Imaging-guided Parenchymal Liver Biopsy: How We Do It.
Liver biopsies are performed for both focal and nonfocal lesions (parenchymal). In our center, majority of liver biopsies are performed for parenchymal liver disease. Parenchymal liver biopsy plays a key role in the diagnosis of various diffuse liver dysfunctions. Results of the biopsy help grade the disease, facilitating prognostication, which helps in planning specific treatment strategies. Imaging guidance is gaining wide acceptance as the standard procedure. Ultrasound (US) guidance is currently considered the most cost-effective and safe way to perform parenchymal liver biopsies. Radiologists worldwide and particularly in the United States are increasingly performing this procedure. Radiologists performing biopsies generally use the cutting needle. Different needle sizes, techniques and preference for biopsy of the right or left lobe have been described. We attribute these preferences to prior training and individual radiologist's comfort level. We describe the algorithm followed at our institution for performing percutaneous US-guided parenchymal liver biopsy. While clinical societies have recommended a minimum of 40 liver biopsies as a requirement for proficiency of clinicians, specific to radiology trainees/fellows interested in pursuing a career in intervention, we feel a total of 20 liver biopsies (includes assisted and independently performed biopsies under supervision) should be adequate training.


Shotgun proteomics implicates protease inhibition and complement activation in the antiinflammatory properties of HDL.
HDL lowers the risk for atherosclerotic cardiovascular disease by promoting cholesterol efflux from macrophage foam cells. However, other antiatherosclerotic properties of HDL are poorly understood. To test the hypothesis that the lipoprotein carries proteins that might have novel cardioprotective activities, we used shotgun proteomics to investigate the composition of HDL isolated from healthy subjects and subjects with coronary artery disease (CAD). Unexpectedly, our analytical strategy identified multiple complement-regulatory proteins and a diverse array of distinct serpins with serine-type endopeptidase inhibitor activity. Many acute-phase response proteins were also detected, supporting the proposal that HDL is of central importance in inflammation. Mass spectrometry and biochemical analyses demonstrated that HDL3 from subjects with CAD was selectively enriched in apoE, raising the possibility that HDL carries a unique cargo of proteins in humans with clinically significant cardiovascular disease. Collectively, our observations suggest that HDL plays previously unsuspected roles in regulating the complement system and protecting tissue from proteolysis and that the protein cargo of HDL contributes to its antiinflammatory and antiatherogenic properties.


Antioxidative phytochemicals from Rhododendron oldhamii Maxim. leaf extracts reduce serum uric acid levels in potassium oxonate-induced hyperuricemic mice.
Some of the genus Rhododendron was used in traditional medicine for arthritis, acute and chronic bronchitis, asthma, pain, inflammation, rheumatism, hypertension and metabolic diseases and many species of the genus Rhododendron contain a large number of phenolic compounds and antioxidant properties that could be developed into pharmaceutical products. In this study, the antioxidative phytochemicals of Rhododendron oldhamii Maxim. leaves were detected by an online HPLC-DPPH method. In addition, the anti-hyperuricemic effect of the active phytochemicals from R. oldhamii leaf extracts was investigated using potassium oxonate (PO)-induced acute hyperuricemia. Six phytochemicals, including (2R, 3R)-epicatechin (1), (2R, 3R)-taxifolin (2), (2R, 3R)-astilbin (3), hyposide (4), guaijaverin (5), and quercitrin (6), were isolated using the developed screening method. Of these, compounds 3, 4, 5, and 6 were found to be major bioactive phytochemicals, and their contents were determined to be 130.8 ± 10.9, 105.5 ± 8.5, 104.1 ± 4.7, and 108.6 ± 4.0 mg per gram of EtOAc fraction, respectively. In addition, the four major bioactive phytochemicals at the same dosage (100 mmol/kg) were administered to the abdominal cavity of potassium oxonate (PO)-induced hyperuricemic mice, and the serum uric acid level was measured after 3 h of administration. H&E staining showed that PO-induced kidney injury caused renal tubular epithelium nuclear condensation in the cortex areas or the appearance of numerous hyaline casts in the medulla areas; treatment with 100 mmol/kg of EtOAc fraction, (2R, 3R)-astilbin, hyposide, guaijaverin, and quercitrin significantly reduced kidney injury. In addition, the serum uric acid level was significantly suppressed by 54.1, 35.1, 56.3, 56.3, and 53.2 %, respectively, by the administrations of 100 mmol/kg EtOAc fraction and the derived major phytochemicals, (2R, 3R)-astilbin, hyposide, guaijaverin, and quercitrin, compared to the PO group. The administration of 10 mg/kg benzbromarone, a well-known uricosuric agent, significantly reduced the serum uric acid level by 45.5 % compared to the PO group. The in vivo decrease in uric acid was consistent with free radical scavenging activity, indicating that the major phytochemicals of R. oldhamii leave extracts and the derived phytochemicals possess potent hypouricemic effects, and they could be potential candidates for new hypouricemic agents.


