[Parity and menarche as risk factors for osteoporosis in postmenopausal women].
Worldwide studies, even in our country, have thrown discrepant results about the relation between osteoporosis, parity and age of menarche. To investigate the relation of osteoporosis in postmenopausal mexican women with multiparity and age of menarche. Transversal, retrospective and analytical study. Non-probabilistic sampling technique was performing with users women of the IMSS in San Luis Potosí. Reproductive history and age of menarche were obtained by the addition of these items to the previously validated Albrand questionnaire. Women were divided into groups according to the number of pregnancies in: normal parity (0 to 3 childbirths) conformed by 112 patients (46%) and multiparity (> or = 4 pregnancies), 131 women (54%). In relation to menarche with an average of 12.98 years, from this number we divided them in: early menarche (before the age of 13) and late menarche (at 13 years of age or after). It was measured bone mineral density with dual distal forearm x-ray absorptiometry to all patients. 243 women were studied, with an average of age of 55.92, rank 31 to 80 years. Using the criteria, of the World Health Organization, 18% of posmenopausal women had osteoporosis, 39% had osteopenia and 41% had bone normality. No association was found between the number of deeds and osteoporosis. Additionally we observed that the women who had 4 or more children were older than the other women. average 57.42 against 54.16. Also there was significant negative correlation (r = -0.43) between age and densitometry. In addition we found that an age greater to 13 years in the appearance of the menarche was related to osteoporosis (OR 4.46; p = 0.035). In posmenopausal women a menarche at the age of 13 years or after is a risk factor for osteoporosis.


Zinc chelation and Klf9 knockdown cooperatively promote axon regeneration after optic nerve injury.
The inability of axons to regenerate over long-distances in the central nervous system (CNS) limits the recovery of sensory, motor, and cognitive functions after various CNS injuries and diseases. Although pre-clinical studies have identified a number of manipulations that stimulate some degree of axon growth after CNS damage, the extent of recovery remains quite limited, emphasizing the need for improved therapies. Here, we used traumatic injury to the mouse optic nerve as a model system to test the effects of combining several treatments that have recently been found to promote axon regeneration without the risks associated with manipulating known tumor suppressors or oncogenes. The treatments tested here include TPEN, a chelator of mobile (free) zinc (Zn2+); shRNA against the axon growth-suppressing transcription factor Klf9; and the atypical growth factor oncomodulin combined with a cAMP analog. Whereas some combinatorial treatments produced only marginally stronger effects than the individual treatments alone, co-treatment with TPEN and Klf9 knockdown had a substantially stronger effect on axon regeneration than either one alone. This combination also promoted a high level of cell survival at longer time points. Thus, Zn2+ chelation in combination with Klf9 suppression holds therapeutic potential for promoting axon regeneration after optic nerve injury, and may also be effective for treating other CNS injuries and diseases.


Effects of the oestrous cycle and gender on acute vasodilatory responses of isolated pressurized rat mesenteric arteries to 17 beta-oestradiol.
The influence of the oestrous cycle and gender on responses of isolated pressurized mesenteric arteries to acute 17 beta-oestradiol was investigated. All vessels, pre-contracted with 60 mM KCl or 10 microM U46619 (9,11 dideoxy-11alpha, 9alpha-epoxy methano-prostaglandin), exhibited concentration-dependent vasodilatory responses to 17 beta-oestradiol (3 - 30 microM). The largest responses were seen in vessels from female rats in pro-oestrous (38.9+/-5.4% U46619 max and 63.1+/-4.0% KCl max for 30 microM oestradiol), the smallest from animals in di-oestrous (20.1+/-3.7% U46619 and 50.1+/-4.5% KCL - both P:<0.05 cf pro-oestrous (all n=8)). Responses of vessels from male rats were similar to those from pro-oestrous rats (41.5+/-9.1% U46619 (n=10) and 54.9+/-2.9% KCl (n =8)). All responsees were unaffected by inhibition of nitric oxide synthase (NOS). Female rats in pro-oestrous had the highest plasma concentrations of 17 beta-oestradiol and testosterone (40.76+/-4.73 pg ml(-1) and 0.29+/-0.05 ng ml(-1) respectively (n=8)) while those in di-oestrous had the lowest (15.24+/-3.94 pg ml(-1) for oestradiol and 0.08+/-0.03 ng ml(-1) for testosterone (n=8)). In male rats the concentration of oestrogen was 10.29+/-1.21 pg ml(-1) (n=7) while that of testosterone was 3.15+/-0.36 ng ml(-1) (n=7). Incubation of arteries isolated from male rats and from female rats in pro-oestrous and di-oestrous with testosterone (1 microM, 3 h) significantly enhanced the subsequent vasodilatory responses to acute 17 beta-oestradiol. Following incubation, the responses to 17 beta-oestradiol were similar in all groups. These observations suggest that gender and the oestrous cycle may influence the vascular responses to acute 17 beta-oestradiol administration.


OsHLP1 is an endoplasmic-reticulum-phagy receptor in rice plants.
The endoplasmic reticulum (ER) is the largest intracellular endomembrane system; it shows dynamic changes upon environmental stress. To maintain ER morphology and homeostasis under stress, the excessive ER membrane and the associated unwanted proteins can be removed via ER-phagy. Although a few ER-phagy receptors have been reported in mammals and yeast, their functional counterparts in plants remain largely unexplored. Here, we report that the HVA22 family protein OsHLP1 is an uncharacterized ER-phagy receptor in rice (Oryza sativa L.). OsHLP1 interacts with OsATG8b and recruits ER subdomains and the cargo protein OsNTL6, a negative immune regulator, to autophagosomes upon infection with the fungus Magnaporthe oryzae, which substantially activates disease resistance in rice. AtHVA22J, an Arabidopsis thaliana OsHLP1 ortholog, induced similar ER-phagy in plants. Altogether, we unraveled a conservative protein family that may act as ER-phagy receptors in higher plants, and in particular, we highlighted their roles in rice immune responses.


GRP78 is implicated in the modulation of tumor aerobic glycolysis by promoting autophagic degradation of IKKβ.
Compared with normal differentiated cells, cancer cells take up much more glucose and metabolize it mainly via aerobic glycolysis. This metabolic phenotype is characterized with high expression of glucose transporters (Gluts) and pyruvate kinase M2 (PKM2). Glucose regulated protein 78 (GRP78) is a glucose-sensing protein and frequently up-regulated in cancer cells, however, whether it is directly implicated in glucose metabolism remains to be elucidated. Here we report that upon glucose deficiency, the induction of GRP78 resulted in enhanced HIF-1α transcription, accompanied by a transient increased expression of Glut-1. In addition, GRP78 was likely to facilitate the membrane translocation of Glut-1 via protein-protein interaction. Glucose starvation-stimulated GRP78 also impaired the expression of PKM2 but promoted the expression of mitochondrial pyruvate dehydrogenase A (PDHA) and B (PDHB), resulting in the metabolic shift from glycolysis to the TCA cycle. Interestingly, the inhibition of PKM2 by GRP78 was abrogated when glucose supply was restored, suggesting that GRP78 and PKM2 expressions are adaptable to the nutritional levels in the microenvironment. Further mechanistic study indicated that GRP78 overexpression activated the Class III PI3K-mediated autophagy pathway and induced autophagic degradation of IKKβ, which caused inactivation of NF-κB pathway and subsequently altered the expression of PKM2 and HIF-1α. Our study establishes GRP78 and PKM2 as the crucial molecular links between cancer cell glucose metabolism and tumor microenvironment alterations.


Lateral neck dissection affects the voice in thyroid cancer patients.
This study aimed to identify the effect of lateral neck dissection on voice change in thyroidectomised patients. Medical records from 264 patients who underwent thyroidectomy with (n = 65) or without (n = 199) lateral neck dissection were reviewed. Clinical and voice evaluation data were compared between the two groups. Patients who underwent surgery that included lateral neck dissection had lower fundamental frequencies and speaking fundamental frequencies. They also had a higher incidence of asymmetric mucosal wave and vocal fold oedema on videostroboscopy during the first month after surgery, with the incidence of vocal fold oedema remaining significantly higher at three months. Self-assessed voice quality scores were significantly higher in lateral neck dissection patients at both one and three months after surgery. In thyroidectomised patients, lateral neck dissection lowers the vocal pitch in the initial period after surgery and induces vocal fold oedema that persists for several months. Although most objective parameters improved within a month, subjective symptoms lasted for longer.


[Current aspects of the evaluation of ERBB2 activation in breast cancer. Therapeutic perspectives].
The ERBB2 (HER-2/neu) protooncogene encodes a transmembrane protein with an intracellular tyrosine kinase activity. It is principally activated by gene amplification and its product, the erbB2 protein, becomes oncogenic when overexpressed. Quantitative PCR is both a simple and reliable method for the evaluation of ERBB2 activation, whereas immunoenzymatic methods allow quantitative determination of erbB2 protein in tissue and sera. ERBB2 amplification and/or surexpression is actually recognized as a prognostic factor in breast cancer and would be predictive in the therapeutic response. It might lead also to new therapeutic modalities using specific targeted drugs.


[The adhesion of clinical isolates of Campylobacter jejuni to intestinal epithelial cells in vitro].
The adhesive activity of C. jejuni isolated from feces of children with Campylobacter infection was studied with the use of a newly developed model. 47 clinical isolates were analyzed; of these, 91% were found to be enteroadhesive to a variable degree. As the result of in vitro studies, Campylobacter were found to have much greater tropism to colonic cells and epithelial cells of Peyer's patches in comparison with the epithelial cells of the small intestine. The correlation between the degree of adhesive activity and the severity of the course of Campylobacter infection in children.


Long-term survivors after breast cancer.
A retrospective analysis of two groups of patients, one surviving 16-20 years and the other dying within 10 years after diagnosis and treatment of primary breast cancer has been undertaken to determine whether there were particular clinical or histological features associated with long-term survival. The striking histological difference between the tumours of the two groups of patients was the prevalence of tumours of 'special' invasive types (cribriform, tubular, lobular and medullary) in the long-term survivors. Micro-invasive and non-invasive carcinomas were also more common in the survivors. The tumours of the surviving group which were not of a 'special' type more commonly had a better histological grade than those tumours of patients dying early from breast cancer. In the overall group elastosis was present in significantly more tumours of the survivors whereas tumour necrosis, vascular and lymphatic invasion were all significantly more common in the short-term survival group. Although there was a significantly increased incidence of earlier stage tumours in the long-term survivors, the histological distinctions between the two groups were independent of the differences in clinical features.


