frequency, suggesting that excess folic acid at this level does not promote or protect against chromosome damage. The results suggest that chronic exposure to folic acid at the levels similar to those achieved through fortification is unlikely to be clastogenic or aneugenic.


Colloidal Stabilization of Submicron-Sized Zeolite NaA in Ethanol-Water Mixtures for Nanostructuring into Thin Films and Nanofibers.
Despite the growing use of organic or mixed solvents in zeolite processing, most studies focus only on aqueous suspension systems. We investigated the colloidal characteristics of submicron-sized zeolite NaA in mixed ethanol-water solvents. The effects of the mixing ratio of solvents and various additives on the dispersion of the zeolite powders were studied. The zeolite NaA particles were destabilized in solvent mixtures at a high ethanol-to-water ratio, a reduction in the zeta potential was observed, and the destabilization was rationalized by the Derjaguin, Landau, Verwey, Overbeek (DLVO) theory. An improved stabilization of the zeolite NaA suspensions was achieved in ethanol-rich solvent mixtures using nonionic low molecular weight organic additives, but not with their ionic counterparts such as anionic, cationic surfactants or inorganic acids or bases. Polyethylene glycol (PEG)-400 was found to be a good dispersant for the submicron-sized zeolite NaA particles in the ethanol-water mixtures, which was attributed to its interaction with the zeolite surface, leading to an increased zeta potential. The PEG-stabilized zeolite suspensions led to low suspension viscosities as well as uniform and consistent spin-coated films.


[Homeostasis disorders in chronic hypoxia in pregnant women with heart defects].
Central hemodynamics, free-radical lipid oxidation, anti-oxidant system, activities of lysosomal enzymes, and homeostasis system were studied in 86 pregnant women with congenital and acquired heart diseases. The studies have revealed a hypodynamic circulation type, activated lipid peroxidation processes, reduced level of alpha-tocopherol, a natural antioxidant, and activated coagulating and depressed anticoagulating system of the blood. These pathologic processes results in development of a mixed form of chronic hypoxia, augmenting with the progress of the heart condition. Assessment of these parameters helps timely start differentiated intensive care and improve labor outcome for the mother and fetus.


Development of cytochrome b and an active oxidase system in association with maturation of a human promyelocytic (HL-60) cell line.
The human HL-60 myeloid leukaemia cell line developed, during maturational changes induced by dimethyl sulphoxide, an enhanced capacity for phorbol myristate acetate- stimulated oxidative activity and acquired a cytochrome b. Titration of the absorbance at 559 nm at potentials of-190 to -370 mV indicated that this cytochrome had a very low potential, differentiating it from mitochondrial and endoplasmic reticulum cytochromes and identifying it as the cytochrome b(-245) that has been recently found in other phagocytic cells. Subcellular fractionation studies of mature HL-60 cells showed that cytochrome b had a dual distribution within the cell. The lighter peak of activity was associated with the plasma membrane markers, adenylate cyclase and receptors for the N- formal-L-methionyl-L-leucyl-L-phenylalanine (f-Met-Leu-Phe) peptide. The denser components localized with the mitochondria but were distinct from mitochondrial cytochromes because whereas the activity of cytochrome c oxidase fell during HL-60 cell maturation, that of this cytochrome b was markedly increased. Concentrations of myeloperoxidase were unrelated to activity of the oxidase system and decreased as the cell matured. The increase in the concentrations of cytochrome b with cellular maturation parallelled the increase in the stimulated nonmitochondrial respiratory activity of these cells. The turnover of the hexose monophosphate shunt of immature cells was increased by the oxidising agents, methylene blue and tert-butylhydroperoxide, indicating that these immature cells have stimulated nonmitochondrial respiratory activity by maturing HL-60 cells is associated with, and is probably dependent upon, the acquisition by these cells of the cytochrome b(-245) oxidase system.