Developing a fall prevention program: what are the views and opinions of people with multiple sclerosis?
Falls are common in people with multiple sclerosis (MS), yet there are a few targeted fall prevention programs. Existing programs report a high dropout rate and a low adherence, which may be due to a mismatch between program characteristics and participants preferences. To clarify a possible discrepancy, this study investigates the views and opinions of persons with MS on fall prevention programs. Two focus groups (n = 11) were conducted with people with MS who have a history of falls, near falls or who are concerned about their balance/falling risk. The data were analyzed using a qualitative content analysis with an inductive approach. Participants preferred short-term programs taking place in rehabilitation clinics, or physiotherapy or occupational therapy practices. They believed that the awareness for fall prevention needs to be raised among healthcare professionals. Participants expected better consultation from physio and occupational therapists regarding mobility aids and home modification. The participants wanted the programs to be practical, in-person and in groups. Online interventions were strongly rejected. Further, participants wanted balance/strength exercises and the inclusion of falling techniques in programs. The competence of knowing and accepting capacity may be an important factor in preventing falls. Investigating the views and opinions of persons with MS on fall prevention programs gave important information which can be used to inform the development of such programs.IMPLICATIONS FOR REHABILITATIONPeople with multiple sclerosis (MS) prefer short-term fall prevention programs that are practical, in-person and in groups. Online interventions were strongly rejected.People with MS want balance/strength exercises and falling techniques included within fall prevention programs.People with MS believe that awareness regarding falls prevention needs to be raised among healthcare professionals. Also, services regarding mobility aids and home modification from physio and occupational therapists are currently unsatisfactory.People with MS believe that competence in knowing and accepting their capacity to engage in activities may be a decisive factor in preventing falls.


The forkhead transcription factor Foxo1 links insulin signaling to Pdx1 regulation of pancreatic beta cell growth.
Diabetes is caused by an absolute (type 1) or relative (type 2) deficiency of insulin-producing beta cells. The mechanisms governing replication of terminally differentiated beta cells and neogenesis from progenitor cells are unclear. Mice lacking insulin receptor substrate-2 (Irs2) develop beta cell failure, suggesting that insulin signaling is required to maintain an adequate beta cell mass. We report that haploinsufficiency for the forkhead transcription factor Foxo1 reverses beta cell failure in Irs2(-/-) mice through partial restoration of beta cell proliferation and increased expression of the pancreatic transcription factor pancreas/duodenum homeobox gene-1 (Pdx1). Foxo1 and Pdx1 exhibit mutually exclusive patterns of nuclear localization in beta cells, and constitutive nuclear expression of a mutant Foxo1 is associated with lack of Pdx1 expression. We show that Foxo1 acts as a repressor of Foxa2-dependent (Hnf-3beta-dependent) expression from the Pdx1 promoter. We propose that insulin/IGFs regulate beta cell proliferation by relieving Foxo1 inhibition of Pdx1 expression in a subset of cells embedded within pancreatic ducts.