Pseudogene rescue: an adaptive mechanism of codon reassignment.
Alterations to the genetic code--codon reassignments--have occurred many times in life's history, despite the fact that genomes are coadapted to their genetic codes and therefore alterations are likely to be maladaptive. A potential mechanism for adaptive codon reassignment, which could trigger either a temporary period of codon ambiguity or a permanent genetic code change, is the reactivation of a pseudogene by a nonsense suppressor mutant transfer RNA. I examine the population genetics of each stage of this process and find that pseudogene rescue is plausible and also readily explains some features of extant variability in genetic codes.


Client characteristics associated with behavior change for treated and untreated aggressive boys.
This study examined the relationship between subject characteristics of aggressive boys and their behavioral changes during a school year. Seventy-six boys in the fourth, fifth, and sixth grades were identified by their teachers as the most disruptive and aggressive in their classes. These boys were assigned to untreated control, anger-coping, anger-coping plus goal-setting treatment, and minimal treatment goal-setting cells. The anger-coping treatment was based on cognitive behavioral procedures. In both anger-coping cells, greater reductions in rates of disruptive/aggressive off-task classroom behavior was predicted by having higher rates of these behaviors initially, and greater reductions in parents' ratings of aggression was predicted by having poor social problem-solving skills initially. Additional predictors of reductions in parents' ratings of aggression in one, but not both, anger-coping cells included having higher rates of somatic symptoms and poorer social acceptance by peers. In contrast to the other cells, those boys in the no-treatment group who demonstrated the greatest spontaneous improvement on these change measures were the ones who initially were the best problem-solvers and who had higher levels of self-esteem. This cognitive-behavioral treatment appeared to have most impact with those boys who were the most in need of intervention.


A Spanish model for quantification and management of construction waste.
Currently, construction and demolition waste (C&D waste) is a worldwide issue that concerns not only governments but also the building actors involved in construction activity. In Spain, a new national decree has been regulating the production and management of C&D waste since February 2008. The present work describes the waste management model that has inspired this decree: the Alcores model implemented with good results in Los Alcores Community (Seville, Spain). A detailed model is also provided to estimate the volume of waste that is expected to be generated on the building site. The quantification of C&D waste volume, from the project stage, is essential for the building actors to properly plan and control its disposal. This quantification model has been developed by studying 100 dwelling projects, especially their bill of quantities, and defining three coefficients to estimate the demolished volume (CT), the wreckage volume (CR) and the packaging volume (CE). Finally, two case studies are included to illustrate the usefulness of the model to estimate C&D waste volume in both new construction and demolition projects.


Save the global: global signal connectivity as a tool for studying clinical populations with functional magnetic resonance imaging.
The global signal is commonly removed from resting-state data, as it was presumed to reflect physiological noise. However, removal of the global signal is now under debate, as this signal may reflect important neuronal components, and its removal may introduce artifacts into the data. Here, we show that the functional connectivity (FC) of the global signal is of functional relevance, as it differentiates between schizophrenia patients and healthy controls during rest. We also demonstrate that other reported findings related to various clinical populations may actually reflect alternations in global signal FC. The evidence of the clinical relevance of the global signal propose its usage as a research tool, and extend previously reported perils of global signal removal in resting-state data of clinical populations.


Does Acetabular Coverage Vary Between the Supine and Standing Positions in Patients with Hip Dysplasia?
Although variation in physiologic pelvic tilt may affect acetabular version and coverage, postural change in pelvic tilt in patients with hip dysplasia who are candidates for hip preservation surgery has not been well characterized, and its clinical importance is unknown. The aim of this study was to determine (1) postural changes in sagittal pelvic tilt between the supine and standing positions; (2) postural changes in the acetabular orientation and coverage of the femoral head between the supine and standing positions; and (3) patient demographic and morphologic factors associated with sagittal pelvic tilt. Between 2009 and 2016, 102 patients underwent pelvic osteotomy to treat hip dysplasia. All patients had supine and standing AP pelvic radiographs and pelvic CT images taken during their preoperative examination. Ninety-five patients with hip dysplasia (lateral center-edge angle < 20°) younger than 60 years old were included. Patients with advanced osteoarthritis, other hip disease, prior hip or spine surgery, femoral head deformity, or inadequate imaging were excluded. Sixty-five patients (64%) were eligible for participation in this retrospective study. Two board-certified orthopaedic surgeons (TT and MF) investigated sagittal pelvic tilt, spinopelvic parameters, and acetabular version and coverage using pelvic radiographs and CT images. Intra- and interobserver reliabilities, evaluated using the intraclass correlation coefficient (0.90 to 0.98, 0.93 to 0.99, and 0.87 to 0.96, respectively), were excellent. Demographic data (age, gender, and BMI) were collected by medical record review. Sagittal pelvic tilt was quantified as the angle formed by the anterior pelvic plane and a z-axis (anterior pelvic plane angle). Using a 2D-3D matching technique, we measured the change in sagittal pelvic tilt, acetabular version, and three-dimensional coverage between the supine and standing positions. We correlated sagittal pelvic tilt with demographic and CT measurement parameters using Pearson's or Spearman's correlation coefficients. Although functional pelvic tilt varied widely among individuals, the pelvis of patients with hip dysplasia tilted posteriorly from the supine to the standing position (mean APP angle 8° ± 6° versus 2° ± 7°; mean difference -6°; 95% CI, -7° to -5°; range -17° to 4.1°; p < 0.001; paired t-test).The pelvis tilted more than 5° posteriorly from the supine to the standing position in 39 patients (60%), and the change was greater than 10° in 12 (18%). In the latter subgroup of patients, the mean acetabular anteversion angle increased (22° ± 5° versus 27° ±5°; mean difference 5°; 95% CI, 4°-6°; p < 0.001) and the mean anterosuperior acetabular sector angle notably deceased from the supine to the standing position (91° ± 11° versus 77° ± 14°; mean difference -14°; 95% CI, -17° to -11°; p < 0.001; paired t-test). Postural change in pelvic tilt was not associated with any of the studied demographic or morphologic parameters, including patient age, gender, BMI, and acetabular version and coverage. On average, the pelvis tilted posteriorly from the supine to the standing position in patients with hip dysplasia, resulting in increased acetabular version and decreased anterosuperior acetabular coverage in the standing position. Thus, assessment with a supine AP pelvic radiograph may overlook changes in acetabular version and coverage in weightbearing positions. We recommend assessing postural change in sagittal pelvic tilt when diagnosing hip dysplasia and planning hip preservation surgery. Further studies are needed to determine how postural changes in sagittal pelvic tilt affect the biomechanical environment of the hip and the clinical results of acetabular reorientation osteotomy. Level IV, diagnostic study.


Safety climate and readiness for implementation of evidence and person centered practice - A national study of registered nurses in general surgical care at Swedish university hospitals.
The rationale behind this study is the increasing research on relationships between patient safety, evidence based practice and person centered care, and the growing interest in outcomes of surgical patients. The aim of this study was to explore the safety climate and readiness to implement evidence-based and person centered care as perceived by registered nurses in Swedish surgical care. The design was an exploratory, cross-sectional survey carried out in a national Swedish context. Data were collected through the Safety Attitudes Questionnaire (SAQ - Short form) and the Context Assessment Index (CAI). In total, 1570 questionnaires were distributed, of which 727 were returned, giving a response rate of 46.3 %. The results revealed that in general, the safety climate in Swedish surgical care is positively related to readiness for evidence-based and person centered care, although specific management and cultural factors may be more sensitive and represent targets for improvement. This study presents new knowledge regarding the safety climate and readiness to implement evidence based practice and person centered care in general surgical wards in university hospitals and indicates important associations between these two areas. While RNs generally reported positive job satisfaction and a good team work culture in their units, there were indications that improvements in organizational management are needed.


Association between interstitial cells of Cajal and anti-vinculin antibody in human stomach.
Interstitial cells of Cajal (ICC) are known as the pacemaker cells of gastrointestinal tract, and it has been reported that acute gastroenteritis induces intestinal dysmotility through antibody to vinculin, a cytoskeletal protein in gut, resulting in small intestinal bacterial overgrowth, so that anti-vinculin antibody can be used as a biomarker for irritable bowel syndrome. This study aimed to determine correlation between serum anti-vinculin antibody and ICC density in human stomach. Gastric specimens from 45 patients with gastric cancer who received gastric surgery at Kangwon National University Hospital from 2013 to 2017 were used. ICC in inner circular muscle, and myenteric plexus were counted. Corresponding patient's blood samples were used to determine the amount of anti-vinculin antibody by enzyme-linked immunosorbent assay. Analysis was done to determine correlation between anti-vinculin antibody and ICC numbers. Patients with elevated anti-vinculin antibody titer (above median value) had significantly lower number of ICC in inner circular muscle (71.0 vs. 240.5, p = 0.047), and myenteric plexus (12.0 vs. 68.5, p < 0.01) compared to patients with lower anti-vinculin antibody titer. Level of serum anti-vinculin antibody correlated significantly with density of ICC in myenteric plexus (r = -0.379, p = 0.01; Spearman correlation). Increased level of circulating anti-vinculin antibody was significantly correlated with decreased density of ICC in myenteric plexus of human stomach.


Clinical trials that have influenced the treatment of venous thromboembolism: a historical perspective.
In 1960, Barritt and Jordan performed the first randomized trial demonstrating the efficacy of anticoagulant therapy in the treatment of venous thromboembolism. Since then, important therapeutic advances have been made in the treatment of deep venous thrombosis and pulmonary embolism. This paper reviews the important clinical trials involving anticoagulant therapy and vena caval interruption. The studies are discussed from a historical perspective, and an attempt is made to analyze both the thought processes that prompted their design and the reasons why they changed practice.


Highest resolution chemical imaging based on secondary ion mass spectrometry performed on the helium ion microscope.
This paper is a review on the combination between Helium Ion Microscopy (HIM) and Secondary Ion Mass Spectrometry (SIMS), which is a recently developed technique that is of particular relevance in the context of the quest for high-resolution high-sensitivity nano-analytical solutions. We start by giving an overview on the HIM-SIMS concept and the underlying fundamental principles of both HIM and SIMS. We then present and discuss instrumental aspects of the HIM and SIMS techniques, highlighting the advantage of the integrated HIM-SIMS instrument. We give an overview on the performance characteristics of the HIM-SIMS technique, which is capable of producing elemental SIMS maps with lateral resolution below 20 nm, approaching the physical resolution limits, while maintaining a sub-nanometric resolution in the secondary electron microscopy mode. In addition, we showcase different strategies and methods allowing to take profit of both capabilities of the HIM-SIMS instrument (high-resolution imaging using secondary electrons and mass filtered secondary sons) in a correlative approach. Since its development HIM-SIMS has been successfully applied to a large variety of scientific and technological topics. Here, we will present and summarise recent applications of nanoscale imaging in materials research, life sciences and geology.