Dosage compensation in mammals: fine-tuning the expression of the X chromosome.
Mammalian females have two X chromosomes and males have only one. This has led to the evolution of special mechanisms of dosage compensation. The inactivation of one X chromosome in females equalizes gene expression between the sexes. This process of X-chromosome inactivation (XCI) is a remarkable example of long-range, monoallelic gene silencing and facultative heterochromatin formation, and the questions surrounding it have fascinated biologists for decades. How does the inactivation of more than a thousand genes on one X chromosome take place while the other X chromosome, present in the same nucleus, remains genetically active? What are the underlying mechanisms that trigger the initial differential treatment of the two X chromosomes? How is this differential treatment maintained once it has been established, and how are some genes able to escape the process? Does the mechanism of X inactivation vary between species and even between lineages? In this review, X inactivation is considered in evolutionary terms, and we discuss recent insights into the epigenetic changes and developmental timing of this process. We also review the discovery and possible implications of a second form of dosage compensation in mammals that deals with the unique, potentially haploinsufficient, status of the X chromosome with respect to autosomal gene expression.


Persistence of Tetracapsuloides bryosalmonae (Myxozoa) in chronically infected brown trout Salmo trutta.
Proliferative kidney disease (PKD) is a widespread disease of farmed and wild salmonid populations in Europe and North America, caused by the myxozoan parasite Tetracapsuloides bryosalmonae. Limited studies have been performed on the epidemiological role in spread of the disease played by fish that survive infection with T. bryosalmonae. The aim of the present study was to evaluate the persistence of T. bryosalmonae developmental stages in chronically infected brown trout Salmo trutta up to 2 yr after initial exposure to laboratory-infected colonies of the parasite's alternate host, the bryozoan Fredericella sultana. Kidney, liver, spleen, intestine, brain, gills and blood were sampled 24, 52, 78 and 104 wk post-exposure (wpe) and tested for T. bryosalmonae by PCR and immunohistochemistry (IHC). Cohabitation trials with specific pathogen free (SPF) F. sultana colonies were conducted to test the viability of T. bryosalmonae. PCR detected T. bryosalmonae DNA in all tissue samples collected at the 4 time points. Developmental stages of T. bryosalmonae were demonstrated by IHC in most samples at the 4 time points. Cohabitation of SPF F. sultana with chronically infected brown trout resulted in successful transmission of T. bryosalmonae to the bryozoan. This study verified the persistence of T. bryosalmonae in chronically infected brown trout and their ability to infect the bryozoan F. sultana up to 104 wpe.


Adjustable, broadband, selective excitation with uniform phase.
An advance in the problem of achieving broadband, selective, and uniform-phase excitation in NMR spectroscopy of liquids is outlined. Broadband means that, neglecting relaxation, any frequency bandwidth may be excited even when the available radiofrequency (RF) field strength is strictly limited. Selective means that sharp transition edges can be created between pure-phase excitation and no excitation at all. Uniform phase means that, neglecting spin-spin coupling, all resonance lines have nearly the same phase. Conventional uniform-phase excitation pulses (e.g., E-BURP), mostly based on amplitude modulation of the RF field, are not broadband: they have an achievable bandwidth that is strictly limited by the peak power available. Other compensated pulses based on adiabatic half-passage, like BIR-4, are not selective. By contrast, inversion pulses based on adiabatic fast passage can be broadband (and selective) in the sense above. The advance outlined is a way to reformulate these frequency modulated (FM) pulses for excitation, rather than just inversion.