Usual dietary salt intake and asthma in children: a case-control study.
A decline in host resistance due to an alteration in diet--primarily of salt--was recently put forward as a possible explanation for rising rates of asthma. A case-control study was conducted in participants in a prevalence survey which included 187 children with asthma (defined by prior diagnosis and/or a decline in forced expiratory volume in one second (FEV1) of > or = 10% after exercise) and 145 age and sex matched controls. Subjects were selected from 989 children aged 5-13 years attending 18 elementary schools on the island of Montreal. Usual dietary salt intake was estimated from a food frequency questionnaire administered to the mother, and a salt intake score was used to group the children into quartiles from I (lowest) to IV (highest salt intake). Bronchial hyperresponsiveness to methacholine was assessed by Yan's method. Cases and controls were combined in one group to examine the relationship of salt intake to bronchial hyperresponsiveness to methacholine. Methacholine responsiveness was expressed as a dose-response slope and ranks of dose-response slopes were used in the analysis. After accounting for important confounding variables, there was no association between asthma and salt intake, while methacholine dose-response slope ranks increased with increasing salt intake and methacholine responsiveness was greater in the highest quartile than in the lowest quartile of salt intake. The median dose-response slopes in % fall in FEV1 per mumol methacholine for quartiles I, II, III, and IV were 5.4, 5.9, 7.7, and 8.7. No association was found between asthma or exercise-induced bronchospasm and dietary salt intake. Bronchial hyperresponsiveness to methacholine did, however, appear to increase with greater salt intake, but the relevance of this association to asthma is unclear.


Autoreactive CD19+CD20- Plasma Cells Contribute to Disease Severity of Experimental Autoimmune Encephalomyelitis.
The contribution of autoantibody-producing plasma cells in multiple sclerosis (MS) remains unclear. Anti-CD20 B cell depletion effectively reduces disease activity in MS patients, but it has a minimal effect on circulating autoantibodies and oligoclonal bands in the cerebrospinal fluid. Recently we reported that MEDI551, an anti-CD19 mAb, therapeutically ameliorates experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. MEDI551 potently inhibits pathogenic adaptive immune responses, including depleting autoantibody-producing plasma cells. In the present study, we demonstrated that CD19 mAb treatment ameliorates EAE more effectively than does CD20 mAb. Myelin oligodendrocyte glycoprotein-specific Abs and short-lived and long-lived autoantibody-secreting cells were nearly undetectable in the CD19 mAb-treated mice, but they remained detectable in the CD20 mAb-treated mice. Interestingly, residual disease severity in the CD20 mAb-treated animals positively correlated with the frequency of treatment-resistant plasma cells in the bone marrow. Of note, treatment-resistant plasma cells contained a substantial proportion of CD19(+)CD20(-) plasma cells, which would have otherwise been targeted by CD19 mAb. These data suggested that CD19(+)CD20(-) plasma cells spared by anti-CD20 therapy likely contribute to residual EAE severity by producing autoreactive Abs. In patients with MS, we also identified a population of CD19(+)CD20(-) B cells in the cerebrospinal fluid that would be resistant to CD20 mAb treatment.


L-selectin-mediated lymphocyte-cancer cell interactions under low fluid shear conditions.
Cell migration in blood flow is mediated by engagement of specialized adhesion molecules that function under hemodynamic shear conditions, and many of the effectors of these adhesive interactions, such as the selectins and their ligands, are well defined. However, in contrast, our knowledge of the adhesion molecules operant under lymphatic flow conditions is incomplete. Among human malignancies, head and neck squamous cell cancer displays a marked predilection for locoregional lymph node metastasis. Based on this distinct tropism, we hypothesized that these cells express adhesion molecules that promote their binding to lymphoid tissue under lymphatic fluid shear stress. Accordingly, we investigated adhesive interactions between these and other cancer cells and the principal resident cells of lymphoid organs, lymphocytes. Parallel plate flow chamber studies under defined shear conditions, together with biochemical analyses, showed that human head and neck squamous cell cancer cells express heretofore unrecognized L-selectin ligand(s) that mediate binding to lymphocyte L-selectin at conspicuously low shear stress levels of 0.07-0.08 dynes/cm(2), consistent with lymphatic flow. The binding of head and neck squamous cancer cells to L-selectin displays canonical biochemical features, such as requirements for sialylation, sulfation, and N-glycosylation, but displays a novel operational shear threshold differing from all other L-selectin ligands, including those expressed on colon cancer and leukemic cells (e.g. HCELL). These data define a novel class of L-selectin ligands and expand the scope of function for L-selectin within circulatory systems to now include a novel activity within shear stresses characteristic of lymphatic flow.