Effect of acute hemorrhagic shock on pulmonary microvascular fluid filtration and protein permeability in sheep.
In an attempt to further delineate the pathophysiology of the shock-lung syndrome, we studied the effect of hemorrhagic shock on the pulmonary microcirculation in the adult sheep with lung lymph flow and lymph protein transport as indices of fluid filtration and vascular permeability to protein. We noted that lymph flow remained at baseline levels during shock, despite significant decreases in pulmonary artery and left atrial pressures. This suggests that microvascular pressure is maintained by an increase in pulmonary venous resistance. We demonstrated that lymph protein transport does not increase during shock, which indicates that a change in pulmonary vascular permeability to protein does not occur.


Mechanical Strain Causes Adaptive Change in Bronchial Fibroblasts Enhancing Profibrotic and Inflammatory Responses.
Asthma is characterized by periodic episodes of bronchoconstriction and reversible airway obstruction; these symptoms are attributable to a number of factors including increased mass and reactivity of bronchial smooth muscle and extracellular matrix (ECM) in asthmatic airways. Literature has suggested changes in cell responses and signaling can be elicited via modulation of mechanical stress acting upon them, potentially affecting the microenvironment of the cell. In this study, we hypothesized that mechanical strain directly affects the (myo)fibroblast phenotype in asthma. Therefore, we characterized responses of bronchial fibroblasts, from 6 normal and 11 asthmatic non-smoking volunteers, exposed to cyclical mechanical strain using flexible silastic membranes. Samples were analyzed for proteoglycans, α-smooth muscle actin (αSMA), collagens I and III, matrix metalloproteinase (MMP) 2 & 9 and interleukin-8 (IL-8) by qRT-PCR, Western blot, zymography and ELISA. Mechanical strain caused a decrease in αSMA mRNA but no change in either αSMA protein or proteoglycan expression. In contrast the inflammatory mediator IL-8, MMPs and interstitial collagens were increased at both the transcriptional and protein level. The results demonstrate an adaptive response of bronchial fibroblasts to mechanical strain, irrespective of donor. The adaptation involves cytoskeletal rearrangement, matrix remodelling and inflammatory cytokine release. These results suggest that mechanical strain could contribute to disease progression in asthma by promoting inflammation and remodelling responses.


Cell cycle checkpoint models for cellular pharmacology of paclitaxel and platinum drugs.
A pharmacokinetic-pharmacodynamic mathematical model is developed for cellular pharmacology of chemotherapeutic drugs for which the decisive step towards cell death occurs at a point in the cell cycle, presumably corresponding to a cell cycle checkpoint. For each cell, the model assumes a threshold level of some intracellular species at that checkpoint, beyond which the cell dies. The threshold level is assumed to have a log-normal distribution in the cell population. The kinetics of formation of the lethal intracellular species depends on the drug, and on the cellular pharmacokinetics and binding kinetics of the cell. Specific models are developed for paclitaxel and for platinum drugs (cisplatin, oxaliplatin and carboplatin). In the case of paclitaxel, two separate mechanisms of cell death necessitate a model that accounts for two checkpoints, with different intracellular species. The model was tested on a number of in vitro cytotoxicity data sets for these drugs, and found overall to give significantly better fits than previously proposed cellular pharmacodynamic models. It provides an explanation for the asymptotic convergence of dose-response curves as exposure time becomes long.


Effect of metformin on the vascular and glucose metabolic actions of insulin in hypertensive rats.
We investigated the long-term effect of metformin treatment on blood pressure, insulin sensitivity, and vascular responses to insulin in conscious spontaneously hypertensive rats (SHR). The rats were instrumented with intravascular catheters and pulsed Doppler flow probes to measure blood pressure, heart rate, and blood flow. Insulin sensitivity was assessed by the euglycemic hyperinsulinemic clamp technique. Two groups of SHR received metformin (100 or 300 mg x kg(-1) x day(-1)) for 3 wk while another group of SHR and a group of Wistar Kyoto (WKY) rats were left untreated. We found that vasodilation of skeletal muscle and renal vasculatures by insulin is impaired in SHR. Moreover, a reduced insulin sensitivity was detected in vivo and in vitro in isolated soleus and extensor digitorum longus muscles from SHR compared with WKY rats. Three weeks of treatment with metformin improves the whole-body insulin-mediated glucose disposal in SHR but has no blood pressure-lowering effect and no influence on vascular responses to insulin (4 mU x kg(-1) x min(-1)). An improvement in insulin-mediated glucose transport activity was detected in isolated muscles from metformin-treated SHR, but in the absence of insulin no changes in basal glucose transport activity were observed. It is suggested that part of the beneficial effect of metformin on insulin resistance results from a potentiation of the hormone-stimulating effect on glucose transport in peripheral tissues (mainly skeletal muscle). The results argue against a significant antihypertensive or vascular effect of metformin in SHR.


Greater mortality and morbidity in extremely preterm infants fed a diet containing cow milk protein products.
Provision of human milk has important implications for the health and outcomes of extremely preterm (EP) infants. This study evaluated the effects of an exclusive human milk diet on the health of EP infants during their stay in the neonatal intensive care unit. EP infants <1,250 g birth weight received a diet consisting of either human milk fortified with a human milk protein-based fortifier (HM) (n=167) or a diet containing variable amounts of milk containing cow milk-based protein (CM) (n=93). Principal outcomes were mortality, necrotizing enterocolitis (NEC), growth, and duration of parenteral nutrition (PN). Mortality (2% versus 8%, p=0.004) and NEC (5% versus 17%, p=0.002) differed significantly between the HM and CM groups, respectively. For every 10% increase in the volume of milk containing CM, the risk of sepsis increased by 17.9% (p<0.001). Growth rates were similar between groups. The duration of PN was 8 days less in the subgroup of infants receiving a diet containing <10% CM versus ≥10% CM (p<0.02). An exclusive human milk diet, devoid of CM-containing products, was associated with lower mortality and morbidity in EP infants without compromising growth and should be considered as an approach to nutritional care of these infants.


Prevalence of increased alcohol use and alcohol use disorders in adult victims of terrorist attacks: a systematic and meta-analytic review.
Background: Previous studies have reviewed the evidence on the increase in alcohol consumption after a terrorist attack. However, an increase does not necessarily imply the presence of an alcohol use disorder.Objectives: To conduct a systematic and meta-analytic review of the literature on the prevalence of increased alcohol consumption and alcohol use disorders in adult exposed to terrorism.Methods: A search of PsycINFO, MEDLINE and PTSDpubs identified 29 studies published up to March 2023 in which 38 adult samples totaling 282,753 persons exposed to terrorism were assessed. Using inverse variance heterogeneity models, pooled prevalence rates of increased alcohol use and alcohol use disorders were calculated.Results: 6% (95% CI [2.9, 9.5]) of the adults exposed to a terrorist attack increased their alcohol consumption. The prevalence of increased alcohol use varied depending on the degree of exposure (p = .006, R2 = .18) and the procedure for measuring increases (p = .043, R2 = .37). The prevalence of alcohol use disorders in adults exposed to a terrorist attack was 5.5% (95% CI [3.7, 7.5]), a rate that was not higher than that obtained in the general population and varied depending on the type of alcohol disorder (p = .015, R2 = .30).Conclusions: A relevant number of adults exposed to terrorist attacks will subsequently increase their alcohol consumption, but this increase is not associated with an increase in the prevalence of alcohol use disorders. Effects of terrorism on people's health are potentially widespread, but concerns of excessive alcohol use after terrorist attacks may be unwarranted.


Assessment of foot posture and related factors in patients with knee osteoarthritis.
The aim of this study was to compare foot posture between patient and control groups, and to identify factors associated with foot posture abnormality in knee osteoarthritis (OA). This case-control study included a total of 115 patients (26 males, 89 females; mean age: 54.4±9.3 years; range, 29 to 73 years) with OA and 77 healthy controls (20 males, 57 females; mean age: 52.1±8.1 years; range, 32 to 69 years) between May 2019 and July 2019. The participants were evaluated using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Visual Analog Scale (VAS), and the Beighton criteria. Radiological assessments were performed using the Kellgren-Lawrence grading, condylar plateau angle, and medial tibiofemoral joint width. The Foot Posture Index-6 (FPI-6) was used for foot posture analysis and three groups were formed as supinated, neutral, and pronated postures. Foot posture was significantly different between the patient and control groups (p<0.05). Of the patients with knee OA, significant differences were found in the VAS, WOMAC-pain, WOMAC-physical function, and WOMAC-total (p<0.05) among the foot postures. No significant difference was found among the foot posture groups in terms of the radiological parameters and WOMAC-stiffness (p>0.05). Hypermobility and WOMAC-total scores were significantly associated with foot posture abnormality (p<0.05). Joint hypermobility and foot posture are the factors which may influence the clinical characteristics of knee OA. Foot posture and joint hypermobility should be taken into consideration during the examination and management of patients with knee OA.


Understanding how Indigenous culturally-based interventions can improve participants' health in Canada.
There is increasing recognition that culturally-based diabetes prevention programs can facilitate the adoption and maintenance of healthy behaviours in the communities in which they are implemented. The Kahnawake School Diabetes Prevention Project (KSDPP) is a health promotion, community-based participatory research project aiming to reduce the incidence of Type 2 diabetes in the community of Kahnawake (Mohawk territory, Canada), with a large range of interventions integrating a Haudenosaunee perspective of health. Building on a qualitative, naturalistic and interpretative inquiry, this study aimed to assess the outcomes of a suite of culturally-based interventions on participants' life and experience of health. Data were collected through semi-structured qualitative interviews of 1 key informant and 17 adult, female Kahnawake community members who participated in KSDPP's suite of interventions from 2007 to 2010. Grounded theory was chosen as an analytical strategy. A theoretical framework that covered the experiences of all study participants was developed from the grounded theory analysis. KSDPP's suite of interventions provided opportunities for participants to experience five different change processes: (i) Learning traditional cooking and healthy eating; (ii) Learning physical activity; (iii) Learning mind focusing and breathing techniques; (iv) Learning cultural traditions and spirituality; (v) Socializing and interacting with other participants during activities. These processes improved participants' health in four aspects: mental, physical, spiritual and social. Results of this study show how culturally-based health promotion can bring about healthy changes addressing the mental, physical, spiritual and social dimensions of a holistic concept of health, relevant to the Indigenous perspective of well-being.


