Non-steroidal anti-inflammatory drugs increase MRP4 expression in an endometriotic epithelial cell line in a PPARa dependent manner.
Endometriosis is a debilitating disease characterized by chronic inflammation. The transporter multidrug resistance-associated protein 4 (MRP4/ABCC4) is expressed in human endometrial tissue; it is overexpressed in ectopic endometrial tissue, and is modulated by the anti-inflammatory lipid Lipoxin A4 (LXA4). Recently, it was demonstrated that aspirin induces platelet MRP4 over-expression, through genomic modulation in megakaryocytes. Since patients with endometriosis frequently use aspirin or other non-aspirin Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), the aim of this study was to verify whether aspirin and other NSAIDs enhance MRP4 expression in 12Z human endometriotic epithelial cells and whether this was peroxisome proliferator-activated receptor alpha (PPARa) dependent. MRP4 and PPARa expression was analyzed by Q-RT-PCR using TaqMan® Master Mix and TaqMan® Assay Reagents (Life Technologies, Monza, Italy) and Western blot. In 12Z cells, aspirin and other NSAIDs enhanced MRP4 mRNA and protein expression; these treatments also induced PPARa expression. Aspirin and diclofenac-induced increases in MRP4 expression were not observed in cells where PPARa was knocked down using siRNA. NSAIDs-induced MRP4 expression was correlated with augmented PGE2 secretion, indicating functional relevance. MRP4 expression was increased in cells treated with NSAIDs and the nuclear receptor PPARa is involved. Elevated PGE2 levels in cell supernatants correlate with its increased transport by MRP4 after NSAID treatment. More importantly, we provide evidence that in endometriotic epithelial cells aspirin and non-aspirin NSAIDs treatments alter gene expression.


A defect of immunoregulatory T cell subsets in systemic lupus erythematosus patients demonstrated with anti-2H4 antibody.
The cell surface phenotype of peripheral blood lymphocytes (PBL) of systemic lupus erythematosus (SLE) patients was characterized with the anti-2H4 monoclonal antibody that defines the human suppressor inducer subset. The T4+2H4+ population of cells has been shown to be critical for the activation of T8+ suppressor cells. Patients with SLE has a markedly decreased percentage of T4+2H4+ cells (13 +/- 2%) in their PBL compared with normal controls (21 +/- 1%) (P less than 0.001). This reduction was greatest in patients with active SLE, especially those with renal disease. Serial analysis of patients with SLE and renal disease showed a correlation between percent positive circulating T4+2H4+ cells and disease activity. Moreover, there was a significant correlation between a low percentage of T4+2H4+ cells and decreased suppressor-inducer function in autologous mixed lymphocyte reaction-activated T4+ cells from SLE patients. Thus, a deficiency exists in SLE patients with active renal disease in the T4+2H4+ suppressor-inducer T cell subset.


Mutations in COL6A3 cause severe and mild phenotypes of Ullrich congenital muscular dystrophy.
Ullrich congenital muscular dystrophy (UCMD) is an autosomal recessive disorder characterized by generalized muscular weakness, contractures of multiple joints, and distal hyperextensibility. Homozygous and compound heterozygous mutations of COL6A2 on chromosome 21q22 have recently been shown to cause UCMD. We performed a genomewide screening with microsatellite markers in a consanguineous family with three sibs affected with UCMD. Linkage of the disease to chromosome 2q37 was found in this family and in two others. We analyzed COL6A3, which encodes the alpha3 chain of collagen VI, and identified one homozygous mutation per family. In family I, the three sibs carried an A-->G transition in the splice-donor site of intron 29 (6930+5A-->G), leading to the skipping of exon 29, a partial reduction of collagen VI in muscle biopsy, and an intermediate phenotype. In family II, the patient had an unusual mild phenotype, despite a nonsense mutation, R465X, in exon 5. Analysis of the patient's COL6A3 transcripts showed the presence of various mRNA species-one of which lacked several exons, including the exon containing the nonsense mutation. The deleted splice variant encodes collagen molecules that have a shorter N-terminal domain but that may assemble with other chains and retain a functional role. This could explain the mild phenotype of the patient who was still ambulant at age 18 years and who showed an unusual combination of hyperlaxity and finger contractures. In family III, the patient had a nonsense mutation, R2342X, causing absence of collagen VI in muscle and fibroblasts, and a severe phenotype, as has been described in patients with UCMD. Mutations in COL6A3 are described in UCMD for the first time and illustrate the wide spectrum of phenotypes which can be caused by collagen VI deficiency.


Blunted erythropoietin production and decreased erythropoiesis in early pregnancy.
After decreasing in the first trimester of pregnancy, the total red blood cell mass increases in the second and third trimesters to peak at term at about 120% to 125% of nonpregnant values, but how this is brought about by changes in the rate of erythropoiesis is not known. We evaluated erythropoiesis by measuring serum transferrin receptor (TfR) levels in 406 women during normal pregnancy (N = 317), at delivery (N = 63), or in the early postpartum (N = 27). Despite the presence of the placenta and the frequent occurrence of iron deficiency, TfR levels remained low in the first two trimesters and increased in the third trimester and at delivery. To explain why erythropoiesic activity was relatively low in early pregnancy, we also measured serum immunoreactive erythropoietin (Epo) in relation to the degree of anemia. There was a very strong correlation between serum TfR and Epo levels in the entire group (r = .59, P less than .0001) as well as in each period of pregnancy. Epo levels remained low for the degree of anemia and did not correlate with hematocrit in the first two trimesters, but recovered afterwards. In the early postpartum, Epo production and erythropoiesis were normal. We conclude that: (1) erythropoiesis is decreased in the first part of pregnancy but increases afterwards; and (2) blunted Epo production in early pregnancy could be responsible for that observation.


Exfoliated epithelial cell transcriptome reflects both small and large intestinal cell signatures in piglets.
Assessing intestinal development and host-microbe interactions in healthy human infants requires noninvasive approaches. We have shown that the transcriptome of exfoliated epithelial cells in feces can differentiate breast-fed and formula-fed infants and term and preterm infants. However, it is not fully understood which regions of the intestine that the exfoliated cells represent. Herein, the transcriptional profiles of exfoliated cells with that of the ileal and colonic mucosa were compared. We hypothesized that exfoliated cells in the distal colon would reflect mucosal signatures of more proximal regions of the gut. Two-day-old piglets (n = 8) were fed formulas for 20 days. Luminal contents and mucosa were collected from ileum (IL), ascending colon (AC), and descending (DC) colon, and mRNA was extracted and sequenced. On average, ∼13,000 genes were mapped in mucosal tissues and ∼10,000 in luminal contents. The intersection of detected genes between three mucosa regions and DC exfoliome indicated an approximately 99% overlap. On average, 49% of the genes in IL, AC, and DC mucosa were present in the AC and DC exfoliome. Genes expressed predominantly in specific anatomic sites (stomach, pancreas, small intestine, colon) were detectable in exfoliated cells. In addition, gene markers for all intestinal epithelial cell types were expressed in the exfoliome representing a diverse array of cell types arising from both the small and large intestine. Genes were mapped to nutrient absorption and transport and immune function. Thus, the exfoliome represents a robust reservoir of information in which to assess intestinal development and responses to dietary interventions.NEW & NOTEWORTHY The transcriptome of exfoliated epithelial cells in stool contain gene signatures from both small and large intestinal mucosa affording a noninvasive approach to assess gut health and function.


Limited effect of structured medication report as the only intervention at discharge from hospital.
To investigate whether a structured medication report at discharge from the hospital could reduce the number of medication discrepancies in primary care. The study was performed as an open, randomised controlled study including patients transferred from one hospital in Norway to nursing home or home care. Both groups received epicrisis on discharge. In addition, the intervention group received a structured medication report. After discharge, the medication list in primary care service was compared with the list at discharge and medication discrepancies identified. In addition, these medication lists were retrospectively compared with the lists prior to admission to the hospital and at admission to hospital. A questionnaire on time spent and quality of the medication information was filled in by nurses in primary care. Medication discrepancies were found for 72% (26) of the patients in the intervention group and 76% (42) in the control group (P=0.918). Most common was drugs omitted or committed to the medication lists in primary care service. Typically, the committed drugs in primary care were omitted drugs after admission to the hospital. Nurses used significantly less time (66%) obtaining medication information in the intervention group (P=0.041). Structured medication report as the only intervention did not reduce the medication discrepancies after discharge from hospital. There is a need for reconciliation at admission to ensure the quality of the medication report. Structured medication report resulted in the nurses spending less time on collecting medication information in primary care service.


Hierarchical clustering using the arithmetic-harmonic cut: complexity and experiments.
Clustering, particularly hierarchical clustering, is an important method for understanding and analysing data across a wide variety of knowledge domains with notable utility in systems where the data can be classified in an evolutionary context. This paper introduces a new hierarchical clustering problem defined by a novel objective function we call the arithmetic-harmonic cut. We show that the problem of finding such a cut is NP-hard and APX-hard but is fixed-parameter tractable, which indicates that although the problem is unlikely to have a polynomial time algorithm (even for approximation), exact parameterized and local search based techniques may produce workable algorithms. To this end, we implement a memetic algorithm for the problem and demonstrate the effectiveness of the arithmetic-harmonic cut on a number of datasets including a cancer type dataset and a corona virus dataset. We show favorable performance compared to currently used hierarchical clustering techniques such as k-Means, Graclus and Normalized-Cut. The arithmetic-harmonic cut metric overcoming difficulties other hierarchical methods have in representing both intercluster differences and intracluster similarities.