The importance of phospholipids combined with long-chain PUFA in formulated diets for pikeperch (Sander lucioperca) larvae.
Dietary phosphoglycerides and n-3 long-chain PUFA (LC-PUFA) play important functions in the development of pikeperch (Sander lucioperca) larvae. This study aimed to determine optimal dietary levels of soyabean lecithin (SBL)-derived phospholipids (PL) in starter feeds for pikeperch larvae 10-30 d post-hatch (DPH) and examine performance and ontogeny by additional supplementation of n-3 LC-PUFA in the form of Algatrium DHA 70 (glyceride product; 660-700 mg/g DHA; EPA 60-75 mg/g). In total, six isoproteic and isoenergetic extruded diets were formulated with increasing levels of PL (3·7, 8·3 or 14·5 % wet weight (w.w.), respectively); however, three of the diets were supplemented with three levels of Algatrium DHA 70 (0·6, 2·0 or 3·4 %, respectively). Liver proteomic analyses of larvae at 30 DPH were included for effects of PL and primarily DHA on performance, physiological expression and interactions in larval proteins. In addition, bone anomalies, digestive enzymatic activity, candidate gene expression and skeleton morphogenesis were examined. Results confirmed the importance of dietary PL levels of at least 8·2 % w.w., and an additional beneficiary effect of supplementation with DHA plus EPA. Thus, combined supplementation of SBL (up to 14·51 % w.w. PL) and n-3 LC-PUFA (1·004 % DM DHA and 0·169 % DM EPA) in the form of TAG resulted in highest growth and lowest incidence of anomalies, improved digestive enzyme activity and had differential effect on liver proteomics. The results denote that essential fatty acids can be supplemented as TAG to have beneficial effects in pikeperch larvae development.


Evolving the comprehensive management of rheumatoid arthritis: identification of unmet needs and development of practical and educational tools.
Despite availability of efficacious treatments, unmet needs still exist, preventing optimal and comprehensive management of rheumatoid arthritis (RA). Evolving the management of RA (eRA) is a European-wide educational initiative aiming to support improved patient care through practical and educational tools addressing specific unmet needs. A multidisciplinary Steering Committee (17 members, 12 countries) identified unmet needs within the management of RA and prioritised those with the greatest impact on patient outcomes. Practical educational tools addressing priority needs were then developed for dissemination and implementation by the rheumatology community across Europe. Five areas of priority need were identified: increasing early recognition of RA and treatment initiation; treating RA to target; optimal, holistic approach to selection of treatment strategy, including shared decision-making; improving identification and management of comorbidities; and non-pharmacological patient management. A suite of 14 eRA tools included educational slides, best-practice guidance, self‑assessment questionnaires, clinical checklists, a multidisciplinary team training exercise, an interactive patient infographic, and case scenarios. By April 2020, rheumatology professionals in 17 countries had been actively engaged in the eRA programme; in 11 countries, eRA tools were selected by national leaders in rheumatology and translated for local dissemination. A web platform, with country-specific pages, was developed to support access to the translated tools (https://www.evolvingthemanagementofra.com/). The eRA programme supports comprehensive management of RA across Europe through development and dissemination of practical educational tools. The eRA tools address priority needs and are available free of charge to the rheumatology community.