The ACR11 encodes a novel type of chloroplastic ACT domain repeat protein that is coordinately expressed with GLN2 in Arabidopsis.
The ACT domain, named after bacterial aspartate kinase, chorismate mutase and TyrA (prephenate dehydrogenase), is a regulatory domain that serves as an amino acid-binding site in feedback-regulated amino acid metabolic enzymes. We have previously identified a novel type of ACT domain-containing protein family, the ACT domain repeat (ACR) protein family, in Arabidopsis. Members of the ACR family, ACR1 to ACR8, contain four copies of the ACT domain that extend throughout the entire polypeptide. Here, we describe the identification of four novel ACT domain-containing proteins, namely ACR9 to ACR12, in Arabidopsis. The ACR9 and ACR10 proteins contain three copies of the ACT domain, whereas the ACR11 and ACR12 proteins have a putative transit peptide followed by two copies of the ACT domain. The functions of these plant ACR proteins are largely unknown. The ACR11 and ACR12 proteins are predicted to target to chloroplasts. We used protoplast transient expression assay to demonstrate that the Arabidopsis ACR11- and ACR12-green fluorescent fusion proteins are localized to the chloroplast. Analysis of an ACR11 promoter-β-glucuronidase (GUS) fusion in transgenic Arabidopsis revealed that the GUS activity was mainly detected in mature leaves and sepals. Interestingly, coexpression analysis revealed that the GLN2, which encodes a chloroplastic glutamine synthetase, has the highest mutual rank in the coexpressed gene network connected to ACR11. We used RNA gel blot analysis to confirm that the expression pattern of ACR11 is similar to that of GLN2 in various organs from 6-week-old Arabidopsis. Moreover, the expression of ACR11 and GLN2 is highly co-regulated by sucrose and light/dark treatments in 2-week-old Arabidopsis seedlings. This study reports the identification of four novel ACT domain repeat proteins, ACR9 to ACR12, in Arabidopsis. The ACR11 and ACR12 proteins are localized to the chloroplast, and the expression of ACR11 and GLN2 is highly coordinated. These results suggest that the ACR11 and GLN2 genes may belong to the same functional module. The Arabidopsis ACR11 protein may function as a regulatory protein that is related to glutamine metabolism or signaling in the chloroplast.


An assessment of the attention demands during random- and blocked-practice schedules.
The reported study used the dual-task methodology to assess the attention demands associated with high and low contextual interference (CI) practice environments. Two specific issues were addressed. First, is there a difference in the attention demands during random and blocked schedules of practice? Second, what is the time course of any differential attention demands that emerge during random and blocked training? In order to address these questions two specific temporal loci were probed during practice: a pre-response interval and the inter-trial interval. It was assumed that the pre-response interval contained the reconstructive activity that is central to the reconstruction position. In contrast, the inter-trial interval has been interpreted in previous work to be the interval in which critical intra- and inter-item processing is performed during random practice. The data revealed a typical CI effect for the primary key-pressing task. Specifically, blocked-practice participants displayed superior performance during training but performed less well than the random-practice individuals at the time of retention. The poorer acquisition performance of the random-practice participants was associated with higher cognitive demand during both the pre-response and the inter-trial intervals than that of individuals assigned to blocked practice. The greater attention demands for random-practice individuals are discussed with respect to processes that might occur in both the pre-response and the inter-trial intervals.


Meal-time Smartphone Use in an Obesogenic Environment: Two Longitudinal Observational Studies.
Despite a large volume of research on the impact of other digital screens (eg, televisions) on eating behavior, little is known about the nature and impact of mealtime smartphone use. We investigated how smartphones are used in everyday meals, whether phone users differ according to mealtime phone use patterns, and whether specific phone functions (particularly food photography) would affect the amount and enjoyment of food eaten. Across 2 studies, we used the experience sampling method to track 1780 meals in situ. In study 1, a total 137 young adults reported on their mealtime smartphone use 3 times per day over 7 consecutive days. This corresponded to each main meal, with participants recording whether they used their phones and what phone functions they engaged in while eating. In study 2, a total of 71 young adults were similarly tracked for 3 meals per day over 7 days. Across the week, participants' meals were randomized to 1 of 3 smartphone conditions: food photography while eating, nonfood photography while eating, or no phone use. As the outcome measures, participants reported on the amount and enjoyment of food they ate. During the week-long tracking, most participants (110/129, 85.3%) recorded at least one instance of mealtime smartphone use, with an average frequency of 1 in 3 meals where phones were used (27.1%; 95% CI 23.6-30.6). Unlike traditional digital screens, mealtime phone use encompassed a wide range of social and nonsocial activities. Further, specific forms of phone use behaviors influenced food intake in different ways. Specifically, in study 2, participants showed the typical pattern of increased food intake across the day when they engaged in nonfood photography during a meal (P<.001); however, this pattern was disrupted when they engaged in food photography (P=.73). Our findings underscore the prevalence and multifaceted nature of mealtime phone use, distinguishing mobile phones from traditional forms of digital screens. ClinicalTrials.gov NCT03299075; https://www.clinicaltrials.gov/ct2/show/NCT03299075 and ClinicalTrials.gov NCT03346785; https://clinicaltrials.gov/ct2/show/NCT03346785.