Evaluation of uncertainty predictions and dose output for model-based dose calculations for megavoltage photon beams.
In many radiotherapy clinics an independent verification of the number of monitor units (MU) used to deliver the prescribed dose to the target volume is performed prior to the treatment start. Traditionally this has been done by using methods mainly based on empirical factors which, at least to some extent, try to separate the influence from input parameters such as field size, depth, distance, etc. The growing complexity of modern treatment techniques does however make this approach increasingly difficult, both in terms of practical application and in terms of the reliability of the results. In the present work the performance of a model-based approach, describing the influence from different input parameters through actual modeling of the physical effects, has been investigated in detail. The investigated model is based on two components related to megavoltage photon beams; one describing the exiting energy fluence per delivered MU, and a second component describing the dose deposition through a pencil kernel algorithm solely based on a measured beam quality index. Together with the output calculations, the basis of a method aiming to predict the inherent calculation uncertainties in individual treatment setups has been developed. This has all emerged from the intention of creating a clinical dose/MU verification tool that requires an absolute minimum of commissioned input data. This evaluation was focused on irregular field shapes and performed through comparison with output factors measured at 5, 10, and 20 cm depth in ten multileaf collimated fields on four different linear accelerators with varying multileaf collimator designs. The measurements were performed both in air and in water and the results of the two components of the model were evaluated separately and combined. When compared with the corresponding measurements the resulting deviations in the calculated output factors were in most cases smaller than 1% and in all cases smaller than 1.7%. The distribution describing the calculation errors in the total dose output has a mean value of -0.04% and a standard deviation of 0.47%. In the dose calculations a previously developed correction of the pencil kernel was applied that managed to contract the error distribution considerably. A detailed analysis of the predicted uncertainties versus the observed deviations suggests that the predictions indeed can be used as a basis for creating action levels and tracking dose calculation errors in homogeneous media.


The intrinsic resistance of female hearts to an ischemic insult is abrogated in primary cardiac hypertrophy.
Important sex differences in cardiovascular disease outcomes exist, including conditions of hypertrophic cardiomyopathy and cardiac ischemia. Studies of sex differences in the extent to which load-independent (primary) hypertrophy modulates the response to ischemia-reperfusion (I/R) damage have not been characterized. We have previously described a model of primary genetic cardiac hypertrophy, the hypertrophic heart rat (HHR). In this study the sex differences in HHR cardiac function and responses to I/R [compared to control normal heart rat (NHR)] were investigated ex vivo. The ventricular weight index was markedly increased in HHR female (7.82 +/- 0.49 vs. 4.80 +/- 0.10 mg/g; P < 0.05) and male (5.76 +/- 0.22 vs. 4.62 +/- 0.07 mg/g; P < 0.05) hearts. Female hearts of both strains exhibited a reduced basal contractility compared with strain-matched males [maximum first derivative of pressure (dP/dt(max)): NHR, 4,036 +/- 171 vs. 4,258 +/- 152 mmHg/s; and HHR, 3,974 +/- 160 vs. 4,540 +/- 259 mmHg/s; P < 0.05]. HHR hearts were more susceptible to I/R (I = 25 min, and R = 30 min) injury than NHR hearts (decreased functional recovery, and increased lactate dehydrogenase efflux). Female NHR hearts exhibited a significantly greater recovery (dP/dt(max)) post-I/R relative to male NHR (95.0 +/- 12.2% vs. 60.5 +/- 9.4%), a resistance to postischemic dysfunction not evident in female HHR (29.0 +/- 5.6% vs. 25.9 +/- 6.3%). Ventricular fibrillation was suppressed, and expression levels of Akt and ERK1/2 were selectively elevated in female NHR hearts. Thus the occurrence of load-independent primary cardiac hypertrophy undermines the intrinsic resistance of female hearts to I/R insult, with the observed abrogation of endogenous cardioprotective signaling pathways consistent with a potential mechanistic role in this loss of protection.


Mechanical Ablation of Larval Zebra Fish Spinal Cord.
Unlike mammals, adult and larval zebra fish exhibit robust regeneration following traumatic spinal cord injury. This remarkable regenerative capacity, combined with exquisite imaging capabilities and an abundance of powerful genetic techniques, has established the zebra fish as an important vertebrate model for the study of neural regeneration. Here, we describe a protocol for the complete mechanical ablation of the larval zebra fish spinal cord. With practice, this protocol can be used to reproducibly injure upward of 100 samples per hour, facilitating the high-throughput screening of factors involved in spinal cord regeneration and repair.


Longitudinal analysis of serological responses of adults to Helicobacter pylori antigens.
Because Helicobacter pylori persist for decades in the human stomach, the aim of this study was to examine the long-term course of H. pylori-specific serum immunoglobulin G (IgG) responses with respect to subclass and antigenic target. We studied paired serum samples obtained in 1973 and in 1994 in Vammala, Finland, from 64 healthy H. pylori-positive adults and from other healthy control subjects. H. pylori serum immunoglobulin A, IgG, and IgG subclass responses were determined by antigen-specific enzyme-linked immunosorbent assays. H. pylori-specific IgG1 and IgG4 subtype responses from 47 subjects were similar in 1973 and 1994, but not when compared with unrelated persons. H. pylori-specific IgG1:IgG4 ratios among the participants varied >1000-fold; however, 57 (89.1%) of 64 subjects had an IgG1:IgG4 ratio >1.0, consistent with a predominant IgG1 (Th1) response. Furthermore, ratios in individual hosts were stable over the 21-year period (r = 0.56; P < .001). The immune response to heat shock protein HspA was unchanged in 49 (77%) of the 64 subjects tested; of the 15 whose serostatus changed, all seroconverted and were significantly younger than those whose status did not change. These findings indicate that H. pylori-specific antibody responses are host-specific with IgG1:IgG4 ratios stable over 21 years, IgG1 responses predominating, and HspA seroconversion with aging.


Detection of equine herpesvirus-1 antigen and the specific antibody by enzyme-linked immunosorbent assay.
Enzyme-linked immunosorbent assays (ELISA) were developed to detect equine herpesvirus-1 (EHV-1) antigens and specific antibodies. Detection of EHV-1 antigens was done by a 4-layer ELISA. In inoculated cell cultures, EHV-1 cell antigen was detected after postinoculation (PI) hour 4, reached approximately twice the value of EHV-1 viral antigen (extra-cellular virus) in PI hour 18, and peaked in PI hour 24, whereas EHV-1 viral antigen appeared after PI hour 12, increased steadily, and peaked higher than EHV-1 cell antigen in 24 hours. The ELISA titer and infectivity titer of 24-hour PI cultures were 200 and 9.2 X 10(5) plaque-forming units/0.1 ml, respectively. Equine anti-EHV-1 antibody (EAEHV-1) from experimentally inoculated pony foals and rabbit anti-EHV-1 antibody (RAEHV-1) were detected by indirect ELISA and direct ELISA, respectively. The RAEHV-1 had ELISA titers of 665,000 and 102,000 when rabbits were immunized with EHV-1 infected cell culture lysate and with sucrose-purified virus, respectively. The corresponding plaque-reduction virus-neutralization titers were 270 and 150 in the absence of complement and were 6,200 and 3,200 in the presence of complement. The EAEHV-1 had a mean ELISA titer of 60,000, and the corresponding mean virus-neutralization titer in the absence of complement was 34 and that in the presence of complement was 2,142.


Coherent averaging of pseudorandom binary stimuli: is the dynamic cerebral autoregulatory response symmetrical?
Previous studies on cerebral autoregulation have shown the existence of hemispheric symmetry, which may be altered in stroke and traumatic brain injury. There is a paucity of data however on whether the response is symmetrical between those disturbances that cause cerebral hyperperfusion, to those that cause hypoperfusion. Our aim was to investigate whether the responses of cerebral autoregulation to haemodynamic stimuli of different directions are symmetrical. Using a previously described assessment method, we employed coherent averaging of the cerebral blood flow velocity (CBFV) responses to thigh cuff inflation and deflation, as driven by pseudorandom binary sequences, whilst simultaneously altering the inspired CO2. The symmetry of the autoregulatory response was assessed with regards to two parameters, its speed and gain. Using the first harmonic method, critical closing pressure (CrCP) and resistance area product (RAP) were estimated, and the gain of the autoregulatory response was calculated by performing linear regression between the coherent averages of arterial blood pressure (ABP) and CBFV, ABP and CrCP and finally ABP and RAP. A two-way repeated measures ANOVA was used to assess for the effect of the direction of change in ABP and the method of CO2 administration. Our results suggest that whilst the direction of ABP change does not have a significant effect, the effect of CO2 administration method is highly significant (p < 10-4). This is the first report to demonstrate the symmetry of the autoregulatory response to stimuli of different directions as well as the short term dynamics of RAP and CrCP under intermittent and constant hypercapnia. As haemodynamic stimulus direction does not appear to have an influence, our findings validate previous work done using different assessment methods.


Fact or artefact? Childhood adversity and adulthood trauma in the U.S. population-based Health and Retirement Study.
Background: Despite the well-known deleterious health effects of childhood adversity (CA) and adulthood trauma (AT) and ageing of the global population, little is known about self-reported CA and AT in older populations. Existing findings are mixed due to methodological and sampling artefacts, in particular, recall and selection biases, and due to age-period-cohort effects. Objectives: We aim to first, provide data on the prevalence of retrospective self-reported CA and AT in a large population-based sample of older adults and, second, to discuss the data in the context of major methodological and sampling artefacts, and age-period-cohort effects. Method: Data are derived from the U.S. population-based Health and Retirement Study (N = 19,547, mean age = 67.24 ± 11.33, 59% female). Seven birth-cohorts were included (<1924, 1924-1930, 1931-1941, 1942-1947, 1948-1953, 1954-1959, >1959). Results: Overall, 35% of participants reported CA and 62% AT, with strong variability among birth-cohorts. Opposing trends were observed regarding prevalence of CA and AT. As age of cohorts increased, prevalence of CAs decreased while that of ATs increased. Investigating the distributions of incidence of specific ATs across age and period per cohort revealed incidence of exposure was associated with (1) age (e.g. having lost a child), (2) time-period (e.g. major disaster), and (3) cohort (e.g. military combat). Conclusions: Retrospective self-reported CA and AT in older samples should be interpreted with caution and with regard to major methodological challenges, including recall and selection biases. Untangling fact from artefact and examining age, period, and cohort effects will help elucidate profiles of lifetime exposures in older populations.