Polymorphisms in the adenomatous polyposis coli gene in Slovak families suspected of FAP.
Polymorphism in the adenomatous polyposis coli (APC) gene was analyzed in 33 families suspected of familial adenomatous polyposis (FAP) without identified APC gene mutation. Screening of 104 members of mentioned families for polymorphism in the APC gene, was performed using single strand conformation polymorphism (SSCP) and DNA sequencing. Twelve different types of polymorphism were found in the cohort of the families analyzed. Nine polymorphisms were located within exon 15, one within exon 6, one within exon 11 and one within exon 13. Of the 12 polymorphisms, 11 were silent substitution and only one was responsible for the amino acid change - D1822V, which was identified in 60% of the families analyzed. The most frequently detected polymorphism D1822V is potentially associated with the risk of colorectal cancer. Three detected polymorphisms - Y486Y, T1493T and S1756S - also seem to be associated with colon cancer risk. All these polymorphisms may be used as markers for diagnosis of colorectal cancer. The importance of other detected polymorphisms remains still unclear, but their involvement is being continuously observed.


Molecular mechanisms for alpha2-adrenoceptor-mediated regulation of synoviocyte populations.
The sympathetic nervous system has been indicated to influence the severity of inflammatory disease including rheumatoid arthritis. In this study, we elucidated the effects of catecholamine on the synovial cell populations. Stimulation with epinephrine or norepinephrine for 1-2 weeks dose- and time-dependently increased the number of synovial A (macrophage-like) cells but decreased that of B (fibroblast-like) cells. These responses in A and B cells were inhibited by the alpha2-antagonist yohimbine, the G-protein inactivator pertussis toxin and the phospholipase C (PLC) inhibitor U-73122. Furthermore, the protein kinase C (PKC) inhibitor calphostin C and mitogen-activated protein (MAP) kinase inhibitors PD98059 and wortmannin also abolished the norepinephrine effects on A and B cell numbers. In A cells cloned from an A and B cell mixture, norepinephrine also increased the cell number. In immunoblotting and immunocytostaining analyses, among the PKC isozymes, only PKC betaII immunoreactivity was observed in the cytoplasm of unstimulated A and B cells. After alpha2-adrenoceptor stimulation, PKC betaII immunoreactivity increased in the plasma membranes of both A and B cells with decreases in the cytoplasm. These findings indicated that alpha2-adrenoceptor stimulation of type A and B synoviocytes produced an increase and a decrease in the respective cell number, probably through Gi-coupled PLC activation and the resulting stimulation of the PKC betaII/MAP kinase.


The association of prison security level with mortality after release from prison: a retrospective national cohort study (2000-16).
Incarceration might contribute to increased mortality in an already marginalised population. A better understanding of the prison-related factors that are associated with mortality is important for preventing the negative health consequences of incarceration. We aimed to investigate all-cause and cause-specific mortality following release from high-security and low-security prisons. In this retrospective national cohort study, we used data from the Norwegian Prison Release study (nPRIS), which includes complete national register data for 96 859 individuals from the Norwegian Prison Register linked to the Norwegian Cause of Death Register from Jan 1, 2000, to Dec 31, 2016. The study cohort included all people in Norway released from a high-security or low-security prison unit. Cause of death was categorised into internal causes (infectious, cancerous, endocrine, circulatory, respiratory, digestive, nervous system diseases, and mental health disorders) and external causes (accidents, suicides, and homicides) according to the 10th revision of the International Classification of Diseases. We calculated crude mortality rates (CMR) and estimated Cox proportional-hazards models. There were 151 790 releases in the study period (68·4% from low-security and 31·6% from high-security prisons) from 91 963 individuals. The overall CMR was 854·4 [95% CI 834·7-874·2] per 100 000 person-years (436·2 [422·1-450·3] per 100 000 person-years for internal causes and 358·3 [345·5-371·1] per 100 000 person-years for external causes). The overall post-release mortality rate was higher in those released from high-security prisons (1142·5 [95% CI 1102·6-1182·5] per 100 000 person-years) than in those released from low-security prisons (714·6 [692·6-736·6] per 100 000 person-years). Our results suggest an association between release from high-security prisons and elevated mortality due to both external causes (adjusted hazard ratio [aHR] 1·75 [95% CI 1·60-1·91]) and internal causes (1·45 [1·33-1·59]), compared to release from low-security prisons. Imprisonment and the post-release period can be an important point for public health interventions. Particular attention to health is warranted for individuals incarcerated in and released from high-security prisons. The potential impact of both individual-level characteristics of people incarcerated in high-security facilities, and of the prison environment itself, on mortality outcomes, should be investigated further. The South-Eastern Norway Regional Health Authority and The Norwegian Research Council.