The identification of regulatory ceRNA network involved in Drosophila Toll immune responses.
Non-coding RNAs play important roles in the innate immunity of Drosophila, with various lncRNAs and miRNAs identified to maintain Drosophila innate immune homeostasis by regulating protein functions. However, it remains unclear whether interactions between lncRNAs and miRNAs give rise to a ceRNA network. In our previous study, we observed the highest differential expression levels of lncRNA-CR11538, lncRNA-CR33942, and lncRNA-CR46018 in wild-type flies after Gram-positive bacterial infection, prompting us to investigate their role in the regulation of Drosophila Toll immune response through RNA-seq analysis. Herein, our comprehensive bioinformatics analysis revealed that lncRNA-CR11538, lncRNA-CR33942, and lncRNA-CR46018 are involved in defense mechanisms and stimulus response. Moreover, lncRNA-CR11538 and lncRNA-CR46018 can also participate in the metabolic recovery processes following Gram-positive bacterial infection. Subsequently, we employed GSEA screening and RT-qPCR to identify seven miRNAs (miR-957, miR-1015, miR-982, miR-993, miR-1007, miR-193, and miR-978) that may be regulated by these three lncRNAs. Furthermore, we predicted the potential target genes in the Toll signaling pathway for these miRNAs and their interaction with the three lncRNAs using TargetScan and miRanda software and preliminary verification. As a result, we established a potential ceRNA regulatory network for Toll immune responses in Drosophila, comprising three lncRNAs and seven miRNAs. This study provides evidence of a ceRNA regulatory network in Drosophila Toll immune responses and offers novel insights into understanding the regulatory networks involved in the innate immunity of other animals.


Oral malignant melanoma treated with Mohs micrographic surgery by fixed-tissue technique.
We describe a 77-year-old man with stage III oral malignant melanoma (Breslow thickness, 4.0 mm) treated with Mohs micrographic surgery by fixed-tissue technique, elective lymph node dissection, and postoperative radiation therapy. This treatment plan permitted complete excision of the melanomatous field, sparing the need for radical resection. Although the patient later died of widespread metastases, there was no evidence of local or regional recurrence and his quality of life was preserved. We believe that Mohs micrographic surgery by fixed-tissue technique followed by radiation therapy offers a safe and alternative treatment option for deep melanomas in the oral cavity.


Hot topics in interventional cardiology: Proceedings from the society for cardiovascular angiography and interventions (SCAI) 2021 think tank.
The Society for Cardiovascular Angiography and Interventions (SCAI) Think Tank is a collaborative venture that brings together interventional cardiologists, administrative partners, and select members of the cardiovascular industry community annually for high-level field-wide discussions. The 2021 Think Tank was organized into four parallel sessions reflective of the field of interventional cardiology: (a) coronary intervention, (b) endovascular medicine, (c) structural heart disease, and (d) congenital heart disease. Each session was moderated by a senior content expert and co-moderated by a member of SCAI's Emerging Leader Mentorship program. This document presents the proceedings to the wider cardiovascular community in order to enhance participation in this discussion, create additional dialog from a broader base, and thereby aid SCAI, the industry community and external stakeholders in developing specific action items to move these areas forward.