Regulation of retinal blood flow in health and disease.
Optimal retinal neuronal cell function requires an appropriate, tightly regulated environment, provided by cellular barriers, which separate functional compartments, maintain their homeostasis, and control metabolic substrate transport. Correctly regulated hemodynamics and delivery of oxygen and metabolic substrates, as well as intact blood-retinal barriers are necessary requirements for the maintenance of retinal structure and function. Retinal blood flow is autoregulated by the interaction of myogenic and metabolic mechanisms through the release of vasoactive substances by the vascular endothelium and retinal tissue surrounding the arteriolar wall. Autoregulation is achieved by adaptation of the vascular tone of the resistance vessels (arterioles, capillaries) to changes in the perfusion pressure or metabolic needs of the tissue. This adaptation occurs through the interaction of multiple mechanisms affecting the arteriolar smooth muscle cells and capillary pericytes. Mechanical stretch and increases in arteriolar transmural pressure induce the endothelial cells to release contracting factors affecting the tone of arteriolar smooth muscle cells and pericytes. Close interaction between nitric oxide (NO), lactate, arachidonic acid metabolites, released by the neuronal and glial cells during neural activity and energy-generating reactions of the retina strive to optimize blood flow according to the metabolic needs of the tissue. NO, which plays a central role in neurovascular coupling, may exert its effect, by modulating glial cell function involved in such vasomotor responses. During the evolution of ischemic microangiopathies, impairment of structure and function of the retinal neural tissue and endothelium affect the interaction of these metabolic pathways, leading to a disturbed blood flow regulation. The resulting ischemia, tissue hypoxia and alterations in the blood barrier trigger the formation of macular edema and neovascularization. Hypoxia-related VEGF expression correlates with the formation of neovessels. The relief from hypoxia results in arteriolar constriction, decreases the hydrostatic pressure in the capillaries and venules, and relieves endothelial stretching. The reestablished oxygenation of the inner retina downregulates VEGF expression and thus inhibits neovascularization and macular edema. Correct control of the multiple pathways, such as retinal blood flow, tissue oxygenation and metabolic substrate support, aiming at restoring retinal cell metabolic interactions, may be effective in preventing damage occurring during the evolution of ischemic microangiopathies.


Biliary atresia and liver transplantation: results and thoughts for primary liver transplantation in select patients.
Biliary atresia (BA) is one of the most common indications for liver transplantation in children. Despite advances in biliary atresia surgical techniques, most children will ultimately require liver transplantation. Possible pre-operative predictors of outcome after the Kasai operation are: 1. Age at operation 2. Presence of the biliary atresia splenic malformation syndrome (BASM) 3. Center specific factors 4. Liver histology and 5. Anatomic pattern of bile ducts found at surgery.Age at surgery is considered a strong predictor of success after portoenterostomy. In a recent study, age of 75 days or more at surgery was associated with less frequent resolution of jaundice and decreased transplant free survival. Similarly, the Ohi type II or III anatomy was associated with a higher risk of transplantation or death than type I. Inflammatory findings on pre-operative biopsy predicted a pooreroutcome after a Kasai procedure than obstructive changes. Nodularity of the liver at surgery as well as ascites was associated with a poorer prognosis.Primary transplantation is rarely done despite excellent outcome. Deaths on the waiting list also have improved with routine use of split and live donor transplantation. The Kasai operation has the highest failure rate in its stated objective than any other operation in pediatric surgery. Failure to achieve any improvement in jaundice occurs in over 30% of all cases, even in the best of hands, and transplantation or listing for transplantation occurs in over half the children with type II and III BA by one year of age in countries where liver transplantation is readily available.There are almost no studies in children with BA that compare the outcome after liver transplantation for BA with or without a prior Kasai procedure. It is postulated that a prospective trial in children predicted to have a poor prognosis after the Kasai procedure based on anatomic pattern, liver histology and presence of BASM, would yield improved care, spare some infants needless surgery, and quite possibly result in diminished morbidity and mortality following liver transplant.


Diagnosis of disseminated candidiasis by measurement of urine D-arabinitol/L-arabinitol ratio.
Relative amounts of D-arabinitol (fungal origin) and L-arabinitol (part of normal human metabolism) in urine were determined by gas chromatography and mass spectrometry from 61 hospitalized patients with hematological malignancies. Seventeen neutropenic patients with acute leukemia (with 53 samples) had disseminated yeast infections and received empiric antifungal therapy before confirmation of the diagnosis. Control groups consisted of 22 hematologic patients (76 samples) with either mucosal (n = 10) or urinary (n = 12) Candida colonization and 22 neutropenic patients (34 samples) with no clinical or laboratory signs of invasive yeast infection. Reference values were also obtained from 50 healthy adults (50 samples). The mean urine D-arabinitol/L-arabinitol ratio +/- standard deviation (range) was 16.91 +/- 41.79 (1.41 to 254.75) in patients with disseminated infection, 2.73 +/- 2.48 (1.11 to 19.00) in colonized hematologic patients, 2.12 +/- 0.84 (1.16 to 5.84) in neutropenic controls, and 1.95 +/- 0.34 (0.97 to 3.44) in healthy adults (P < 0.001 between patients with disseminated infection and all control groups). The sensitivity and specificity of the assay for detecting disseminated yeast infection were, respectively, 88 and 91% per patient (upper limit of normal, 4.00). Seventy-one percent of patients already expressed elevated values at the onset of empiric antifungal therapy. The diagnosis of disseminated infection was confirmed on average 21.7 days after the first elevation of the D-arabinitol/L-arabinitol ratio. The method contributes to diagnosis of disseminated yeast infection and helps in monitoring patients at risk, to support the initiation of antifungal therapy at an early stage of the disease.


Medication reconciliation effect on prolonged inpatient stress ulcer prophylaxis.
While medication reconciliation (MR) has been shown to reduce medication errors by limiting errors of transcription, omission, and duplicate therapy, its impact on the provision of unnecessary prophylaxis is largely unknown. To determine the effect of MR on the incidence of prolonged stress ulcer prophylaxis (SUP) across the continuum of care from hospital admission to discharge as well as evaluate clinical conditions associated with prolonged SUP. This retrospective study assessed patients who were admitted to the intensive care unit (ICU) and had SUP initiated. Patients were excluded if they were receiving gastroprotective therapy prior to ICU admission, were being treated for an acute gastrointestinal hemorrhage, or died. The need for SUP was determined using risk factors adapted from evidence-based guidelines developed by the American Society of Health-System Pharmacists. The use of SUP was assessed upon transfer from the ICU to a non-ICU setting and at hospital discharge. Results were compared between pre-MR and post-MR groups. Data from 114 (pre-MR, n = 53; post-MR, n = 61) medical and surgical ICU patients were evaluated. There was no significant difference in the use of prolonged SUP upon transfer from the ICU to a non-ICU setting in the pre-MR and post-MR groups, respectively (85% [45/53] vs 79% [48/61], p = 0.393). Similarly, there was no significant difference in the use of prolonged SUP upon hospital discharge in the pre-MR and post-MR groups, respectively (14% [6/44] vs 23% [10/43], p = 0.247). There were no clinical conditions for which prolonged SUP use was predominant. The strategy of MR alone will not decrease the incidence of prolonged SUP in hospitalized patients. Other techniques should be evaluated to encourage appropriate use of acid-suppressive agents.


A systematic review and qualitative synthesis of the experience of living with colorectal cancer as a chronic illness.
Advances in detection and treatment mean that over 50% of people diagnosed with colorectal cancer can expect to live for more than ten years following treatment. Studies show that colorectal cancer patients can experience numerous physical and psychological late effects. The aim of this study was to conduct a systematic review and qualitative synthesis on the experiences of living with colorectal cancer as a chronic illness. Electronic searches of online databases were undertaken of peer reviewed and grey literature. Forty-seven papers were eligible for inclusion in the review, capturing the experiences of over 700 participants, the findings from which were analysed using thematic synthesis. Three higher order concepts were identified which were prevalent across studies and countries and which related to the supportive care needs of patients; common physical and psychological late effects of cancer; and methods of psychosocial adjustment to living with and beyond colorectal cancer. The results are considered in the context of existing theoretical approaches to chronic illness and the need to develop a theoretical approach which fully encapsulates the experience of living with colorectal cancer as a chronic illness in order to inform interventions to support patient adjustment.


A novel spatiotemporal muscle activity imaging approach based on the Extended Kalman Filter.
A novel spatiotemporal muscle activity imaging (sMAI) approach has been developed using the Extended Kalman Filter (EKF) to reconstruct internal muscle activities from non-invasive multi-channel surface electromyogram (sEMG) recordings. A distributed bioelectric dipole source model is employed to describe the internal muscle activity space, and a linear relationship between the muscle activity space and the sEMG measurement space is then established. The EKF is employed to recursively solve the ill-posed inverse problem in the sMAI approach, in which the weighted minimum norm (WMN) method is utilized to calculate the initial state and a new nonlinear method is developed based on the propagating features of muscle activities to predict the recursive state. A series of computer simulations was conducted to test the performance of the proposed sMAI approach. Results show that the localization error rapidly decreases over 35% and the overlap ratio rapidly increases over 45% compared to the results achieved using the WMN method only. The present promising results demonstrate the feasibility of utilizing the proposed EKF-based sMAI approach to accurately reconstruct internal muscle activities from non-invasive sEMG recordings.


Characteristics of the distribution of doctors in the Mais Médicos (More Doctors) Program in the states of Brazil's Northeast.
Inequalities in access to health, reflecting shortages and inadequate geographical distribution of health professionals, have been indicated as a challenge for Brazil. This paper analyzes the geographical distribution of professionals of the Mais Médicos Program allocated in the Northeastern Region of Brazil, through a descriptive cross-sectional study. Secondary data provided by the Health Ministry were used, and thematic maps of distribution of doctors in the Region were prepared. Data on 4,716 doctors who became members of health teams in 1,294 municipalities in six Indigenous Health Districts in the years 2013 and 2014 were analyzed. The greater part of the municipalities of the Region received between one and five doctors. The municipalities most benefited had, at least, 20% of their population in extreme poverty. 99.9% of the doctors were allocated in a Health Center or Primary Healthcare Unit. The majority were women (57%), predominantly of the 45-49 age group (24%). In spite of the advances achieved by the Program - such as distribution of the doctors in locations with greater vulnerability - some States continue to have significant shortages of healthcare.