Differential effects of cognitive load on subjective versus motor responses to ambiguously valenced facial expressions.
Valence is a principal dimension by which we understand emotional experiences, but oftentimes events are not easily classified as strictly positive or negative. Inevitably, individuals vary in how they tend to interpret the valence of ambiguous situations. Surprised facial expressions are one example of a well-defined, ambiguous affective event that induces trait-like differences in the propensity to form a positive or negative interpretation. To investigate the nature of this affective bias, we asked participants to organize emotional facial expressions (surprised, happy, sad) into positive/negative categories while recording their hand-movement trajectories en route to each response choice. We found that positivity-negativity bias resulted in differential hand movements for modal versus nonmodal response trajectories, such that when an individual categorized a surprised face according to his or her nonmodal interpretation (e.g., a negatively biased individual selecting a positive interpretation), the hand showed an enhanced spatial attraction to the alternative, modal response option (e.g., negative) in the opposite corner of the computer screen (Experiment 1). Critically, we also demonstrate that this asymmetry between modal versus nonmodal response trajectories is mitigated when the valence interpretations are made under a cognitive load, although the frequency of modal interpretations is unaffected by the load (Experiment 2). These data inform a body of seemingly disparate findings regarding the effect of cognitive effort on affective responses, by showing within a single paradigm that varying cognitive load selectively alters the dynamic motor movements involved in indicating affective interpretations, whereas the subjective interpretations themselves remain consistent across variable cognitive loads. (PsycINFO Database Record


Five ovine mitochondrial lineages identified from sheep breeds of the near East.
Archaeozoological evidence indicates that sheep were first domesticated in the Fertile Crescent. To search for DNA sequence diversity arising from previously undetected domestication events, this survey examined nine breeds of sheep from modern-day Turkey and Israel. A total of 2027 bp of mitochondrial DNA (mtDNA) sequence from 197 sheep revealed a total of 85 haplotypes and a high level of genetic diversity. Six individuals carried three haplotypes, which clustered separately from the known ovine mtDNA lineages A, B, and C. Analysis of genetic distance, mismatch distribution, and comparisons with wild sheep confirmed that these represent two additional mtDNA lineages denoted D and E. The two haplogroup E sequences were found to link the previously identified groups A and C. The single haplogroup D sequence branched with the eastern mouflon (Ovis orientalis), urial (O. vignei), and argali (O. ammon) sheep. High sequence diversity (K = 1.86%, haplogroup D and O. orientalis) indicates that the wild progenitor of this domestic lineage remains unresolved. The identification in this study of evidence for additional domestication events adds to the emerging view that sheep were recruited from wild populations multiple times in the same way as for other livestock species such as goat, cattle, and pig.