The patient-rated wrist evaluation (PRWE): cross-cultural adaptation into German and evaluation of its psychometric properties.
To cross-culturally adapt the Patient-Rated Wrist Evaluation form (PRWE) into German (PRWE-G) and to evaluate its reliability and validity. A cross-cultural adaptation of the PRWE was carried out, according to established guidelines. 103 patients, who had undergone resection interposition arthroplasty (RIAP) for carpometacarpal osteoarthritis approximately 6.2 years earlier, completed a questionnaire booklet containing the PRWE-G, the Short Form 36 (SF-36), the Disabilities of Arm, Shoulder, and Hand (DASH); they also underwent clinical assessment with the Hand Function Index (HFI, Keitel) and Custom Score including grip and pinch strength tests. The results were used to assess the criterion and construct validity of the PRWE-G. To measure the re-test reliability, 51 patients completed a second PRWE-G within 2 weeks. The test-retest reliability of the PRWE-G was acceptable for the pain and function sub-scales and for the global score, with intraclass correlation coefficients of 0.78-0.87. The PRWE-G showed a high internal consistency (Cronbach's alphas of 0.92-0.97 for the scales and the total score). The typical error of measurement for the global score was 8.1 points, giving a minimal detectable change (MDC<inf>95%</inf>) of approximately 22.5 points. The PRWE-G scores correlated well with those of the DASH (r=0.82, p<0.001) but less well with those of the physical component summary of the SF-36 (r=0.53, p<0.001) and not at all with the mental component summary scores of the SF-36 (r=0.04, p>0.05). The PRWE-G scores correlated moderately with certain clinical findings of the HFI, Custom Score, and grip/pinch strength tests (r=0.30-0.59, p<0.001). The PRWE-G represents a valid and reliable instrument to evaluate self-rated outcome in German-speaking patients with hand and wrist pathology.


Diminished adhesion of Anaplasma phagocytophilum-infected neutrophils to endothelial cells is associated with reduced expression of leukocyte surface selectin.
Anaplasma phagocytophilum propagates within neutrophils and causes a disease marked by inflammatory tissue injury or complicated by opportunistic infections. We hypothesized that infection with A. phagocytophilum modifies the binding of neutrophils to endothelial cells and the expression of neutrophil adhesion molecules and studied these changes in vitro. Infected dimethyl sulfoxide-differentiated HL-60 cells and neutrophils showed reduced binding to cultured brain and systemic endothelial cells and lost expression of P-selectin glycoprotein ligand 1 (PSGL-1, CD162) and L-selectin (CD62L) (to 33 and 5% of control values, respectively), at a time when the levels of beta(2) integrin and immunoglobulin superfamily adhesion molecules and activation markers Mac-1 and intercellular adhesion molecule 1 increased (5 to 10 times that of the control). The loss of CD162 and CD62L expression was inhibited by EDTA, which suggests that neutrophil activation and sheddase cleavage occurred. The loss of selectin expression and the retained viability of the neutrophils persisted for at least 18 h with A. phagocytophilum infection, whereas Escherichia coli and Staphylococcus aureus rapidly killed neutrophils. The adhesion defect might increase the numbers of infected cells and their persistence in the blood prior to tick bites. However, decreased CD162 expression and poor endothelial cell binding may partly explain impaired host defenses, while simultaneous neutrophil activation may aggravate inflammation. These observations may help us to understand the modified biological responses, host inflammation, and immune response that occur with A. phagocytophilum infections.