Antimicrobial activity of copper and copper(i) oxide thin films deposited via aerosol-assisted CVD.
Hospital acquired infections are prevalent in many hospitals and contaminated touch surfaces are a route of transmission. To find a solution for this, copper and copper oxide thin films were deposited via aerosol assisted chemical vapour deposition using copper nitrate as the precursor and the films were characterised by a range of techniques including powder X-ray diffraction and scanning electron microscopy. The antimicrobial activity of the deposited copper and copper oxide films were investigated against Staphylococcus aureus (S. aureus) and Escherichia coli (E. coli). A 5-log10 reduction in the viable counts of E. coli was observed on the copper thin films after 30 minutes while a 2-log10 reduction was observed on copper oxide films after 1 hour. In the case of S. aureus both copper and copper oxide films exhibited 4-log10 reduction after 1 hour. The high antimicrobial efficacy of the Cu2O films, approaching that of the pure copper films, suggests that oxide formation on copper objects should not significantly impair their antimicrobial activity.


Different effects of four rest periods after the last weekly training session on young male professional soccer players' physical performance.
The main aim of this study was to analyze the optimal pre-competitive recovery period for young male professional soccer players to be in the best conditions to achieve a higher physical performance. Seventeen young male professional soccer players (age: 20.7 ± 1.0 years) who participated in the Tunisian soccer league participated in this study. Players underwent a fitness test battery after four different recovery periods: 12, 24, 36, and 48h following their last training session. The battery fitness test included a linear sprint test (i.e., 5 and 20m distances), squat jumps (SJ), countermovement jumps (CMJ), ball shooting test, a Yo-yo endurance intermittent test (YYIRT-1) and a 15-m ball dribbling agility test (Ag). The main findings indicated that the 12h recovery period resulted in better performance in the 5m sprint test compared to 36h, as well as in the SJs and CMJs as compared to the 48h recovery period. Additionally, the 24h recovery period showed significantly better results in the 20-m sprint test compared to all other recovery periods, as well as in the SJ and Ag tests compared to the 48h recovery period. In practical terms, these findings suggest that coaches should consider scheduling the last training session for soccer players 12-24h before the match to enhance their physical performance, particularly in linear sprinting, vertical jumps, and agility variables. However, in situations where it is not possible to adjust the timing of the last training session, an alternative approach is to incorporate "priming-day" exercises on the match day, around 6-8h prior to the competition.


Ripple-triggered stimulation of the locus coeruleus during post-learning sleep disrupts ripple/spindle coupling and impairs memory consolidation.
Experience-induced replay of neuronal ensembles occurs during hippocampal high-frequency oscillations, or ripples. Post-learning increase in ripple rate is predictive of memory recall, while ripple disruption impairs learning. Ripples may thus present a fundamental component of a neurophysiological mechanism of memory consolidation. In addition to system-level local and cross-regional interactions, a consolidation mechanism involves stabilization of memory representations at the synaptic level. Synaptic plasticity within experience-activated neuronal networks is facilitated by noradrenaline release from the axon terminals of the locus coeruleus (LC). Here, to better understand interactions between the system and synaptic mechanisms underlying "off-line" consolidation, we examined the effects of ripple-associated LC activation on hippocampal and cortical activity and on spatial memory. Rats were trained on a radial maze; after each daily learning session neural activity was monitored for 1 h via implanted electrode arrays. Immediately following "on-line" detection of ripple, a brief train of electrical pulses (0.05 mA) was applied to LC. Low-frequency (20 Hz) stimulation had no effect on spatial learning, while higher-frequency (100 Hz) trains transiently blocked generation of ripple-associated cortical spindles and caused a reference memory deficit. Suppression of synchronous ripple/spindle events appears to interfere with hippocampal-cortical communication, thereby reducing the efficiency of "off-line" memory consolidation.


The outcome of allogeneic HSCT in older AML patients is determined by disease biology and not by the donor type: an analysis of 96 allografted AML patients ≥ 50 years from the Czech acute leukaemia clinical register (alert).
Older patients with AML have poor prognosis after chemotherapy and allo-SCT was historically limited to the young patients. In the multicentre retrospective study we analyzed 96 consecutive AML patients ≥ 50 years allografted with related (n=59) or unrelated (n=37) donor. The 2- year OS and DFS rates were 45 % and 42 % for the whole group. The corresponding figures for related patients were 48% and 42% whereas for unrelated 42% and 42%, respectively (OS p=0,721, DFS p= 0,896). The cumulative incidences of relapse (28% of all patients) and NRM mortality (26%) were low with no significant differences among related and unrelated cohorts. Multivariate analysis revealed the only major independent variables associated with an inferior OS were unfavourable cytogenetics (RR 3.36; CI 1.66-6.83; p=0.001) and advanced disease status (RR 2.30; CI 1.21-4.37; p=0.011). Unfavourable cytogenetics (RR 3.00; CI 1.50-5.99; p=0.002) and advanced disease at SCT (RR 2.27; CI 1.22-4.22; p=0.009) were also the only independent variables associated with inferior DFS. In conclusion, our analysis indicates that outcomes of allografted AML patients aged ≥ 50 years are determined by cytogenetic risk category and disease status at transplantation and not by the type of donor.


Maternal thyroid disease, thyroid medication use, and selected birth defects in the National Birth Defects Prevention Study.
Although thyroid disorders are present in approximately 3% of pregnant women, little is known about the association between maternal thyroid disease and birth defects. We assessed the association between maternal thyroid disease, thyroid medication use, and 38 types of birth defects among 14,067 cases and 5875 controls in the National Birth Defects Prevention Study, a multisite, population-based, case-control study. Infants in this study were born between October 1997 and December 2004. Information on exposures including maternal diseases and use of medications was collected by telephone interview. We found statistically significant associations between maternal thyroid disease and left ventricular outflow tract obstruction heart defects (1.5; 95% CI, 1.0-2.3), hydrocephaly (2.9; 95% CI, 1.6-5.2), hypospadias (1.6; 95% CI, 1.0-2.5), and isolated anorectal atresia (2.4; 95% CI, 1.2-4.6). Estimates for the association between periconceptional use of thyroxine and specific types of birth defects were similar to estimates for any thyroid disease. Given that antithyroid medication use was rare, we could not adequately assess risks for their use for most case groups. Our results are consistent with the positive associations between maternal thyroid disease or thyroid medication use and both hydrocephaly and hypospadias observed in some previous studies. New associations with left ventricular outflow tract obstruction heart defects and anorectal atresia may be chance findings.


Tumor cell secretion of soluble factor(s) for specific immunosuppression.
Studies of tumor models using syngeneic transplantation have advanced our understanding of tumor immunity, including both immune surveillance and evasion. Murine mammary carcinoma 4T1 cells secrete immunosuppressive soluble factors as demonstrated in splenocyte culture. Cultured primary splenocytes secrete IFN-γ, which was strikingly elevated when the cells were isolated from 4T1 tumor-bearing mice. The secretion of IFN-γ peaked a week after 4T1 inoculation and then declined. This reduction may be due to the relatively decreased lymphocytes and increased granulocytes in a spleen accompanied by splenomegaly with time after the 4T1 inoculation. IFN-γ production was further suppressed with the addition of the conditioned media from 4T1 cells to the splenocyte culture. This suppressive effect was more evident in the splenocytes isolated from mice that had 4T1 tumors for a longer period of time and was not observed in the conditioned medium either from CT26 cells or with splenocytes isolated from CT26 tumor-bearing mice. These results suggest that the IFN-γ suppression is 4T1 tumor-specific. The soluble factor(s) in the 4T1-conditioned media was a protein between 10 to 100 kDa. The cytokine tip assay demonstrated several known cytokines that negatively regulate immune responses and may be candidates for this immunosuppression activity.


Role of growth factors in oesophageal mucosal healing: A work in progress.
Reflux of gastroduodenal contents into the oesophagus results in dynamic cycles of injury followed by cell proliferation and repair. These processes are receiving increased attention due to the high incidence of gastro-oesophageal reflux disease and the rising incidence of adenocarcinoma of the oesophagus. Repeated cycles of injury and repair may lead to abnormal differentiation followed by abnormal growth. This article summarizes the research performed by our group in the field of oesophageal injury and repair. We initially developed an in vivo perfused rabbit oesophagus model that served to study the effects of various components of the gastroduodenal juice on several parameters of oesophageal injury. We have shown that pepsin causes severe morphological oesophagitis at an acidic pH but is ineffective at an alkaline pH. We have also demonstrated that trypsin causes severe morphological oesophagitis at an alkaline pH but not at an acidic pH. Bile salts were found to disrupt the oesophageal barrier at both pH levels. We have also studied the effects of epidermal growth factor (EGF) and insulin-like growth factor-I (IGF-I) on oesophageal regeneration. We used an ex vivo oesophageal explant model for these experiments. Both EGF and IGF-I cause a dose-dependent increase in oesophageal DNA synthesis, cell proliferation and mucosal growth. These effects are synergistic and can be inhibited by specific tyrphostins. We are currently studying the role of growth factors as therapeutic agents and the role of growth factors in the development of Barrett's oesophagus and adenocarcinoma.


Evaluation of multiple biomarkers of cardiovascular stress for risk prediction and guiding medical therapy in patients with stable coronary disease.
Circulating biomarkers can offer insight into subclinical cardiovascular stress and thus have the potential to aid in risk stratification and tailoring of therapy. We measured plasma levels of 4 cardiovascular biomarkers, midregional pro-atrial natriuretic peptide (MR-proANP), midregional pro-adrenomedullin (MR-proADM), C-terminal pro-endothelin-1 (CT-proET-1), and copeptin, in 3717 patients with stable coronary artery disease and preserved left ventricular ejection fraction who were randomized to trandolapril or placebo as part of the Prevention of Events With Angiotensin Converting Enzyme (PEACE) trial. After adjustment for clinical cardiovascular risk predictors and left ventricular ejection fraction, elevated levels of MR-proANP, MR-proADM, and CT-proET-1 were independently associated with the risk of cardiovascular death or heart failure (hazard ratios per 1-SD increase in log-transformed biomarker levels of 1.97, 1.48, and 1.47, respectively; P≤0.002 for each biomarker). These 3 biomarkers also significantly improved metrics of discrimination when added to a clinical model. Trandolapril significantly reduced the risk of cardiovascular death or heart failure in patients who had elevated levels of ≥2 biomarkers (hazard ratio, 0.53; 95% confidence interval, 0.36-0.80), whereas there was no benefit in patients with elevated levels of 0 or 1 biomarker (hazard ratio, 1.09; 95% confidence interval, 0.74-1.59; P(interaction)=0.012). In patients with stable coronary artery disease and preserved left ventricular ejection fraction, our results suggest that elevated levels of novel biomarkers of cardiovascular stress may help identify patients who are at higher risk of cardiovascular death and heart failure and may be useful to select patients who derive significant benefit from angiotensin-converting enzyme inhibitor therapy.