'Listen to me, tell me': a qualitative study of partnership in care for people with non-specific chronic low back pain.
To investigate and summarize participant experience of exercise programmes for non-specific chronic low back pain and the effects of these experiences on exercise participation and engagement. Three groups of six adults (>18 years) who speak, read and understand English and who had participated in an exercise programme for non-specific chronic low back pain. Qualitative research methods were used and three focus groups were conducted by an experienced facilitator. Each group was guided with a set of pre-determined questions and participants were encouraged to give personal opinions. Transcribed data were read independently by two researchers and analysed thematically according to Grounded Theory. Preference for partnership in care emerged as a significant theme from all focus group transcripts. The following subthemes emerged: (1) engagement with the health care process; (2) 'listen to me; I know my own body'; (3) 'tell me: explain it to me'. People with non-specific chronic low back pain want an active role in their rehabilitation. They expressed anger and frustration at not being listened to, not being provided with adequate explanations and education and not being given credit for knowing their own bodies. Tension existed between patients' wanting a genuine voice in the partnership and them wanting a care-provider to give explicit diagnosis and best management instruction. A gap exists between care-seeker experiences of, and preferences for, exercise programmes for back pain. Care-seekers consider that care-providers should adopt a willingness to listen and consider care-seeker's experiences when designing exercise programmes.


Systematic review of the relationship between quick returns in rotating shift work and health-related outcomes.
A systematic literature search was carried out to investigate the relationship between quick returns (i.e., 11.0 hours or less between two consecutive shifts) and outcome measures of health, sleep, functional ability and work-life balance. A total of 22 studies published in 21 articles were included. Three types of quick returns were differentiated (from evening to morning/day, night to evening, morning/day to night shifts) where sleep duration and sleepiness appeared to be differently affected depending on which shifts the quick returns occurred between. There were some indications of detrimental effects of quick returns on proximate problems (e.g., sleep, sleepiness and fatigue), although the evidence of associations with more chronic outcome measures (physical and mental health and work-life balance) was inconclusive. Modern societies are dependent on people working shifts. This study systematically reviews literature on the consequences of quick returns (11.0 hours or less between two shifts). Quick returns have detrimental effects on acute health problems. However, the evidence regarding effects on chronic health is inconclusive.


50 Years of Pediatric Hemostasis: Knowledge, Diagnosis, and Treatment.
Studies from the past 50 years have contributed to the expanding knowledge regarding developmental hemostasis. This is a dynamic process that begins in the fetal phase and is characterized by physiological variations in platelet counts and function, and concentrations of most coagulation factors and the native coagulation inhibitors in early life, as compared with adulthood. The developmental hemostasis studies since the 1980 to 1990s established the laboratory reference values for coagulation factors. It was only a decade or two later, that thromboelastography (TEG) or (rotational thromboelastometry [ROTEM]) as well as thrombin generation studies, provided special pediatric reference values along with the ability to evaluate clot formation and lysis. In addition, global whole blood-based clotting assays provided point of care guidance for proper transfusion support to children hospitalized in intensive care units or undergoing surgery. Although uncommon, thrombosis in children and neonates is gaining increasing recognition, typically as a secondary complication in sick children. Bleeding in children, and particularly intracerebral hemorrhage in newborns, still represent a therapeutic challenge. Notably, our review will outline the advancements in understanding developmental hemostasis and its manifestations, with respect to the pathophysiology of thrombosis and bleeding complications in young children. The changes of transfusion policy and approach to thrombophilia testing during the last decade will be mentioned. Subsequently, a brief summary of the data on anticoagulant treatments in pediatric patients will be presented. Finally, we will point out the 10 most cited articles in the field of pediatric and neonatal hemostasis.


Dimethyl Sulfoxide Complexes Detected at Ambient Conditions.
Dimethyl sulfoxide (DMSO) is an important intermediate in the atmospheric oxidation of dimethyl sulfide (DMS). DMS, emitted from the ocean, is the main natural sulfur source, and its oxidation products are essential in the formation of sulfate aerosols. The high atmospheric concentration of water makes hydrogen bonding with DMS and its oxidation products likely. Through hydrogen bonding, water can potentially catalyze and affect the steps of the oxidation. We investigate binary hydrogen-bound complexes involving DMSO. Both water·DMSO and methanol·DMSO complexes are identified in an Ar matrix, and at room temperature, a Gibbs free energy of 0.7 kJ/mol for the formation of the methanol·DMSO complex is determined. Assuming a similar Gibbs free energy of the hydrate, it would suggest a relatively high abundance of the DMSO hydrate relative to the monomer in the atmosphere. The effect of changing the atom divalently bound to the hydrogen bond accepting oxygen, from S to C (DMSO to acetone), is found to significantly decrease the equilibrium constant of complex formation.


Populations at high alcoholism risk: recent findings.
This article reviews recent studies of men at high risk for the future development of alcoholism. The most promising differences between young men with and without a family history of this disorder include a decreased intensity of reaction to ethanol for sons of alcoholics compared with control subjects, a decreased amplitude of the P300 wave of the event-related potential, and a different pattern of background cortical electroencephalograms (alpha waves) for subjects at high risk for future alcoholism. The implications of these and other findings and their possible future impact on the clinical practice are discussed.


Standardization of 8-color flow cytometry across different flow cytometer instruments: A feasibility study in clinical laboratories in Switzerland.
The EuroFlow Consortium developed a fully standardized flow cytometric approach from instrument settings, through antibody panel, reagents and sample preparation protocols, to data acquisition and analysis. The Swiss Cytometry Society (SCS) promoted a study to evaluate the feasibility of using such standardized measurements of 8-color data across two different flow cytometry platforms - Becton Dickinson (BD) FACSCanto II and Beckman Coulter (BC) Navios, aiming at increasing reproducibility and inter-laboratory comparability of immunophenotypic data in clinical laboratories in Switzerland. The study was performed in two phases, i.e. a learning phase (round 1) and an analytical phase (rounds 2 and 3) consisting of a total of three rounds. Overall, 10 laboratories using BD FACSCanto II (n=6) or BC Navios (n=4) flow cytometers participated. Each laboratory measured peripheral blood samples from healthy donors stained with a uniform antibody panel of reagents - EuroFlow Lymphoid Screening Tube (LST) - applying the EuroFlow standardized protocols for instrument setup and sample preparation (www.EuroFlow.org). All data files were analyzed centrally and median fluorescence intensity (MedFI) values for individual markers on defined lymphocyte subsets were recorded; variability from reference MedFI values was assessed using performance scores. Data troubleshooting and discussion of the results with the participants followed after each round at SCS meetings. The results of the learning phase demonstrated that standardized instrument setup and data acquisition are feasible in routine clinical laboratories without previous experience with EuroFlow. During the analytical phase, highly comparable data were obtained at the different laboratories using either BD FACSCanto II or BC Navios. The coefficient of variation of MedFI for 7 of 11 markers performed repeatedly below 30%. In the last study round, 89% of participants scored over 90% MedFI values within the acceptance criteria (P-score), in line with the results of the EuroFlow quality assessment rounds performed by the EuroFlow expert laboratories(Kalina et al., 2015). Central analysis of data allowed identification of deviations from the standardized procedures and technical issues (e.g. failure to perform correct instrument setup and improper compensation). In summary, here we show that inter-laboratory cross-platform standardization of 8-color flow cytometric measurements in clinical laboratories is feasible and allows for fully comparable MedFI results across BD FACSCanto II and BC Navios instruments. However, adherence to standardized protocols is crucial. Thus, training of the laboratory personnel in the EuroFlow standardized procedures is highly recommended to prevent errors in instrument setup and sample preparation.


Global estimates of syphilis in pregnancy and associated adverse outcomes: analysis of multinational antenatal surveillance data.
The World Health Organization initiative to eliminate mother-to-child transmission of syphilis aims for ≥ 90% of pregnant women to be tested for syphilis and ≥ 90% to receive treatment by 2015. We calculated global and regional estimates of syphilis in pregnancy and associated adverse outcomes for 2008, as well as antenatal care (ANC) coverage for women with syphilis. Estimates were based upon a health service delivery model. National syphilis seropositivity data from 97 of 193 countries and ANC coverage from 147 countries were obtained from World Health Organization databases. Proportions of adverse outcomes and effectiveness of screening and treatment were from published literature. Regional estimates of ANC syphilis testing and treatment were examined through sensitivity analysis. In 2008, approximately 1.36 million (range: 1.16 to 1.56 million) pregnant women globally were estimated to have probable active syphilis; of these, 80% had attended ANC. Globally, 520,905 (best case: 425,847; worst case: 615,963) adverse outcomes were estimated to be caused by maternal syphilis, including approximately 212,327 (174,938; 249,716) stillbirths (>28 wk) or early fetal deaths (22 to 28 wk), 91,764 (76,141; 107,397) neonatal deaths, 65,267 (56,929; 73,605) preterm or low birth weight infants, and 151,547 (117,848; 185,245) infected newborns. Approximately 66% of adverse outcomes occurred in ANC attendees who were not tested or were not treated for syphilis. In 2008, based on the middle case scenario, clinical services likely averted 26% of all adverse outcomes. Limitations include missing syphilis seropositivity data for many countries in Europe, the Mediterranean, and North America, and use of estimates for the proportion of syphilis that was "probable active," and for testing and treatment coverage. Syphilis continues to affect large numbers of pregnant women, causing substantial perinatal morbidity and mortality that could be prevented by early testing and treatment. In this analysis, most adverse outcomes occurred among women who attended ANC but were not tested or treated for syphilis, highlighting the need to improve the quality of ANC as well as ANC coverage. In addition, improved ANC data on syphilis testing coverage, positivity, and treatment are needed. Please see later in the article for the Editors' Summary.


Distribution of 109Cd in the nervous system of rats after intravenous injection.
The distribution of intravenously injected 109Cd in the nervous system was studied in rats twenty-four hr and one week after the injection. Measurements by gamma scintillation showed a high uptake of cadmium in peripheral sensory and autonomic ganglia whereas the uptake was low in the brain, cerebellum and spinal cord. The accumulation of cadmium in the sciatic nerve was significantly higher than in the brain and spinal nerve roots but lower than in ganglia. Autoradiography confirmed that there was no uptake of cadmium in the major part of the brain parenchyma, but showed an accumulation of the metal in areas outside the blood-brain barrier such as the hypophysis, meninges, choroid plexus and pineal gland. Within the peripheral nervous system, the autoradiography showed a localization of cadmium to dorsal root ganglia and, in addition, an uptake was seen in the connective tissue sheaths surrounding the sciatic nerve. The results indicate that the uptake of cadmium is correlated to regional variations in the permeability of blood vessels. The accumulation of cadmium in certain nervous structures may explain some of the neurotoxicological effects which have been demonstrated in animal experiments.