Options for tracking GFP-Labeled transplanted myoblasts using in vivo fluorescence imaging: implications for tracking stem cell fate.
Green fluorescent protein (GFP) is a useful biomarker, widely used in biomedical research to track stem cells after transplantation and/or to assess therapeutic transgene expression. However, both GFP and therapeutic gene products themselves may be immunogenic to the recipient. The main aim of this study was to use animal models to evaluate potential impact of GFP on the cell engraftment and to optimize tracking strategies prior to transplantation. By using a fluorescent imaging (FLI) system, we investigated the dynamic cell behavior of GFP-transduced myoblasts in tibialis anterior (TA) muscles of immunocompetent mdx mice and immuno-compromised nude mice over a period of three months. The results suggested an apparent underlying host immunorejection in the mdx mice. Dystrophin immunostaining showed that the engraftment of wild type myoblasts was much more effective than that of the GFP-labeled counterparts in the mdx mice, further confirming an antigen role of GFP in this process. We tracked the GFP-transduced myoblasts in C57BL/6 mice and found GFP to be minimally immunogenic in these animals, as indicated by the GFP signal maintaining a much stronger level than that found in mdx and BALB/c mice at parallel time points. We also compared the in vivo cell behavior differences between myoblasts from virally GFP-transduced and GFP transgenic mice. The latter displayed much better engraftment, as determined both biomaging and histological observations. Our results not only demonstrated the immunogenicity of GFP in immunocompetent mice, but determined the optimized conditions for GFP-based in vivo stem cells tracking, that can potentially be extrapolated to human biomedical research.


Arbor: comparative analysis workflows for the tree of life.
We describe our efforts to develop a software package, Arbor, that will enable scientific research in all aspects of comparative biology. This software will enable developmental biologists, geneticists, ecologists, geographers, paleobiologists, educators, and students to analyze diverse types of comparative data at multiple phylogenetic and spatiotemporal scales using an intuitive visual interface. Arbor's user-defined workflows will be exported and shared so that entire analyses can be quickly replicated with new or updated data. Arbor will also be designed to easily and seamlessly expand to include novel analytical tools as they are developed. Here we describe the core components of Arbor, as well as provide details of one proposed test case to illustrate the software's key functionality.


Olaparib maintenance for first-line treatment of ovarian cancer: will SOLO1 reset the standard of care?
Maintenance therapy with PARP inhibitors has heralded a new era in the management of recurrent epithelial ovarian cancer. The greatest effect is seen in women with BRCA1/2 tumors but those without this mutation also benefit. However, in most patients, the drugs eventually fail to prevent progression, so alternative strategies are needed. The SOLO1 trial randomized women with BRCA1/2-mutated advanced ovarian cancer to olaparib or placebo maintenance after first-line chemotherapy. Olaparib significantly improved progression-free survival to a degree that has not been seen in other first-line trials in ovarian cancer. This landmark trial is likely to change practice for this group of women. Here, we focus on the SOLO1 results in the context of the current management of advanced ovarian cancer.


Body contouring surgery after weight reduction.
I reviewed the cases of 50 consecutive patients who had a total of 75 plastic surgery procedures after weight reduction. The average weight loss was 126 lb. There were 28 women and 22 men. The 75 operations were abdominoplasty (24), face-lift (18), reduction mammaplasty (ten), blepharoplasty (eight), mastopexy (eight), thigh reduction (five), and arm reduction (two). Twenty-one patients also had adjunctive nonplastic surgery. The average hospital stay was 5.3 days. Seromas were encountered in 42% of the abdominoplasty group as the most frequent complication. Response to a questionnaire showed that 39 patients (82%) believed the surgical results improved their self-esteem; 35 (72%) stated that plastic surgery did not provide an incentive for maintaining their weight reduction.