Host affinity of endophytic fungi and the potential for reciprocal interactions involving host secondary chemistry.
Interactions between fungal endophytes and their host plants present useful systems for identifying important factors affecting assembly of host-associated microbiomes. Here we investigated the role of secondary chemistry in mediating host affinity of asymptomatic foliar endophytic fungi using Psychotria spp. and Theobroma cacao (cacao) as hosts. First, we surveyed endophytic communities in Psychotria species in a natural common garden using culture-based methods. Then we compared differences in endophytic community composition with differences in foliar secondary chemistry in the same host species, determined by liquid chromatography-tandem mass spectrometry. Finally, we tested how inoculation with live and heat-killed endophytes affected the cacao chemical profile. Despite sharing a common environment and source pool for endophyte spores, different Psychotria host species harbored strikingly different endophytic communities that reflected intrinsic differences in their leaf chemical profiles. In T. cacao, inoculation with live and heat-killed endophytes produced distinct cacao chemical profiles not found in uninoculated plants or pure fungal cultures, suggesting that endophytes, like pathogens, induce changes in secondary chemical profiles of their host plant. Collectively our results suggest at least two potential processes: (1) Plant secondary chemistry influences assembly and composition of fungal endophytic communities, and (2) host colonization by endophytes subsequently induces changes in the host chemical landscape. We propose a series of testable predictions based on the possibility that reciprocal chemical interactions are a general property of plant-endophyte interactions.


Amino acid residue Val362 plays a critical role in maintaining the structure of C terminus of connexin 50 and in lens epithelial-fiber differentiation.
We have previously shown that connexin (Cx) 50, unlike the other two lens connexins, Cx43 and Cx46, promotes chicken lens epithelial-fiber differentiation in a channel-independent manner. Here, we show that deletion of the PEST motif at the C terminus (CT) domain of Cx50 attenuates the stimulatory effect of Cx50 on lens fiber differentiation. Valine 362, a residue located within the PEST domain, is functionally involved. The structure of the Cx50 CT predicted by molecular modeling revealed four alpha-helices and Val(362) was found to be located in the middle of the 3rd helix. Replacement of Val(362) with amino acid residues that disrupt the alpha-helical structure predicted by molecular modeling, such as arginine, glutamate, or phenylalanine, attenuated the stimulatory effects of Cx50 on lens differentiation, whereas replacement with threonine, isoleucine, leucine, or proline, which maintain the structure preserved the function of Cx50. Circular dichroism (CD) studies supported the structural predictions and showed that the substitution with Glu, but not Thr or Pro, disrupted the alpha-helix, which appears to be the structural feature important for lens epithelial-fiber differentiation. Together, our results suggest that Val(362) is important for maintaining the helical structure and is crucial for the role of Cx50 in promoting lens epithelial-fiber differentiation.


Dehydroepiandrosterone protects endothelial cells against inflammatory events induced by urban particulate matter and titanium dioxide nanoparticles.
Particulate matter (PM) and nanoparticles (NPs) induce activation and dysfunction of endothelial cells characterized by inhibition of proliferation, increase of adhesion and adhesion molecules expression, increase of ROS production, and death. DHEA has shown anti-inflammatory and antioxidant properties in HUVEC activated with proinflammatory agents. We evaluated if DHEA could protect against some inflammatory events produced by PM10 and TiO2 NPs in HUVEC. Adhesion was evaluated by a coculture with U937 cells, proliferation by crystal violet staining, and oxidative stress through DCFDA and Griess reagent. PM10 and TiO2 NPs induced adhesion and oxidative stress and inhibited proliferation of HUVEC; however, when particles were added in combination with DHEA, the effects previously observed were abolished independently from the tested concentrations and the time of addition of DHEA to the cultures. These results indicate that DHEA exerts significant anti-inflammatory and antioxidative effects on the damage induced by particles in HUVEC, suggesting that DHEA could be useful to counteract the harmful effects and inflammatory diseases induced by PM and NPs.


Diagnosis of biofilm infections in cystic fibrosis patients.
Chronic Pseudomonas aeruginosa biofilm lung infection in cystic fibrosis patients is the best described biofilm infection in medicine. The initial focus can be the paranasal sinuses and then follows repeated colonization and infection of the lungs by aspiration. The matrix of the biofilms is dominated by alginate and the pathogenesis of tissue damage is immune complex-mediated chronic inflammation dominated by polymorphonuclear leukocytes and their products (DNA, oxygen radicals and proteases). The P. aeruginosa biofilm infection can be diagnosed by microscopy of lung tissue, sputum and mucus from the paranasal sinuses, where aggregates of the bacteria are found surrounded by the abundant alginate matrix. Specific PNA-FISH probes can be used to identify P. aeruginosa and other pathogens in situ in the biofilms. Growth of mucoid colonies from the locations mentioned above is also diagnostic for biofilm infection. Rise of specific anti-P. aeruginosa antibodies is likewise diagnostic, IgG in serum in case of lung infection, sIgA in saliva or nasal secretions in case of paranasal sinus infection. Similar approaches have been developed to diagnose chronic biofilm infections in cystic fibrosis caused by other pathogens e.g., Stenotrophomonas, Burkholderia multivorans, Achromobacter xylosoxidans and Mycobacterium abscessus complex.


Women's Mental Health and Intimate Partner Violence Following Natural Disaster: A Scoping Review.
Introduction Survivors of natural disasters in the United States experience significant health ramifications. Women particularly are vulnerable to both post-disaster posttraumatic stress disorder (PTSD) and depression, and research has documented that these psychopathological sequelae often are correlated with increased incidence of intimate partner violence (IPV). Understanding the link between these health concerns is crucial to informing adequate disaster response and relief efforts for victims of natural disaster. Purpose The purpose of this review was to report the results of a scoping review on the specific mental health effects that commonly impact women following natural disasters, and to develop a conceptual framework with which to guide future research. A scoping review of mental and physical health effects experienced by women following natural disasters in the United States was conducted. Articles from 2000-2015 were included. Databases examined were PubMed, PsycInfo, Cochrane, JSTOR, Web of Science, and databases available through ProQuest, including ProQuest Research Library. A total of 58 articles were selected for inclusion, out of an original 149 that were selected for full-text review. Forty-eight articles, or 82.8%, focused on mental health outcomes. Ten articles, or 17.2%, focused on IPV. Discussion Certain mental health outcomes, including PTSD, depression, and other significant mental health concerns, were recurrent issues for women post-disaster. Despite the strong correlation between experience of mental health consequences after disaster and increased risk of domestic violence, studies on the risk and mediating factors are rare. The specific challenges faced by women and the interrelation between negative mental health outcomes and heightened exposure to IPV following disasters require a solid evidence base in order to facilitate the development of effective interventions. Additional research informed by theory on probable health impacts is necessary to improve development/implementation of emergency relief policy. Bell SA , Folkerth LA . Women's mental health and intimate partner violence following natural disaster: a scoping review. Prehosp Disaster Med. 2016;31(6):648-657.


Analysis of anterior, middle and posterior deltoid activation during single and multijoint exercises.
Although comparison between multi and single joint exercises has been conducted, there is insufficient evidence that these exercises could lead to different muscle activations. The aim of this study was to compare deltoid muscle activation during multi and single joint exercises. Twelve male participants (23.4±1.6 years) with at least one year of strength training experience were assessed performing inclined lat pull-down, reverse peck deck and seated row exercises. Surface electromyography was used to measure activation of anterior, middle and posterior portions of deltoid muscle during each exercise. Deltoid activation was recorded during maximum voluntary isometric contraction (MVIC) and during dynamic isoinertial exercises of ten maximum repetitions for inclined lateral pull-down, reverse peck deck and seated row. There was no difference in activation of the anterior portion of deltoid muscle for any of the three exercises (P=0.08). The middle portion presented greater activation during the reverse peck deck (P=0.03) and during the seated row (P=0.03) compared to the inclined lat pull-down. For the posterior portion of deltoid muscle there was greater activation during the reverse peck deck (P=0.001) compared to the seated row and to the inclined lat pull-down. Results indicate that reverse peck deck and seated row should be more appropriate for recruitment of the middle portion of the deltoid muscle than the inclined lat pull-down. Differently, the reverse peck deck should be primarily used rather than the seated row and the lat pull-down for recruitment of the posterior portion of the deltoid muscle.


[The detection of leptin and metabolic markers of insulin resistance in patients with myocardial infarction].
The shortage of data concerning the character of changes of leptin concentration and its role information of insulin resistance under development of acute coronary events determined the appropriateness of the present study. The cardiac infarction patients with and without diabetes type II were examined. The identified hyperleptinemia, its relationship with basal and post-prandial hyperglycemia and with increase of C-peptide concentration and free fatty acids made possible to consider leptin both as one of the important components in the series of carbohydrate and lipid metabolism disorders and the additional marker of development of insulin resistance under cardiac infarction. These study results can be applied to patients with diabetes anamnesis and to patients without this concomitant pathology. The study results can be used as a foundation for new diagnostic and therapy tactics of metabolic disorders correction in patients with acute coronary vascular pathology.


The Impact of Diagnostic Status on Quality of Life in Irritable Bowel Syndrome.
The aim of the study was to examine the impact of diagnostic status (i.e., having a clinical diagnosis of irritable bowel syndrome (IBS) or being symptomatic but undiagnosed on quality of life (QoL)). We also examined whether the relationships between QoL and variables such as symptom frequency, pain catastrophizing, visceral sensitivity, and psychological distress are moderated by diagnostic status. The online sample comprised 404 participants (Mage = 33.59, SD = 12.43), of which 98 had been diagnosed with IBS and 306 were symptomatic but undiagnosed. The findings suggest that even after adjusting for symptom frequency, those diagnosed with IBS experience poorer QoL, relative to those without a diagnosis. Moreover, there was evidence that the relationship between specific QoL domains (namely, sex, food avoidance, and health worry) and psychological variables (namely, pain catastrophizing, and depression) was moderated by diagnostic status. The results indicate that diagnostic status in relation to IBS has psychological implications for QoL outcomes distinct from symptom frequency, age, and gender. This highlights a substantial gap in our current understanding of how a diagnosis of IBS can impact the lives of those suffering from IBS symptomology and calls into question the intended purpose of diagnosis.