Carriers of an apolipoprotein E epsilon 4 allele are more vulnerable to a dietary deficiency in omega-3 fatty acids and cognitive decline.
Carriers of an epsilon 4 allele (E4) of apolipoprotein E (APOE) develop Alzheimer's disease (AD) earlier than carriers of other APOE alleles. The metabolism of plasma docosahexaenoic acid (DHA, 22:6n-3), an omega-3 fatty acid (n-3 FA), taken up by the brain and concentrated in neurons, is disrupted in E4 carriers, resulting in lower levels of brain DHA. Behavioural and cognitive impairments have been observed in animals with lower brain DHA levels, with emphasis on loss of spatial memory and increased anxiety. E4 mice provided a diet deficient in n-3 FA had a greater depletion of n-3 FA levels in organs and tissues than mice carrying other APOE alleles. However, providing n-3 FA can restore levels of brain DHA in E4 animals and in other models of n-3 FA deficiency. In E4 carriers, supplementation with DHA as early as possible might help to prevent the onset of AD and could halt the progression of, and reverse some of the neurological and behavioural consequences of their higher vulnerability to n-3 FA deficiency.


A telemedicine-based approach with real-time transmission of blood glucose data improves metabolic control in insulin-treated diabetes: the DIAMONDS randomized clinical trial.
To evaluate if a web-based telemedicine system (the Glucoonline® system) is effective to improve glucose control in insulin-treated patients with type 1 and type 2 diabetes, as compared to standard of care. This was a prospective, randomized, controlled trial, carried out at three tertiary referral centers for diabetes in Italy. Adults with insulin-treated type 1 and type 2 diabetes, inadequate glycemic control, and no severe diabetes-related complications and/or comorbidities were eligible for this study. Patients were randomized to either perform telemedicine-assisted (Group A) or standard (Group B) self-monitoring blood glucose (SMBG) for 6 months. In Group A, patients received prompt feedback about their blood glucose levels and therapy suggestions from the study staff via phone/SMS, when appropriate. In Group B, patients had no remote assistance from the study staff between planned visits. 123 patients were included in the final analysis. After 6 months, patients achieved a significant reduction in HbA1c in Group A (-0.38%, p < 0.05) but not in Group B (+ 0.08%, p = 0.53). A significant difference in the percentage of patients with HbA1c < 7% between Group A and Group B was found after 3 months (28.6% vs 11.1%, p = 0.02). Also, fewer patients (p < 0.05) with HbA1c > 8.5% were found in Group A vs Group B, respectively, after both 3 months (14.3% vs 35.2%) and 6 months (21.8% vs 42.9%). The use of the Glucoonline™ system resulted in improved metabolic control. Telemedicine services have potential to support diabetes self-management and provide the patients with remote, prompt assistance using affordable technological equipment. Trial registration This study was registered at clinicaltrials.gov (NCT01804803) on March 5, 2013.


The Association of Alzheimer's Disease-related Blood-based Biomarkers with Cognitive Screening Test Performance in the Congolese Population in Kinshasa.
Alzheimer's Disease (AD), the most common cause of dementia, poses a significant global burden. Diagnosis typically involves invasive and costly methods like neuroimaging or cerebrospinal fluid (CSF) biomarker testing of phosphorylated tau (p-tau) and amyloid-β42/40 (Aβ42/40). Such procedures are especially impractical in resource-constrained regions, such as the Democratic Republic of Congo (DRC). Blood-based biomarker testing may provide a more accessible screening opportunity. This study aims to examine if AD-related blood-based biomarkers are associated with cognitive test performance in the Congolese population, where limited research has been conducted. In this cross-sectional study of 81 Congolese individuals, cognitive assessments (Alzheimer's Questionnaire (AQ) and Community Screening Interview for Dementia (CSID)) distinguished dementia cases from controls. Blood draws were taken to assess p-tau 181 and Aβ42/40 biomarkers. Relationships between the biomarkers and cognitive performance were analyzed using multiple linear regression models. Lower plasma Aβ42/40 was significantly associated with lower CSID scores and higher AQ scores, indicative of AD (p<0.001). These relationships were observed in healthy controls (CSID p=0.01, AQ p=0.03), but not in dementia cases. However, p-tau 181 did not exhibit significant associations with either measure. Factors such as age, sex, education, presence of APOE e4 allele, did not alter these relationships. Understanding relationships between AD-related screening tests and blood-biomarkers is a step towards utilization of blood-based biomarker tests as a screening tool for AD, especially in resource-limited regions. Further research should be conducted to evaluate blood biomarker test efficacy in larger samples and other populations.


Conversion of a chaperonin GroEL-independent protein into an obligate substrate.
Chaperones assist protein folding by preventing unproductive protein aggregation in the cell. In Escherichia coli, chaperonin GroEL/GroES (GroE) is the only indispensable chaperone and is absolutely required for the de novo folding of at least ∼60 proteins. We previously found that several orthologs of the obligate GroE substrates in Ureaplasma urealyticum, which lacks the groE gene in the genome, are E. coli GroE-independent folders, despite their significant sequence identities. Here, we investigated the key features that define the GroE dependence. Chimera or random mutagenesis analyses revealed that independent multiple point mutations, and even single mutations, were sufficient to confer GroE dependence on the Ureaplasma MetK. Strikingly, the GroE dependence was well correlated with the propensity to form protein aggregates during folding. The results reveal the delicate balance between GroE dependence and independence. The function of GroE to buffering the aggregation-prone mutations plays a role in maintaining higher genetic diversity of proteins.


Predictable factors for lymph node metastasis in early gastric cancer analysis of clinicopathologic factors and biological markers.
Predicting lymph node metastasis (LNM) accurately is very important to decide treatment strategies preoperatively. The aim of this study was to explore risk factors that predict the presence of LNM in early gastric cancer (EGC). A total of 230 patients with EGC who underwent curative gastrectomy with lymph adenectomy at Xinhua Hospital from January 2006 to July 2014 were retrospectively reviewed. We studied the relationship between clinicopathological factors, biological markers (p53, ki67, nm23, vascular endothelial growth factor (VEGF), epidermal growth factor receptor (EGFR), E-cadherin (E-cad), beta-catenin (b-catenin), glutathione S-transferase (GST), and topoisomerase II (Topo II)), and LNM of EGC patients by chi-square test and logistic regression analysis. Meta-analyses were further conducted to review the effects of the proteins (P53, ki67, E-cad, and b-catenin) on LNM in ECG patients. LNM was detected in 42 (18.3 %) of 230 patients. Incidences of LNM was distinct in different tumor size (p = 0.044), depth of submucosal invasion (p < 0.0001), and P53 overexpression (p = 0.004). Multivariate analysis further indentified that large tumor size (≥20 mm, odds ratio (OR) = 2.168, p = 0.041), submucosa (OR = 4.000, p = 0.0005), and P53 overexpression (OR = 3.010, p = 0.022) were independent risk factors of LNM in EGC patients. The meta-analysis revealed a significantly statistical association of P53, ki67, and b-catenin with an increased risk of LNM in EGC patients (P53, OR = 1.81, p = 0.017; ki67, OR = 2.53, p = 0.0003; b-catenin, OR = 0.53, p = 0.01). Tumor size (≥20 mm), the depth of invasion (submucosa), and P53 overexpression may be helpful predictors of LNM in EGC patients. Furthermore, the results of meta-analysis revealed that P53, ki67 overexpression, and abnormal expression of b-catenin may be associated with LNM in EGC. The results need further validation in single large studies.


DYRK-family kinases regulate Candida albicans morphogenesis and virulence through the Ras1/PKA pathway.
Candida albicans is an opportunistic human fungal pathogen that frequently causes life-threatening infections in immunocompromised individuals. To cause disease, the fungus employs several virulence traits, including its ability to transition between yeast and filamentous states. Previous work identified a role for the kinase Yak1 in regulating C. albicans filamentation. Here, we demonstrate that Yak1 regulates morphogenesis through the canonical cAMP/PKA pathway and that this regulation is environmentally contingent, as host-relevant concentrations of CO2 bypass the requirement of Yak1 for C. albicans morphogenesis. We show a related kinase, Pom1, is important for filamentation in the absence of Yak1 under these host-relevant conditions, as deletion of both genes blocked filamentous growth under all conditions tested. Finally, we demonstrate that Yak1 is required for filamentation in a mouse model of C. albicans dermatitis using genetic and pharmacological approaches. Overall, our results expand our understanding of how Yak1 regulates an important virulence trait in C. albicans.


A role for the cerebellum in the control of verbal interference: Comparison of bilingual and monolingual adults.
We evaluate brain structure sensitivity to verbal interference in a sentence interpretation task, building on previously reported evidence that those with better control of verbal interference show higher grey matter density in the posterior paravermis of the right cerebellum. We compare brain structure sensitivity to verbal interference control across two groups, English monolingual (N = 41) and multilingual (N = 46) adults. Using voxel-based morphometry, our primary goal was to identify and explore differences in regional patterns of grey matter sensitivity to performance on the sentence interpretation task, controlling for group variability in age, nonverbal reasoning and vocabulary knowledge. There was no group difference in performance but there was a significant group effect in grey matter sensitivity to task performance in our region of interest: stronger sensitivity in the paravermis in bilinguals compared to monolinguals in accuracy performance in the high (relative to low) verbal interference condition. This effect was observed when the linguistic interference was presented in an unfamiliar language (Greek) but not when presented in the familiar language (English). Our findings suggest that multilanguage acquisition mediates regional involvement within the language network, conferring enhanced functional plasticity within structures (including the paravermis) in the service of control of linguistic interference.