Persistent ER stress induces the spliced leader RNA silencing pathway (SLS), leading to programmed cell death in Trypanosoma brucei.
Trypanosomes are parasites that cycle between the insect host (procyclic form) and mammalian host (bloodstream form). These parasites lack conventional transcription regulation, including factors that induce the unfolded protein response (UPR). However, they possess a stress response mechanism, the spliced leader RNA silencing (SLS) pathway. SLS elicits shut-off of spliced leader RNA (SL RNA) transcription by perturbing the binding of the transcription factor tSNAP42 to its cognate promoter, thus eliminating trans-splicing of all mRNAs. Induction of endoplasmic reticulum (ER) stress in procyclic trypanosomes elicits changes in the transcriptome similar to those induced by conventional UPR found in other eukaryotes. The mechanism of up-regulation under ER stress is dependent on differential stabilization of mRNAs. The transcriptome changes are accompanied by ER dilation and elevation in the ER chaperone, BiP. Prolonged ER stress induces SLS pathway. RNAi silencing of SEC63, a factor that participates in protein translocation across the ER membrane, or SEC61, the translocation channel, also induces SLS. Silencing of these genes or prolonged ER stress led to programmed cell death (PCD), evident by exposure of phosphatidyl serine, DNA laddering, increase in reactive oxygen species (ROS) production, increase in cytoplasmic Ca(2+), and decrease in mitochondrial membrane potential, as well as typical morphological changes observed by transmission electron microscopy (TEM). ER stress response is also induced in the bloodstream form and if the stress persists it leads to SLS. We propose that prolonged ER stress induces SLS, which serves as a unique death pathway, replacing the conventional caspase-mediated PCD observed in higher eukaryotes.


Human RTEL1 stabilizes long G-overhangs allowing telomerase-dependent over-extension.
Telomere maintenance protects the cell against genome instability and senescence. Accelerated telomere attrition is a characteristic of premature aging syndromes including Dyskeratosis congenita (DC). Mutations in hRTEL1 are associated with a severe form of DC called Hoyeraal-Hreidarsson syndrome (HHS). HHS patients carry short telomeres and HHS cells display telomere damage. Here we investigated how hRTEL1 contributes to telomere maintenance in human primary as well as tumor cells. Transient depletion of hRTEL1 resulted in rapid telomere shortening only in the context of telomerase-positive cells with very long telomeres and high levels of telomerase. The effect of hRTEL1 on telomere length is telomerase dependent without impacting telomerase biogenesis or targeting of the enzyme to telomeres. Instead, RTEL1 depletion led to a decrease in both G-overhang content and POT1 association with telomeres with limited telomere uncapping. Strikingly, overexpression of POT1 restored telomere length but not the overhang, demonstrating that G-overhang loss is the primary defect caused by RTEL1 depletion. We propose that hRTEL1 contributes to the maintenance of long telomeres by preserving long G-overhangs, thereby facilitating POT1 binding and elongation by telomerase.


Linkage disequilibrium due to random genetic drift in finite subdivided populations.
In order to clarify the mechanisms responsible for the observed linkage disequilibrium, such as that found between markers in the major histocompatibility complex of man and mouse, linkage disequilibrium between two linked loci was studied for a finite population with a subdivided structure. The infinite allele model was used. In analogy with the subdivision of the inbreeding coefficient, the linkage disequilibrium coefficient was subdivided, and various variance components of disequilibrium were defined. It was found that the disequilibrium components may get very large when migration is limited if the correlation of alleles at the two loci within a colony is taken relative to that of the entire population. In other words, with limited migration, random genetic drift of gamete types prevails in each colony. A possible test in which the variance components of disequilibrium are compared is suggested; the test discriminates between epistatic natural selection and limited migration, showing the former as the main cause of the observed linkage disequilibrium. It is pointed out that the major histocompatibility complex polymorphism is in accord with the population genetics model of multigene families that incorporate gene conversion or double unequal crossing-over between the loci in the supergene family.