Predicting Thrombosis Formation in 1-mm-Diameter Arterial Anastomoses with Transit-Time Ultrasound Technology.
Thrombosis is a common source of failure in anastomoses, flaps, and vascular grafts. Ensuring vessel patency is critical to the success of microvascular procedures. Any tool that can accurately predict the patency of an anastomosis intraoperatively would enable the surgeon to detect and correct flow restrictions while the patient is still in the operating room. The authors used transit-time ultrasound technology in this pilot study to investigate whether a minimal cutoff value for quantitative postoperative blood flow (in milliliters per minute) could be established that would reliably predict sustained vessel patency at 24 hours postoperatively. Surgical end-to-end anastomoses were performed on 56 Sprague-Dawley rat femoral arteries with diameters ranging from 0.6 to 1.2 mm. Postoperative blood volume flow measurements were taken at 20-minute intervals up to 1 hour, and then again at 24 hours, to assess patency. Forty-seven anastomoses (83.9 percent ) were patent 24 hours after surgery. Nine anastomoses (16.1 percent ) thrombosed within 24 hours. Based on a receiver operating characteristic curve analysis, the optimal cutoff value for immediate postoperative flow for predicting thrombosis within 24 hours of microvascular anastomosis is 0.21 ml/minute. At 20 minutes postoperatively, blood flows greater than 0.30 ml/minute are highly suggestive of patency, and flows less than 0.21 ml/minute are highly suggestive of failure. The authors therefore recommend a minimal cutoff flow value of 0.30 ml/minute for vessels ranging from 0.6 to 1.2 mm in diameter to predict long-term postoperative vascular patency.


Twins born over weekends: are they at risk for elevated infant mortality?
To assess the impact of the day of birth on twin mortality in a population sample. We analyzed weekend versus weekday twin births from the United States national twin birth data for the periods 1989-2002. We computed adjusted hazard ratios (HR) and 95% confidence intervals (CI) to assess the association between infant mortality and weekday of birth using the Cox proportional hazards model. The crude rates for all types of mortality were found to be significantly higher for twins born on weekends than on weekdays. After adjustment, only post-neonatal mortality risk was higher on weekends as compared to weekdays [Hazards ratio (HR)=1.19, CI: 1.04, 1.36]. Twins of white mothers were at greater risk for neonatal death (HR=1.16, CI: 1.08, 1.24) but were less likely to experience post-neonatal death (HR=0.68, CI: 0.64, 0.76) as compared to twins of black mothers. We found an interaction between maternal age and weekday of birth. Twins born on weekends to teenage mothers (age<18) had a 35% greater risk for neonatal death (HR=1.35, CI: 1.06, 1.71) while those born on weekends to older mothers did not show elevated risk for any of the mortality indices. Increased risks for post-neonatal death are significantly higher amongst twins born on weekends as compared to weekdays. Further research is required to identify the detailed differences in structure and procedures that result in the disadvantage associated with weekend birth.


Stem cell regeneration of degenerated intervertebral discs: current status.
Low back pain (LBP) is one of the most common musculoskeletal conditions, and intervertebral disc (IVD) degeneration is associated with most cases. Although many treatment options are available, they focus on the removal of symptoms rather than repair of the degenerate tissue. However, there is a growing interest in the potential of cell-based tissue engineering strategies for regeneration of the damaged IVD. To achieve this, investigators are now focusing on the use of mesenchymal stem cells (MSCs), which offer several advantages over more mature cell types. A number of problems must be overcome for MSC-based IVD regeneration to be successful, including determining a method for the differentiation of stem cells into nucleus pulposus-like cells. Although this is still a relatively new field, it offers huge potential for the clinical treatment of IVD degeneration and LBP in the future.


5-Hydroxymethylcytosine Signatures in Circulating Cell-Free DNA as Early Warning Biomarkers for COVID-19 Progression and Myocardial Injury.
Background: The symptoms of coronavirus disease 2019 (COVID-19) range from moderate to critical conditions, leading to death in some patients, and the early warning indicators of the COVID-19 progression and the occurrence of its serious complications such as myocardial injury are limited. Methods: We carried out a multi-center, prospective cohort study in three hospitals in Wuhan. Genome-wide 5-hydroxymethylcytosine (5hmC) profiles in plasma cell-free DNA (cfDNA) was used to identify risk factors for COVID-19 pneumonia and develop a machine learning model using samples from 53 healthy volunteers, 66 patients with moderate COVID-19, 99 patients with severe COVID-19, and 38 patients with critical COVID-19. Results: Our warning model demonstrated that an area under the curve (AUC) for 5hmC warning moderate patients developed into severe status was 0.81 (95% CI 0.77-0.85) and for severe patients developed into critical status was 0.92 (95% CI 0.89-0.96). We further built a warning model on patients with and without myocardial injury with the AUC of 0.89 (95% CI 0.84-0.95). Conclusion: This is the first study showing the utility of 5hmC as an accurate early warning marker for disease progression and myocardial injury in patients with COVID-19. Our results show that phosphodiesterase 4D and ten-eleven translocation 2 may be important markers in the progression of COVID-19 disease.


Strategies Used in Production of Phenylalanine-Free Foods for PKU Management.
Phenylketonuria (PKU) is one of the most widespread dysfunctions caused by an inheritable problem in the phenylalanine metabolism. In this metabolic disease, gene mutations in phenylalanine hydroxylase (PAH) result in phenylalanine accumulation that causes varying degrees of mental retardation. The most effective treatment is restriction of phenylalanine in diet provided through different strategies including combination of low-protein foods, hydrolyzing of protein-rich foods, or use of protein substitutes. Meat and meat products, sea foods, milk and infant formula, cereal products, and beans are among the modified foods for PKU management. Elimination of phenylalanine from food presents major technological, nutritional, and organolleptic challenges because protein, as an essential structure-building and nutritional element, is removed. In addition, following this program is laborious, boring, and restrictive for both patients and their families. This paper reviews the current findings about PKU and the recent developments in the production of phenylalanine-free foods. Also, the nutritional requirements and challenges encountered by PKU individuals and food technologists are finally discussed.


Reducing motion artifacts for long-term clinical NIRS monitoring using collodion-fixed prism-based optical fibers.
As the applications of near-infrared spectroscopy (NIRS) continue to broaden and long-term clinical monitoring becomes more common, minimizing signal artifacts due to patient movement becomes more pressing. This is particularly true in applications where clinically and physiologically interesting events are intrinsically linked to patient movement, as is the case in the study of epileptic seizures. In this study, we apply an approach common in the application of EEG electrodes to the application of specialized NIRS optical fibers. The method provides improved optode-scalp coupling through the use of miniaturized optical fiber tips fixed to the scalp using collodion, a clinical adhesive. We investigate and quantify the performance of this new method in minimizing motion artifacts in healthy subjects, and apply the technique to allow continuous NIRS monitoring throughout epileptic seizures in two epileptic in-patients. Using collodion-fixed fibers reduces the percent signal change of motion artifacts by 90% and increases the SNR by 6 and 3 fold at 690 and 830 nm wavelengths respectively when compared to a standard Velcro-based array of optical fibers. The SNR has also increased by 2 fold during rest conditions without motion with the new probe design because of better light coupling between the fiber and scalp. The change in both HbO and HbR during motion artifacts is found to be statistically lower for the collodion-fixed fiber probe. The collodion-fixed optical fiber approach has also allowed us to obtain good quality NIRS recording of three epileptic seizures in two patients despite excessive motion in each case.


Reductive Amination in the Synthesis of Pharmaceuticals.
Reductive amination plays a paramount role in pharmaceutical and medicinal chemistry owing to its synthetic merits and the ubiquitous presence of amines among biologically active compounds. It is one of the key approaches to C-N bond construction due to its operational easiness and a wide toolbox of protocols. Recent studies show that at least a quarter of C-N bond-forming reactions in the pharmaceutical industry are performed via reductive amination. This Review concisely compiles information on 71 medical substances that are synthesized by reductive amination. Compounds are grouped according to the principle of action, which includes drugs affecting the central nervous system, drugs affecting the cardiovascular system, anticancer drugs, antibiotics, antiviral and antifungal medicines, drugs affecting the urinary system, drugs affecting the respiratory system, antidiabetic medications, drugs affecting the gastrointestinal tract, and drugs regulating metabolic processes. A general synthetic scheme is provided for each compound, and the description is focused on reductive amination steps. The green chemistry metric of reaction mass efficiency was calculated for all reactions.


Cost-effectiveness of ticagrelor and generic clopidogrel in patients with acute coronary syndrome in Switzerland.
The aim of this study was to evaluate the cost-effectiveness of ticagrelor and generic clopidogrel as add-on therapy to acetylsalicylic acid (ASA) in patients with acute coronary syndrome (ACS), from a Swiss perspective. Based on the PLATelet inhibition and patient Outcomes (PLATO) trial, one-year mean healthcare costs per patient treated with ticagrelor or generic clopidogrel were analysed from a payer perspective in 2011. A two-part decision-analytic model estimated treatment costs, quality-adjusted life years (QALYs), life years and the cost-effectiveness of ticagrelor and generic clopidogrel in patients with ACS up to a lifetime at a discount of 2.5% per annum. Sensitivity analyses were performed. Over a patient's lifetime, treatment with ticagrelor generates an additional 0.1694 QALYs and 0.1999 life years at a cost of CHF 260 compared with generic clopidogrel. This results in an Incremental Cost Effectiveness Ratio (ICER) of CHF 1,536 per QALY and CHF 1,301 per life year gained. Ticagrelor dominated generic clopidogrel over the five-year and one-year periods with treatment generating cost savings of CHF 224 and 372 while gaining 0.0461 and 0.0051 QALYs and moreover 0.0517 and 0.0062 life years, respectively. Univariate sensitivity analyses confirmed the dominant position of ticagrelor in the first five years and probabilistic sensitivity analyses showed a high probability of cost-effectiveness over a lifetime. During the first five years after ACS, treatment with ticagrelor dominates generic clopidogrel in Switzerland. Over a patient's lifetime, ticagrelor is highly cost-effective compared with generic clopidogrel, proven by ICERs significantly below commonly accepted willingness-to-pay thresholds.