Recessive lethal mutations and the maintenance of duplication-bearing strains of Dictyostelium discoideum.
Recessive lethal mutations have been isolated and used to maintain n + 1 aneuploid strains of Dictyostelium discoideum carrying a duplication of part or all of linkage group VII. The recessive lethal mutations, relA351 and relB352, arose spontaneously in diploids; no mutagenic treatment was used in the isolation of these mutations. The probable gene order on linkage group VII is: centromere, relB couA, bsgB, cobA, relA. Maintenance of aneuploids disomic for linkage group VII was made possible by complementation of a rel mutation on each linkage group VII homologue by the corresponding wild-type allele on the other linkage group VII homologue. The duplication-bearing disomic strains were slow-growing and produced faster-growing sectors on the colony edge. Haploid sectors probably arise by a combination of mitotic recombination and subsequent loss of one homologue, diploid sectors may be formed by chromosome doubling to 2n + 2, followed by chromosome loss to return to 2n, and aneuploid sectors may arise by deletion or new mutation.


CIRCADIAN CLOCK ASSOCIATED1 and LATE ELONGATED HYPOCOTYL function synergistically in the circadian clock of Arabidopsis.
The circadian clock is an endogenous mechanism that coordinates biological processes with daily and seasonal changes in the environment. Heterodimerization of central clock components is an important way of controlling clock function in several different circadian systems. CIRCADIAN CLOCK ASSOCIATED1 (CCA1) and LATE ELONGATED HYPOCOTYL (LHY) are Myb-related proteins that function in or close to the central oscillator in Arabidopsis (Arabidopsis thaliana). Single mutants of cca1 and lhy have a phenotype of short-period rhythms. cca1 lhy double mutants show an even shorter period phenotype than the cca1 single mutant, suggesting that CCA1 and LHY are only partially functionally redundant. To determine whether CCA1 and LHY act in parallel or synergistically in the circadian clock, we examined their expression in both light-grown and etiolated seedlings. We have shown that LHY and CCA1 bind to the same region of the promoter of a Light-harvesting chlorophyll a/b protein (Lhcb, also known as CAB). CCA1 and LHY can form homodimers, and they also colocalize in the nucleus and heterodimerize in vitro and in vivo. In Arabidopsis, CCA1 and LHY physically interact in a manner independent of photoperiod. Moreover, results from gel filtration chromatography indicate that CCA1 and LHY are present in the same large complex in plants. Taken together, these results imply that CCA1 and LHY function synergistically in regulating circadian rhythms of Arabidopsis.


Localization of type VI collagen in tissue-engineered cartilage on polymer scaffolds.
Together, the chondrocyte and its pericellular matrix have been collectively termed the chondron. Current opinion is that the pericellular matrix has both protective and signalling functions between chondrocyte and extracellular matrix. Formation of a native chondrocyte pericellular matrix or chondron structure might therefore be advantageous when tissue engineering a functional hyaline cartilage construct. The presence of chondrons has not been previously described in cartilage engineered on a scaffold. In this paper, we describe a modified immunochemical method to detect collagen VI, a key molecular marker for the pericellular matrix, and an investigation of type VI collagen distribution in engineered hyaline cartilage constructs. Cartilage constructs were engineered from adult human or bovine hyaline chondrocytes cultured on sponge or nonwoven fiber based HYAFF 11 scaffolds. Type VI collagen was detected in all constructs, but a distinctive, high-density, chondron-like distribution of collagen VI was present only in constructs exhibiting additional features of hyaline cartilage engineered using nonwoven HYAFF 11. Chondron structures were localized in areas of the extracellular matrix displaying strong collagen II and GAG staining of constructs where type II collagen composed a high percentage (over 65%) of the total collagen.


Are our people health conscious? Results of a patients survey in Karachi, Pakistan.
Life style is known to influence health and may be responsible for certain diseases. There is a need to document the life style on health among the Pakistani population. The study was conducted on patients visiting the Family Practice Center, the Aga Khan University, Karachi. A questionnaire was used to collect information on the demographic profile, and the life style on health. The ethical requirements for conducting the study were met. 393 patients were surveyed. The majority were young married men, in either private or government service. Preference for consumption of fats/oils, sweets, spicy foods, salt, fruits/vegetables, tea, coffee, cola drinks and alcohol was found among 103 (26%), 84 (22%), 86 (22%), 110 (28%), 239 (61%), 319 (81%), 117 (30%), 253 (64%) and 13 (03%) respondents respectively. Hand washing after defecation, before eating food and after work was seen among 341 (87%), 296 (75%) and 256 (65%) respondents respectively. Brushing of teeth after eating food, before breakfast and bedtime was seen in 56 (14%), 346 (88%) and 176 (45%) respondents respectively. Preventive dental check-up was practiced by 102 (26%) of the respondents. Sleep of less than 6 hours per day among 74 (19%), water consumption of less than 1 liter daily among 84 (21%) and fish consumption on once a week basis among 173 (44%) respondents was found. Tobacco and betel nuts use was found among 69 (17%) and 79 (20%) respondents. We have documented a clear need to raise public awareness on the issue of life style on health. There is a need and we strongly recommend debate and further research, along with interventional strategies in line with the available evidence on healthy life style.


Combined Plaque Incision, Buccal Mucosa Grafting, and Additional Tunica Albuginea Plication for Peyronie's Disease.
Surgery remains the gold standard for treatment in stable patients with penile deformity associated to Peyronie's disease (PD). To evaluate the long-term results of plaque incision and buccal mucosa grafting (BMG), with or without additional tunica albuginea plication (TAP), in the correction of severe penile curvatures secondary to PD. 72 patients with severe curvature caused by PD, normal erections, and stable disease entered this prospective study. Preoperatively, they underwent penile duplex ultrasounds with measurement of curvature and length of affected side. All procedures were carried out by 1 surgeon. Patients were seen at 1, 3, 6, and 12 months postoperatively, then yearly. Subjective outcome was assessed by the Sexual Encounter Profile (SEP) questionnaire, and objective outcome was assessed by an intracavernous injection (ICI) test performed within the first year for evaluating penile rigidity, straightness, and length. Long-term outcomes include penile straightening, penile shortening, and sexual satisfaction. Mean curvature was 71.32 ± 17.6° (range 40-110); 33 (45.8%) patients had a 2-sided curvature with a mean second curvature of 33.79 ± 12.2° (range 10-60). Additional TAP was needed in 60% of patients for complete straightening or graft stretching. All patients resumed unassisted intercourse 1 month after surgery; 4 (5.5%) refused follow-up, claiming excessive penile shortening. In the remaining 68, the ICI test showed no recurvature, shortening, or de novo erectile dysfunction. At mean follow-up of 62.01 ± 34.3 months (range 12-135), all were able to obtain an erection (SEP-1), 97.1% to penetrate (SEP-2), and 89.7% to successfully complete intercourse (SEP-3); 80.9% of them were satisfied with erection hardness (SEP-4) and 86.8% were overall satisfied (SEP-5), with the main reason for dissatisfaction being expectation of better length and rigidity. BMG, with or without TAP, provides excellent long-term results and is safe and reproducible, representing a valuable treatment option for PD, but great care should be taken in patient counseling to avoid unrealistic expectations. Cormio L, Mancini V, Massenio P. Combined Plaque Incision, Buccal Mucosa Grafting, and Additional Tunica Albuginea Plication for Peyronie's Disease. Sex Med 2019;7:48-53.


[Description of the process of preparation and response of local health authorities facing the introduction of the Chikungunya virus in Colombia, 2014].
Objective To describe the process of preparation and response of local health authorities in key public health issues while facing the introduction stage of an unusual virus: Chikungunya in Colombia in 2014. Methods A cross-sectional study was conducted using a survey that was developed for this study and sent to Public Health coordinators and to the person in charge of vector borne-diseases in the country's territorial entities. Results 23 out of the 35 territories at risk from the transmission of Chikungunya agreed to answer the survey. A global review of the survey scores for each evaluated section shows better performances in the areas of knowledge management, comprehensive patient care, epidemiological intelligence, and health promotion. According to the results of this study, the epidemiological surveillance system during the Chikungunya epidemic had a low acceptability and flexibility, possibly contributing to the underreporting of cases. Conclusions In general, knowledge and implementation by local authorities of the Integrated Health Strategy- EGI (Estrategia de Gestión Integral, by its Spanish acronym)- for vector-borne diseases was evident from the themes evaluated in this study. However, it is necessary to reinforce the communication of risks, laboratory, and outbreak and contingencies management areas faced during the introduction of new viruses.


Long-term treatment outcomes of depression with associated anxiety: efficacy of continuation treatment with fluoxetine.
Severity of anxiety does not appear to influence the antidepressant response to fluoxetine during acute treatment of major depressive disorder (MDD). We report a retrospective pooled analysis of 2 studies to assess the effect of associated anxiety on the efficacy of fluoxetine in the continuation treatment phase of MDD. Patients whose MDD remitted (study 1) or responded (study 2) after approximately 12 to 13 weeks of open-label treatment with fluoxetine 20 mg daily were randomly assigned in double-blind fashion to placebo, continued treatment with fluoxetine 20 mg daily, or, in study 2 only, treatment with enteric-coated fluoxetine 90 mg once weekly, for at least 25 weeks. Both studies included male and female outpatients who met criteria for MDD as assessed by DSM-III-R (study 1) or DSM-IV (study 2). Patients were categorized into high anxiety (> or = 7) or low anxiety (< 7) subgroups based on baseline Hamilton Rating Scale for Depression (HAM-D) anxiety/somatization subfactor scores. Subgroups were compared by therapy for time from randomization to relapse and change in efficacy scores. No significant differences in time to relapse were observed between anxiety subgroups in either active treatment group. However, in patients switched to placebo for continuation treatment, the high anxiety subgroup had a significantly higher risk of relapse than those with low anxiety (risk ratio = 1.63, p =.013). Significant differences between anxiety groups were seen in change in HAM-D anxiety/somatization subfactor scores in the fluoxetine 20 mg and placebo treatment groups, and in change in HAM-D-17 scores in the placebo treatment group (p <.05). Although high baseline anxiety does not appear to impact the benefit of continuation therapy with fluoxetine, it does appear to predict increased risk of relapse in individuals who do not remain on antidepressant therapy for the duration of continuation treatment.