Canadian National Guidelines and Recommendations for Integrating Career Advising Into Medical School Curricula.
Career planning, decision making about specialty choice, and preparation for residency matching are significant sources of stress for medical students. Attempts have been made to structure and formalize career advising by including it in accreditation standards. There is an expressed need for national guidelines on career advising for medical students. The Future of Medical Education in Canada Postgraduate (FMEC PG) Implementation Project was created to ensure Canadian medical trainees receive the best education possible. From this, a diverse sub-working group (SWG), representing different Canadian regions, was formed to review career advising processes across the country. The SWG developed, through a modified formal consensus methodology, a strategy for medical student career advising that is adaptable to all schools in alignment with existing accreditation standards. The SWG outlined five guiding principles and five essential elements for Canadian universities offering an MD degree with recommendations on how to integrate the elements into each school's career advising system. The five essential elements are a structured approach to career advising, information about available career options, elective guidance, preparation for residency applications, and social accountability. This Perspective endorses the view of the FMEC PG Implementation Project that national guidelines are important to ensure Canadian medical schools are consistently meeting accreditation standards by providing reliable and quality career advising to all medical students. The SWG's position, based on national and provincial feedback, is that these guidelines will stimulate discourse and action regarding the requirements and processes to carry out these recommendations nationwide and share across borders.


mu-receptor mediates elevated glucose and corticosterone after third ventricle injection of opioid peptides.
Four experiments were done to determine which receptor type(s) mediates the effects of third ventricular microinjections of four opioid peptide agonists on blood levels of glucose, free fatty acids, and corticosterone. Tests were performed in unanesthetized adult male albino rats having chronic intraventricular cannulas; blood samples were taken from the tail tip at 0, 15, 30, 60, 90, and 120 min postmicroinjection. In experiment 1, the agonists DAGO (Tyr-D-Ala-Gly-N-methyl-Phe-Gly-ol), beta-endorphin, DSLET (d-Ser2-Leu-enkephalin-Thr), and dynorphin A-(1-17) (0, 0.3, 1, 3, and 10 nmol/rat) produced three distinct patterns of changes in serum glucose, free fatty acid, and corticosterone values. Experiment 2 showed that the effects of DAGO and beta-endorphin were inhibited by prior injection with the opiate-receptor blocker naloxone (1 mg/kg sc) and that the effects of dynorphin were not diminished. Experiment 3 determined that dynorphin effects were also not diminished by naloxone given intraventricularly. Experiment 4 found that blockade of the mu-receptor by intraventricular pretreatment with the specific antagonist beta-funaltrexamine (20 micrograms/rat, 24 h before) completely abolished the effects of DAGO and beta-endorphin on glucose and corticosterone. The mu-receptor is critical to the mediation of the hyperglycemia and hypercorticosteronemia induced by the central administration of opiate agonists. These results imply that mu-opioid binding sites previously identified in central autonomic regions may be involved in the regulation of circulating glucose and corticosterone.


Single-molecule protein folding: diffusion fluorescence resonance energy transfer studies of the denaturation of chymotrypsin inhibitor 2.
We report single-molecule folding studies of a small, single-domain protein, chymotrypsin inhibitor 2 (CI2). CI2 is an excellent model system for protein folding studies and has been extensively studied, both experimentally (at the ensemble level) and theoretically. Conformationally assisted ligation methodology was used to synthesize the proteins and site-specifically label them with donor and acceptor dyes. Folded and denatured subpopulations were observed by fluorescence resonance energy transfer (FRET) measurements on freely diffusing single protein molecules. Properties of these subpopulations were directly monitored as a function of guanidinium chloride concentration. It is shown that new information about different aspects of the protein folding reaction can be extracted from such subpopulation properties. Shifts in the mean transfer efficiencies are discussed, FRET efficiency distributions are translated into potentials, and denaturation curves are directly plotted from the areas of the FRET peaks. Changes in stability caused by mutation also are measured by comparing pseudo wild-type CI2 with a destabilized mutant (K17G). Current limitations and future possibilities and prospects for single-pair FRET protein folding investigations are discussed.