Improving the MEDLARS search interview: a checklist approach.
An analogy is drawn between searching a computer data base and conducting laboratory research: the crucial process in both is phrasing the question to the system to obtain meaningful and useful results. The searcher must act as an intermediary for the library user in questioning the data base; for this reason every effort must be made to maximize the efficiency with which a query is transferred from requester to searcher. Studies reported in the literature tend to distribute themselves into one of two categories: flowchart analyses or nonverbal communication approaches. Because message transfer in an interview is an entirely human process, the flowchart approach, while perhaps providing a correct analysis, is rejected as a means of improvement. Similarly, emphasis on nonverbal cues and communication inhibitors is assessed as misplaced. Rather, the method recommended is guided practice, using a checklist of areas to be covered in an interview for a MEDLARS search. Topic appropriateness, form design, and postsearch follow-through are included in the discussion.


Burial leakage: A human accustomed groundwater contaminant sources and health hazards study near cemeteries in Benin City, Nigeria.
This study was carried out to assess the levels of physico-chemical parameters that could be impacted by burial leakage and associated human health risks in Benin City, Nigeria. A total of thirty groundwater samples were collected from two cemeteries and analysed for pH, alkalinity, chloride, sulphate, nitrate, phosphate, ammonia- N, calcium, sodium, potassium, BOD₅, COD, Mn, Cd, Cu, Ni, Pb, Zn and Fe. The concentrations of the parameters were compared to national and international standards. The results revealed that the groundwater is highly acidic in nature. Principal component analysis (PCA) revealed that except for alkalinity, all other parameters characterised contributed significantly to various principal components (PC) with eigenvalues ≥ 1. Moreover, the significance of the PC depicted decomposition of the body corpse and associated burial materials. Water quality index (WQI), heavy metal evaluation index (HEI) and Nemerov pollution index (NI) indicated that groundwater from the study area is of poor quality, and highly contaminated by heavy metals. We determined the Chronic health risk through exposure by calculating the hazard quotient (HQ) and hazard index (HI), for both children and adults. For the oral exposure, approximately 33% of samples suggest the high category of chronic risk for children while the medium category was indicated for adults. We found that oral exposure showed relatively higher risk than dermal exposure, and chronic risk for children and adults ranged from low to negligible. However, the carcinogenic risk of Ni and Pb via oral exposure route suggests, very high risk for Ni and medium risk for Pb. In consideration that long term exposure to low concentrations of some heavy metals (including Pb, Cd, and Ni) could result in different manifestations of cancer, we recommend that residents of these areas should find an alternative source of water for drinking and other domestic uses.


The lasso technique' - a simple intracorporeal two-port laparoscopic appendectomy: technical considerations and review of four other intracorporeal two-port techniques.
To decrease surgical trauma and scar formation we present intracorporeal two-port procedure in selected patients. Supraumbilical 5mm port is used for the laparoscope. Suprapubic 12mm port is in the midline or left paramedian position below the underpants line. Pretied loop suture is tied around the base, 1-2 cm distally from the origin of the appendix, or below the macroscopically changed appendix. Endoclose is introduced 1-2 cm cranially from the location of appendiceal base and the endoloop is exteriorized and the appendix elevated. Harmonic scalpel is used for dissection and skeletonization and the appendix is divided with 45 mm linear cutting stapler. Two-port appendectomy was attempted in 11 consecutive patients. In 3 patients operation was converted to open procedure and in 2 patients the third port was needed. Finally 6 (54%) patients were operated with the similar operating time (36-51 min) as standard three-port technique with the same postoperative pain and bowel function recovery. The postoperative stay ranged 2 - 4 days. There was one wound infection of 12-mm port. This intracorporeal two-port appendectomy in selected patients does not prolong operation time and further improves the minimal invasiveness and contributes to excellent cosmetic results.


A clinical study of 130 patients with biliary tract cancers and periampullary tumors.
A retrospective review of 130 patients with peripheral-type cholangiocarcinomas (PTCC), hilar-type cholangiocarcinomas (HTCC), extrahepatic cholangiocarcinomas (EHCC), gallbladder cancers (GBCA), and periampullary cancers (PACA), seen at National Cheng Kung University Hospital and Tainan Municipal Hospital from June 1987 to July 1993 was performed. There were 47 (36%) HTCC, 32 (25%) PACA, 24 (19%) PTCC, 17 (13%) GBCA, and 10 (8%) EHCC patients. The distribution is completely different from that reported in western countries. These cancers mainly occur in elderly patients. HTCC and GBCA were predominantly noted in female patients. Biliary cancers in Taiwan were not related to liver fluke infestation, inflammatory bowel disease or hepatitis B virus infection. However, a close association with biliary lithiasis was found. The incidence of gallstones was 67, 39, 20, 29 and 19% for PTCC, HTCC, EHCC, GBCA and PACA, respectively. The most common presentation for PTCC and GBCA was abdominal pain, or jaundice for HTCC, EHCC and PACA. These symptoms correlate well with the location of the tumors. Among serum tumor markers, the elevation of CA19-9 was most frequent, occurring in 86% of the patients while CA125 and CEA occurred in 47% and 30% of the patients, respectively. During the course of disease, infection developed in 61% of the patients and was the main cause of death in 25%. Biliary tract infection and sepsis were the two leading manifestations and occurred in 49% and 32% of the patients, respectively. Overall survival was poor except in patients whose tumor could be completely resected.


Mapping substrate interactions of the human membrane-associated neuraminidase, NEU3, using STD NMR.
Saturation transfer difference (STD) nuclear magnetic resonance (NMR) is a powerful technique which can be used to investigate interactions between proteins and their substrates. The method identifies specific sites of interaction found on a small molecule ligand when in complex with a protein. The ability of STD NMR to provide specific insight into binding interactions in the absence of other structural data is an attractive feature for its use with membrane proteins. We chose to employ STD NMR in our ongoing investigations of the human membrane-associated neuraminidase NEU3 and its interaction with glycolipid substrates (e.g., GM3). In order to identify critical substrate-enzyme interactions, we performed STD NMR with a catalytically inactive form of the enzyme, NEU3(Y370F), containing an N-terminal maltose-binding protein (MBP)-affinity tag. In the absence of crystallographic data on the enzyme, these data represent a critical experimental test of proposed homology models, as well as valuable new structural data. To aid interpretation of the STD NMR data, we compared the results with molecular dynamics (MD) simulations of the enzyme-substrate complexes. We find that the homology model is able to predict essential features of the experimental data, including close contact of the hydrophobic aglycone and the Neu5Ac residue with the enzyme. Additionally, the model and STD NMR data agree on the facial recognition of the galactose and glucose residues of the GM3-analog studied. We conclude that the homology model of NEU3 can be used to predict substrate recognition, but our data indicate that unstructured portions of the NEU3 model may require further refinement.


CD34-positive infantile myofibromatosis: Case report and review of hemangiopericytoma-like pattern tumors.
We describe a case of CD34-positive infantile myofibromatosis with hemangiopericytoma-like pattern. A 2-day-old Japanese boy presented with multiple hemispherical nodules on the extremities and back. There was a biphasic histological growth in the dermis, accompanied by a hemangiopericytoma-like pattern with antler-like branching vessels. Tumor cells were oval to spindle-shaped myoid cells with bland appearance. Immunohistochemically, vimentin, calponin and CD34 were positive, while α-smooth muscle actin, h-caldesmon, HHF35 and desmin were negative. Although CD34 was positive, the present case could be diagnosed as infantile myofibromatosis. Myopericytoma, myofibroma/myofibromatosis, glomus tumor, glomangiopericytoma and angioleiomyoma share a continuous spectrum of benign hemangiopericytoma-like pattern tumors. Myofibroma/myofibromatosis is nearly included in myopericytoma among pericytic (perivascular) tumors, and could be positive for CD34. Several immunohistochemical panels of smooth muscle markers are needed for the diagnosis of pericytic (perivascular) tumors.


Structural basis for mobility in the 1.1 A crystal structure of the NG domain of Thermus aquaticus Ffh.
The NG domain of the prokaryotic signal recognition protein Ffh is a two-domain GTPase that comprises part of the prokaryotic signal recognition particle (SRP) that functions in co-translational targeting of proteins to the membrane. The interface between the N and G domains includes two highly conserved sequence motifs and is adjacent in sequence and structure to one of the conserved GTPase signature motifs. Previous structural studies have shown that the relative orientation of the two domains is dynamic. The N domain of Ffh has been proposed to function in regulating the nucleotide-binding interactions of the G domain. However, biochemical studies suggest a more complex role for the domain in integrating communication between signal sequence recognition and interaction with receptor. Here, we report the structure of the apo NG GTPase of Ffh from Thermus aquaticus refined at 1.10 A resolution. Although the G domain is very well ordered in this structure, the N domain is less well ordered, reflecting the dynamic relationship between the two domains previously inferred. We demonstrate that the anisotropic displacement parameters directly visualize the underlying mobility between the two domains, and present a detailed structural analysis of the packing of the residues, including the critical alpha4 helix, that comprise the interface. Our data allows us to propose a structural explanation for the functional significance of sequence elements conserved at the N/G interface.


Genetic research in the blood bank: acceptability to Northern California donors.
Blood banks have large altruistic donor populations and existing infrastructure that make them attractive sites for genetic epidemiologic research, but donors' willingness to participate and the impact on blood donation are unknown. A total of 2162 blood donors in Northern California responded to a cross-sectional questionnaire in August and September 2007. Participants were asked their likelihood of participation and future blood donation under three different scenarios: identity-linked genetic research, identity-unlinked genetic research, and genetic testing as a service. The majority of blood donors indicated that they would be likely or very likely to participate in identity-linked genetic research (67%) and in identity-unlinked genetic research (54%). While older donors and more frequent donors were more likely to participate in identity-linked research, younger, Caucasian, more educated, and more frequent donors were more likely to participate in identity-unlinked research. Less than 10% of donors indicated they would be less likely to donate blood in the future if genetic research was conducted at blood banks. More than 75% of donors would be interested in genetic testing as an optional service at the blood bank, but more than 20% of donors would be less likely to donate if such a service was offered. Overall, we found that the majority of blood donors would be likely to participate in genetic research and that less than 10% would be less inclined to donate if such research was conducted by blood banks.