Can a gait-dependent model predict wear on retrieved total knee arthroplasty components?
A retrospective longitudinal study was conducted to compare directly volumetric wear of retrieved polyethylene inserts to predicted volumetric wear modelled from individual gait mechanics of total knee arthroplasty (TKA) patients. In total, 11 retrieved polyethylene tibial inserts were matched with gait analysis testing performed on those patients. Volumetric wear on the articular surfaces was measured using a laser coordinate measure machine and autonomous reconstruction. Knee kinematics and kinetics from individual gait trials drove computational models to calculate medial and lateral tibiofemoral contact paths and forces. Sliding distance along the contact path, normal forces and implantation time were used as inputs to Archard's equation of wear to predict volumetric wear from gait mechanics. Measured and modelled wear were compared for each component. Volumetric wear rates on eight non-delaminated components measured 15.9 mm3/year (standard error (SE) ± 7.7) on the total part, 11.4 mm3/year (SE ± 6.4) on the medial side and 4.4 (SE ± 2.6) mm3/year on the lateral side. Volumetric wear rates modelled from patient gait mechanics predicted 16.4 mm3/year (SE 2.4) on the total part, 11.7 mm3/year (SE 2.1) on the medial side and 4.7 mm3/year (SE 0.4) on the lateral side. Measured and modelled wear volumes correlated significantly on the total part (p = 0.017) and the medial side (p = 0.012) but not on the lateral side (p = 0.154). In the absence of delamination, patient-specific knee mechanics during gait directly affect wear of the tibial component in TKA. Cite this article: Bone Joint J 2020;102-B(6 Supple A):129-137.


Qigong and hypertension: a critique of research.
Research studies have pointed to various health-related positive effects of qigong; however, problems in much of the current qigong research methodology have limited interpretation of the potential benefits of qigong. Examples of research on qigong and hypertension are used to bring to light some of these methodological issues. In a review of 30 representative studies, various areas of concern are addressed, including: the sources of studies, lack of random assignment, selection biases, treatment effects, placebo response issues, expectancy biases, blinded outcome assessment, adherence to treatment, reliability of blood pressure measurements, regression to the mean, publication biases, and lack of consistency of measurement. One of the longest term studies, conducted by Kuang et al. (1991) and updated by Wang et al. (1993) is examined in greater detail to illustrate these issues. This study took place over 20 years and reported significant differences between a group practicing qigong and a control group in a variety of measures including a reduction of total mortality rate. The weight of evidence suggests that practicing qigong may have a positive effect on hypertension. Whether qigong alone can affect hypertension is not necessarily the most important question. Further research will be required to better assess and understand the effect of adding qigong into an integrated, multifaceted program that selectively incorporates diet, moderate aerobic exercise, relaxation training, and social and psychological dimensions.


Photoinduced Domain Pattern Transformation in Ferroelectric-Dielectric Superlattices.
The nanodomain pattern in ferroelectric-dielectric superlattices transforms to a uniform polarization state under above-band-gap optical excitation. X-ray scattering reveals a disappearance of domain diffuse scattering and an expansion of the lattice. The reappearance of the domain pattern occurs over a period of seconds at room temperature, suggesting a transformation mechanism in which charge carriers in long-lived trap states screen the depolarization field. A Landau-Ginzburg-Devonshire model predicts changes in lattice parameter and a critical carrier concentration for the transformation.


Commensal Microbiota Enhance Both Osteoclast and Osteoblast Activities.
Recent studies suggest that the commensal microbiota affects not only host energy metabolism and development of immunity but also bone remodeling by positive regulation of osteoclast activity. However, the mechanism of regulation of bone cells by the commensal microbiota has not been elucidated. In this study, 8-week-old specific pathogen-free (SPF) and germ-free (GF) mice were compared in terms of alveolar bones and primary osteoblasts isolated from calvarias. Micro-CT analysis showed that SPF mice had larger body size associated with lower bone mineral density and bone volume fraction in alveolar bones compared with GF mice. Greater numbers of osteoclasts in alveolar bone and higher serum levels of tartrate-resistant acid phosphatase 5b were observed in SPF mice. Tissue extracts from SPF alveolar bone showed higher levels of cathepsin K, indicating higher osteoclast activity. SPF alveolar extracts also showed elevated levels of γ-carboxylated glutamic acid⁻osteocalcin as a marker of mature osteoblasts compared with GF mice. Polymerase chain reaction (PCR) array analysis of RNA directly isolated from alveolar bone showed that in SPF mice, expression of mRNA of osteocalcin, which also acts as an inhibitor of bone mineralization, was strongly enhanced compared with GF mice. Cultured calvarial osteoblasts from SPF mice showed reduced mineralization but significantly enhanced expression of mRNAs of osteocalcin, alkaline phosphatase, insulin-like growth factor-I/II, and decreased ratio of osteoprotegerin/receptor activator of nuclear factor-kappa B ligand compared with GF mice. Furthermore, PCR array analyses of transcription factors in cultured calvarial osteoblasts showed strongly upregulated expression of Forkhead box g1. In contrast, Gata-binding protein 3 was strongly downregulated in SPF osteoblasts. These results suggest that the commensal microbiota prevents excessive mineralization possibly by stimulating osteocalcin expression in osteoblasts, and enhances both osteoblast and osteoclast activity by regulating specific transcription factors.


Glycyrrhizic acid ameliorates submandibular gland oxidative stress, autophagy and vascular dysfunction in rat model of type 1 diabetes.
The burden of diabetes mellitus (DM) and associated complications is increasing worldwide, affecting many organ functionalities including submandibular glands (SMG). The present study aims to investigate the potential ameliorative effect of glycyrrhizic acid (GA) on diabetes-induced SMG damage. Experimental evaluation of GA treatment was conducted on a rat model of type I diabetes. Animals were assigned to three groups; control, diabetic and GA treated diabetic groups. After 8 weeks, the SMG was processed for assessment of oxidative stress markers, autophagy related proteins; LC3, Beclin-1 and P62, vascular regulator ET-1, aquaporins (AQPs 1.4 and 5), SIRT1 protein expressions in addition to LC3 and AQP5 mRNA expressions. Also, parenchymal structures of the SMG were examined. GA alleviated the diabetes-induced SMG damage via restoring the SMG levels of oxidative stress markers and ET-1 almost near to the normal levels most probably via regulation of SIRT1, AQPs and accordingly LC-3, P62 and Beclin-1levels. GA could be a promising candidate for the treatment of diabetes-induced SMG damage via regulating oxidative stress, autophagy and angiogenesis.


Structure and composition of insulin fibril surfaces probed by TERS.
Amyloid fibrils associated with many neurodegenerative diseases are the most intriguing targets of modern structural biology. Significant knowledge has been accumulated about the morphology and fibril-core structure recently. However, no conventional methods could probe the fibril surface despite its significant role in the biological activity. Tip-enhanced Raman spectroscopy (TERS) offers a unique opportunity to characterize the surface structure of an individual fibril due to a high depth and lateral spatial resolution of the method in the nanometer range. Herein, TERS is utilized for characterizing the secondary structure and amino acid residue composition of the surface of insulin fibrils. It was found that the surface is strongly heterogeneous and consists of clusters with various protein conformations. More than 30% of the fibril surface is dominated by β-sheet secondary structure, further developing Dobson's model of amyloid fibrils (Jimenez et al. Proc. Natl. Acad. Sci. U.S.A. 2002, 99, 9196-9201). The propensity of various amino acids to be on the fibril surface and specific surface secondary structure elements were evaluated. β-sheet areas are rich in cysteine and aromatic amino acids, such as phenylalanine and tyrosine, whereas proline was found only in α-helical and unordered protein clusters. In addition, we showed that carboxyl, amino, and imino groups are nearly equally distributed over β-sheet and α-helix/unordered regions. Overall, this study provides valuable new information about the structure and composition of the insulin fibril surface and demonstrates the power of TERS for fibril characterization.


Were the English sweating sickness and the Picardy sweat caused by hantaviruses?
The English sweating sickness caused five devastating epidemics between 1485 and 1551, England was hit hardest, but on one occasion also mainland Europe, with mortality rates between 30% and 50%. The Picardy sweat emerged about 150 years after the English sweat disappeared, in 1718, in France. It caused 196 localized outbreaks and apparently in its turn disappeared in 1861. Both diseases have been the subject of numerous attempts to define their origin, but so far all efforts were in vain. Although both diseases occurred in different time frames and were geographically not overlapping, a common denominator could be what we know today as hantavirus infections. This review aims to shed light on the characteristics of both diseases from contemporary as well as current knowledge and suggests hantavirus infection as the most likely cause for the English sweating sickness as well as for the Picardy sweat.


Changes in gene expression variability reveal a stable synthetic lethal interaction network in BRCA2-ovarian cancers.
Synthetic lethal interactions (SLIs) are robust mechanisms that provide cells with the ability to remain viable despite having mutations in genes critical to the DNA damage response, a core cellular process. Studies in model organisms such as S. cerevisiae showed that thousands of genes important in maintaining DNA integrity cooperated in a SLI network. Two genes participate in a SLI when a mutation in one gene has no effect on the cell, but mutations in both interacting genes are lethal. Furthermore in C. elegans, a mutation in a critical gene that is important for development induced a change in expression variability in the synthetic lethal interactor. In cancer, targeting SLIs shows promise in selectively killing cancer cells. For example, targeting PARP1 is an effective treatment for BRCA1/2- breast and ovarian cancers. Although PARP1 is already identified as having a SLI with BRCA1/2-, computationally searching for other genes that cooperate in the SLI network could highlight genes that may have promise for being a cancer-specific drug target. Using RNA sequencing data for ovarian cancer patients with BRCA2 mutations and the R Bioconductor package pathVar, we showed that genes whose expression changes to an invariant, stable expression state are likely candidates for SLIs with BRCA2. Our results highlight the interactions between the genes with predicted SLIs and protein-coding genes that are functionally important in the DNA damage response. The method of analyzing expression variability to computationally identify genes with SLIs can be applied to query SLIs in other tumor types.


Computer-based identification of type 2 diabetic subjects with and without neuropathy using dynamic planter pressure and principal component analysis.
Diabetes is a chronic disease that is characterized by an increased blood glucose level due to insulin resistance. Type 2 diabetes is common in middle aged and old people. In this work, we present a technique to analyze dynamic foot pressures images and classify them into normal, diabetes type 2 with and without neuropathy classes. Plantar pressure images were obtained using the F-Scan (Tekscan, USA) in-shoe measurement system. We used Principal Component Analysis (PCA) and extracted the eigenvalues from different regions of the foot image. The features extracted from region 1 of the foot pressure image, which were found to be clinically significant, were fed into the Fuzzy classifier (Sugeno model) for automatic classification. Our results show that the proposed method is able to identify the unknown class with an accuracy of 93.7%, sensitivity of 100%, and specificity of 83.3%. Moreover, in this work, we have proposed an integrated index using the eigenvalues to differentiate the normal subjects from diabetes with and without neuropathy subjects using just one number. This index will help the clinicians in easy and objective daily screening, and it can also be used as an adjunct tool to cross check their diagnosis.