(+)-Catechin inhibits intestinal tumor formation and suppresses focal adhesion kinase activation in the min/+ mouse.
Colorectal cancer is sensitive to dietary influences. Epidemiological data linking high intake of fruits and vegetables to decreased cancer risk have prompted the search for specific plant constituents implicated in tumor prevention. This task is difficult because of the complex chemical composition of plant foods and the multifactorial nature of carcinogenesis. Researchers are aided in this effort by the C57BL/6J-Min/+ (Min/+) mouse, an animal bearing a germline defect in Apc that is similar to the initiating genetic event in the majority of human colorectal cancers. In this study, we treated Min/+ mice with (+)-catechin, a phenolic antioxidant abundant in certain fruits. Administration of (+)-catechin in an AIN-76A diet at doses of 0.1 and 1% decreased the intestinal tumor number by 75 and 71%, respectively. Mechanistic studies linked this effect to (+)-catechin-induced changes in integrin-mediated intestinal cell-survival signaling, including structural alteration of the actin cytoskeleton and decreased focal adhesion kinase (FAK) tyrosine phosphorylation. Immunoblot analysis of small intestine scrapings from Min/+ mice and Apc+/+ wild-type C57BL/6J littermates together with excised Min/+ adenomas showed increased expression of phosphorylated FAK in the macroscopically normal enterocytes of untreated Min/+ mice and adenomas. Confirming the relevance of this signaling pathway, treatment of Min/+ mice with (+)-catechin reduced the expression of phosphorylated FAK to a level similar to the wild-type littermate controls. Thus, the natural abundance and favorable bioavailability of (+)-catechin make it a promising addition to the list of potential colorectal cancer chemopreventive agents.


Differential effects of retinal degeneration on sleep and wakefulness responses to short light-dark cycles in albino mice.
This study characterizes the different response patterns of sleep and wakefulness (W) to short light-dark (LD) cycles in albino mice and examines whether retinal degeneration resulting from prolonged bright light treatment and/or rd/rd mutation alters such response patterns. Eight young male Institute for Cancer Research (ICR) mice with normal eyes, seven young male rd/rd Friend Virus B type (FVB) mice, six young ICR and five young rd/rd FVB mice receiving 48-h bright light treatment, and five older rd/rd FVB mice were implanted with skull and muscle electrodes to record sleep and W. All the mice were maintained in 12-h-12-h LD cycles at baseline and received 2 days of short LD cycle treatment, which included 5-min-5-min LD cycles for a total of 24 cycles presented 4h after lights-on and again 4h after lights-off. All the five mouse groups maintained photo-entrainment of sleep and W rhythms at the baseline and showed a preference for paradoxical sleep (PS) occurrence in the 5-min dark period and non-rapid eye movement sleep (NREMS) in the 5-min light period and a brief alerting effect of light onset on experimental days. Retinal degeneration rising from bright light treatment and/or genetic mutation failed to eliminate or reduce the response of PS and NREMS to short LD cycles, although it enhanced the LD contrast of W, i.e., bright light treatment prolonged the alerting effect of light and the rd mutation increased the suppressing effect of the dark on W. These results suggest that sleep responses to short LD cycles and the brief alerting effect of light were independent of the photoreceptors in the outer retina. Furthermore, the residual photoreceptors in the outer retina and/or the photosensitive cells in the inner retina may actively modulate the effect of light and dark signals on W.


Rethinking the extrinsic incubation period of malaria parasites.
The time it takes for malaria parasites to develop within a mosquito, and become transmissible, is known as the extrinsic incubation period, or EIP. EIP is a key parameter influencing transmission intensity as it combines with mosquito mortality rate and competence to determine the number of mosquitoes that ultimately become infectious. In spite of its epidemiological significance, data on EIP are scant. Current approaches to estimate EIP are largely based on temperature-dependent models developed from data collected on parasite development within a single mosquito species in the 1930s. These models assume that the only factor affecting EIP is mean environmental temperature. Here, we review evidence to suggest that in addition to mean temperature, EIP is likely influenced by genetic diversity of the vector, diversity of the parasite, and variation in a range of biotic and abiotic factors that affect mosquito condition. We further demonstrate that the classic approach of measuring EIP as the time at which mosquitoes first become infectious likely misrepresents EIP for a mosquito population. We argue for a better understanding of EIP to improve models of transmission, refine predictions of the possible impacts of climate change, and determine the potential evolutionary responses of malaria parasites to current and future mosquito control tools.


Occupational risk factors for urothelial carcinoma: agent-specific results from a case-control study in Germany. MURC Study Group. Multicenter Urothelial and Renal Cancer.
This multicentre population-based case-control study was conducted to estimate the urothelial cancer risk for occupational exposure to aromatic amines, polycyclic aromatic hydrocarbons (PAH), and chlorinated hydrocarbons besides other suspected risk factors. In a population-based multicentre study, 1035 incident urothelial cancer cases and 4298 controls matched for region, sex, and age were interviewed between 1991 and 1995 for their occupational history and lifestyle habits. Exposure to the agents under study was self-assessed as well as expert-rated with two job-exposure matrices and a job task-exposure matrix. Conditional logistic regression was used to calculate smoking adjusted odds ratios (OR) and to control for study centre and age. Urothelial cancer risk following exposure to aromatic amines was only slightly elevated. Among males, substantial exposures to PAH as well as to chlorinated solvents and their corresponding occupational settings were associated with significantly elevated risks after adjustment for smoking (PAH exposure, assessed with a job-exposure matrix: OR = 1.6, 95% CI: 1.1-2.3, exposure to chlorinated solvents, assessed with a job task-exposure matrix: OR = 1.8, 95% CI: 1.2-2.6). Metal degreasing showed an elevated urothelial cancer risk among males (OR = 2.3, 95% CI: 1.4-3.8). In females also, exposure to chlorinated solvents indicated a urothelial cancer risk. Because of small numbers the risk evaluation for females should be treated with caution. Occupational exposure to aromatic amines could not be shown to be as strong a risk factor for urothelial carcinomas as in the past. A possible explanation for this finding is the reduction in exposure over the last 50 years. Our results strengthen the evidence that PAH may have a carcinogenic potential for the urothelium. Furthermore, our results indicate a urothelial cancer risk for the use of chlorinated solvents.


[Contact tracing a year back is worthwhile. Follow the Vasterbottens example to prevent Chlamydia transmission in Sweden!].
Contact tracing is proved to be a good way to prevent asymptomatic sexually transmitted infections, such as Chlamydia trachomatis, from spreading. According to the Swedish law a physician has to report all cases of genital C. trachomatis to the County Medical Officer of Health and to the National institute for Infectious Disease Control and perform contact tracing. An evaluation of the sexual history 6 months back in time is recommended and standard in most of the country. The county of Västerbotten has one of the lowest incidenses of C. trachomatis in Sweden though the population is younger than the Swedish average. During year 2002 the contact tracing in Västerbotten was evaluated by sending a questionnaire to everyone who reported a case of genital C. trachomatis. We recived 534 (98%) out of 544 questionnaires. The patients reported 1360 partners, 2.5 on average, 1129 were identified. 761 had a known test result and 497 of them were positive, 0.9 on average. 72% of the contact tracers evaluated the sexual history > or = 12 months back in time. 78% of the contact tracings were performed by four social workers. Their patients reported 2.5 partners on average and 80% evaluated > or = 12 months back in time. 14 persons did only one contact tracing, 1.3 partners/index on average, 40% evaluated > or = 12 months back in time. 82% of the partners had sex with the infected patient 0-6 months before the patients was diagnosed with C. trachomatis, 75% out of those with a known test result were infected, 16% had sex 7-12 months before diagnosis, 30% infected. (The C. trachomatis prevalence in Sweden is estimated to be 2.7-4.9% among young women.) A few experienced persons tracing for at least 12 month back in time is probably two important reasons why Västerbotten has such a small C. trachomatis incidence.


DNA damage is an early event in doxorubicin-induced cardiac myocyte death.
Anthracyclines are antitumor agents the main clinical limitation of which is cardiac toxicity. The mechanism of this cardiotoxicity is thought to be related to generation of oxidative stress, causing lethal injury to cardiac myocytes. Although protein and lipid oxidation have been documented in anthracycline-treated cardiac myocytes, DNA damage has not been directly demonstrated. This study was undertaken to determine whether anthracyclines induce cardiac myocyte DNA damage and whether this damage is linked to a signaling pathway culminating in cell death. H9c2 cardiac myocytes were treated with the anthracycline doxorubicin at clinically relevant concentrations, and DNA damage was assessed using the alkaline comet assay. Doxorubicin induced DNA damage, as shown by a significant increase in the mean tail moment above control, an effect ameliorated by inclusion of a free radical scavenger. Repair of DNA damage was incomplete after doxorubicin treatment in contrast to the complete repair observed in H2O2-treated myocytes after removal of the agent. Immunoblot analysis revealed that p53 activation occurred subsequent in time to DNA damage. By a fluorescent assay, doxorubicin induced loss of mitochondrial membrane potential after p53 activation. Chemical inhibition of p53 prevented doxorubicin-induced cell death and loss of mitochondrial membrane potential without preventing DNA damage, indicating that DNA damage was proximal in the events leading from doxorubicin treatment to cardiac myocyte death. Specific doxorubicin-induced DNA lesions included oxidized pyrimidines and 8-hydroxyguanine. DNA damage therefore appears to play an important early role in anthracycline-induced lethal cardiac myocyte injury through a pathway involving p53 and the mitochondria.


Computed tomography in endometrial carcinoma.
To determine the value of computed tomography (CT) scans for preoperatively detecting extrauterine-nodal disease and postoperative recurrent disease in patients with endometrial cancer. We reviewed records of 702 women with primary endometrial carcinoma that was diagnosed between 1979 and 1993. Preoperative CT findings were compared with pathologic findings to assess nodal disease. The yield of postoperative CT was reviewed in clinically suspicious and routine settings. Among 492 women eligible for analysis, 178 (36%) had a total 326 CT scans. Among 56 women who had preoperative CT scans and lymph node samplings, positive and negative predictive values for nodal involvement were 50% and 94%, respectively, and sensitivity and specificity were 57% and 92%, respectively. Preoperative CT findings altered treatment plans in only six patients (8%). Forty-five asymptomatic women had 73 routine CT scans, and recurrence was diagnosed by CT in only two (4.4%). Thirty-seven women had CT scans for suspicion of recurrence, which was confirmed in 17 (46%). Kaplan-Meyer analysis showed no survival advantage in women with subclinical recurrences diagnosed by CT scan. Routine preoperative CT scanning rarely alters treatment and is a poor predictor of nodal disease. Computed tomography in the postoperative period might be helpful for detection and follow-up of recurrent disease, but there was no difference in survival when subclinical recurrence was found by CT. Thus, CT scanning of any woman with endometrial cancer should be discouraged unless it is to evaluate symptoms.


Preference-based patient participation in intermediate care: Translation, validation and piloting of the 4Ps in Norway.
The implementation and evaluation of patient participation to obtain high-quality transitional care for older people is an international priority. Intermediate care (IC) services are regarded as an important part of the patient's pathway from the specialist to the primary care levels, bridging the gap between the hospital and the home. Patients may experience varying capacities and conditions for patient participation. Yet, few tools for evaluating patients' preferences for patient participation within IC services are at hand. Accordingly, further knowledge is needed to understand and scaffold processes for patient participation in IC. Therefore, the aim of this project was to translate, validate and pilot test the Patient Preferences for Patient Participation (the 4Ps) with patients in IC services in Norway. This project comprised two phases: (1) a careful translation and cultural adaptation process, followed by a content validity trial among 15 patients and staff in Norwegian IC and (2) a cross-sectional survey of the instrument with 60 patients admitted to IC. The translation between Swedish and Norwegian required no conceptual or contextual adaptations. The subsequent cross-sectional study, designed as a dialogue between the patients and staff, revealed that only 50% of the participants received a sufficient level of patient participation based on their preferences, mostly indicating that patients were receiving less-than-preferred conditions for engaging in their health and healthcare issues. The 4Ps instrument was deemed suitable for measuring patient participation based on patient preferences in the IC context and was feasible for both healthcare professionals and patients to complete in an interview when arriving at and leaving services. This may support person-centred communication and collaboration, calling for further research on what facilitates patient participation and the implementation of person-centred services for patients in IC. First, the current paper is part of the IPIC study (i.e., the implementation of patient participation in IC). Influenced by a James Lind Alliance process, the study addresses research uncertainties identified by patients, next of kin, staff and researchers in the cocreation process. Second, cognitive interviewing was conducted with 15 representatives of the target population: seven patients receiving IC services, one home-dwelling previous IC patient (altogether four women and four men, most of them 80 years or older) and seven healthcare staff working in IC services. The interviews determined the relevance, comprehensiveness and clarity of the 4Ps. Finally, 60 patients admitted to IC took part in the cross-sectional study.


Reduction of hypoxic-ischemic brain swelling in the neonatal rat with PAF antagonist WEB 2170: lack of long-term protection.
Platelet activating factor (PAF) is an inflammatory lipid mediator released by ischemic brain. Our objectives were to use an inhibitor of PAF that does not readily cross the blood-brain barrier, WEB 2170, to study the role of intravascular PAF on brain swelling and subsequent brain atrophy in a neonatal rat model of hypoxic-ischemic brain injury. We injured the right cerebral hemisphere of 7-d-old rats by ligating the right common carotid artery and exposing the rats to 8% oxygen for 2.25 h. Forty-two rats received saline or the PAF antagonist WEB 2170, 1 h before hypoxia. We found that WEB 2170 pretreatment reduced swelling by 64% (p = 0.003). In contrast, treatment immediately after hypoxic-ischemic injury did not reduce swelling. In two additional experiments involving 103 rats, we found that pretreatment or repeated doses of PAF antagonist before and after hypoxic-ischemic injury did not reduce atrophy. We also found that the brain-penetrating PAF antagonist, BN 52021, did not prevent atrophy in our Wistar rat model. In conclusion, we were unable to reduce long-term brain injury with either PAF antagonist. WEB 2170 pretreatment reduced brain swelling by 64% without reducing atrophy. This suggests that although brain swelling may accompany cerebral infarction, it does not contribute to the pathogenesis of infarction and subsequent atrophy in the neonatal rat. The ability to reduce early postischemic brain swelling without reducing atrophy may be particularly unique to the immature animal with a compliant skull.


Comparison of the clinical results of isolated Bankart and SLAP 5 lesions after arthroscopic repair.
This study aims to compare the clinical results of patients with traumatic isolated Bankart lesions and type V superior labrum anterior to posterior (SLAP) lesions after arthroscopic repair. Patients who underwent arthroscopic repair for traumatic anterior glenohumeral instability were evaluated retrospectively between December 2014 and January 2019. Fifty-one patients (49 males, 2 females; mean age 25 years; range, 18 to 36 years) without bone defects affecting >20% of the glenoid fossa, off-track engaging Hills-Sachs lesions, multidirectional instability, or ligamentous laxity were included in the study. Group 1 had 31 patients with isolated Bankart lesions and group 2 had 20 patients with type V SLAP lesions. There were only two female patients in group 1 and all patients were male in group 2. The mean age was 25 years (range, 18 to 36 years) in group 1 and 25 years (range, 19 to 35 years) in group 2. Rowe, Constant, and Western Ontario Shoulder Instability (WOSI) scoring systems were used to evaluate the clinical outcomes of the patients preoperatively and at the last follow-up. The mean follow-up time was 32 months (range, 12 to 48 months) in group 1 and 28.5 months (range, 12 to 42 months) in group 2. There were no statistically significant differences between the two groups in terms of the number of shoulder dislocations before the surgery, mean age at the time of surgery, and the mean time from the first dislocation to surgical treatment. When the Rowe, Constant, and WOSI scores were evaluated preoperatively and at the last follow-up, there were statistically significant changes within, but not between, the two groups. In type V SLAP lesions, the affected and repaired labrum surface area is larger than isolated Bankart lesions. However, as a result of appropriate surgical treatment, the affected surface area does not have a negative effect on clinical outcomes, and similar clinical results can be obtained in patients with type V SLAP lesions compared to patients with isolated Bankart lesions.


Influencing referral practice using feedback of adherence to NICE guidelines: a quality improvement report for dyspepsia.
Rising demand and increasing waiting times for upper gastrointestinal endoscopy (gastroscopy). Quality improvement study with pre- and post-intervention data collection. Three endoscopy units in two hospital trusts (Singleton, Morriston and Baglan Hospitals endoscopy units), UK. Number of gastroscopy requests from general practitioners (GPs) and hospital doctors; their adherence to dyspepsia referral guidelines and the referral-to-procedure interval for upper gastroscopy. Data collected for six months before and for five months after the intervention. Referrals were assessed against the National Institute for Health and Clinical Excellence (NICE) guidelines for the management of dyspepsia by two part-time GPs and feedback sent to clinicians where requests did not adhere to the referrals criteria Adherence to guideline criteria increased significantly among GPs after the intervention (from 55% to 75%). There was no similar effect for hospital doctors, although their adherence rate (70%) was at a higher level than that of GPs before the intervention. The number of gastroscopy referrals for dyspepsia declined after the intervention, particularly from hospital doctors where a drop of 31% was observed, from 26.6 to 18.4 referrals per week. With the inclusion of seasonal effects, an estimated drop of 3.2 referrals per week from general practice was not significant (p = 0.065) while an estimated drop of 10.0 referrals per week for hospital doctors was very significant (p<0.001). Referral assessment can be successfully introduced and shows promise as a way of improving the quality of referrals and reducing demand. Hospital clinicians are more resistant than GPs to referral assessment but nevertheless responded to the feedback by reducing their endoscopy gastroscopy requests. Most such referrals are generated in hospitals rather than in primary care: this finding has important implications for demand management.


[Results of international clinical trials with raloxifene].
A new drug class called Selective Estrogen Receptor Modulators (SERM) could combine ideal properties for a product designed for menopausal women. The most widely studied member of this class is raloxifene which is currently marketed in several countries for the prevention of osteoporosis in menopaused women. This product is a nonsteroidal derivative of benzothiophene which, like estrogens, has a preventive effect against bone loss involving the spine and peripheral skeleton and a cholesterol lowering effect, both in the ovariectomized rat and in menopausal women. Unlike estrogens, raloxifene does not stimulate breast or uterine tissue. These interesting properties make raloxifene a possible preventive treatment for osteoporosis and other menopause-related risks for menopausal women of all ages. Multicenter studies have been conducted in recently menopausal women who received either raloxifene at the doses of 30, 60, or 150 mg/day or a placebo in a randomized protocol. All subjects were also given calcium supplementation. Bone density was measured twice a year for 36 months by dual X-rays absorptiometry and showed a significant decrease at all sites in the placebo group while there was a significant increase in the spine, the hip and the overall skeleton for all three raloxifen groups. After 24 months of treatment, mean increase over placebo was 2.4% for 60 mg raloxifene measured on the spine and total hip and 2% for the overall skeleton. Markers of bone formation (serum osteocalcin and bone alkaline phasphatase) and resorption (urinary CrossLaps) decreased significantly reaching, after 3 to 6 months of treatment, the levels observed in non menopausal women. In addition, total serum cholesterol as well as LDL-cholesterol decreased significantly in a dose-dependent fashion in all groups treated with raloxifene. Serum HDL-cholesterol and triglycerides did not very significantly during treatment. Hot flashes were the most frequently observed undesirable effect, at a frequency slightly higher in the raloxifene group (25%) than in the placebo group (18%). This undesirable effect was of low intensity and generally occurred during the first months of treatment. It did not cause a higher drop out rate (raloxifen 1.5%; placebo 2.1%). The preliminary data at two years follow-up suggest that raloxifene is not associated with an increased risk of breast cancer. In conclusion, raloxifene is a particularly interesting drug for menopausal women showing very promising efficacy and clinical tolerance.