Spinal cord stimulator explantation for magnetic resonance imaging: a case series.
Spinal cord stimulator (SCS) systems are implanted to treat pain conditions such as neuropathic, radicular, and ischemic pain syndromes. Prior to July 2013, SCS systems were not magnetic resonance imaging (MRI) compatible due to the risk of thermal injury at the site of the leads and generator. Although there are some case reports of patients undergoing MRI studies with SCS systems in place, these stimulators are frequently explanted when clinical care has necessitated an MRI. The purpose of this case series is to discuss the role of SCS explantation in order to acquire an MRI. This study was performed at a tertiary academic pain medicine clinic. After exempt status was obtained via the institutional review board, patients were identified via the use of Common Procedural Terminology codes for implantable devices. A chart review was performed to identify all patients >18 years of age who had a lumbar or thoracic dorsal column SCS implanted during January 2001-December 2011. The charts were then followed to identify any patients who underwent a surgery for explantation of the device. Data collection included the total number of patients undergoing permanent SCS implantation, the total number of explantation of these devices, patient demographic factors, indication for SCS implantation, incidence of revisions and the indication, duration between implantation and explant of the device, and indication for explantation. During the time between 2001 and 2011, 199 patients were identified who underwent a thoracic or lumbar SCS implant after a successful trial. Among 199 implants, 33 devices were explanted, and of these, four were explanted due to the primary need for an MRI scan.


Strengthening Youth Friendly Health Services through Expanding Method Choice to include Long-Acting Reversible Contraceptives for Ethiopian Youth.
Despite robust evidence regarding long-acting reversible contraceptive (LARC) low failure rates, immediate return to fertility and safety, LARC uptake among youth is low. We evaluated the effect on contraceptive uptake of training youth-friendly service providers to counsel and provide all contraceptive methods including LARCs in the same unit. A convenience purposive sampling technique was used to select 20 youth friendly health units; ten each in Amhara and Tigray regions, Ethiopia; randomly allocated to the intervention (five) and non-intervention (five) arms. Data were abstracted from the family planning registers over an eleven-month period: three months pre-intervention and eight months post-intervention. Analysis of contraceptive uptake and chi-square tests of association were conducted. The number of LARCs new acceptors in the intervention arm was 781 (pre-intervention=116; post intervention=665) as compared to 358 in the non-intervention arm (pre-intervention=95; post intervention=263). Odds of adopting LARCs at pre-intervention (0.70); rose to 1.30 for the post-intervention phase (p-value <0.0001); comparing intervention to non-intervention study arms. Training youth friendly service providers to counsel and provide all contraceptive methods including LARCs in one location resulted in higher LARCs uptake for all sexually active young women; including those planning on delaying their first pregnancy.


The logic of kinetic regulation in the thioredoxin system.
The thioredoxin system consisting of NADP(H), thioredoxin reductase and thioredoxin provides reducing equivalents to a large and diverse array of cellular processes. Despite a great deal of information on the kinetics of individual thioredoxin-dependent reactions, the kinetic regulation of this system as an integrated whole is not known. We address this by using kinetic modeling to identify and describe kinetic behavioral motifs found within the system. Analysis of a realistic computational model of the Escherichia coli thioredoxin system revealed several modes of kinetic regulation in the system. In keeping with published findings, the model showed that thioredoxin-dependent reactions were adaptable (i.e. changes to the thioredoxin system affected the kinetic profiles of these reactions). Further and in contrast to other systems-level descriptions, analysis of the model showed that apparently unrelated thioredoxin oxidation reactions can affect each other via their combined effects on the thioredoxin redox cycle. However, the scale of these effects depended on the kinetics of the individual thioredoxin oxidation reactions with some reactions more sensitive to changes in the thioredoxin cycle and others, such as the Tpx-dependent reduction of hydrogen peroxide, less sensitive to these changes. The coupling of the thioredoxin and Tpx redox cycles also allowed for ultrasensitive changes in the thioredoxin concentration in response to changes in the thioredoxin reductase concentration. We were able to describe the kinetic mechanisms underlying these behaviors precisely with analytical solutions and core models. Using kinetic modeling we have revealed the logic that underlies the functional organization and kinetic behavior of the thioredoxin system. The thioredoxin redox cycle and associated reactions allows for a system that is adaptable, interconnected and able to display differential sensitivities to changes in this redox cycle. This work provides a theoretical, systems-biological basis for an experimental analysis of the thioredoxin system and its associated reactions.


Pseudomonas aeruginosa Alters Its Transcriptome Related to Carbon Metabolism and Virulence as a Possible Survival Strategy in Blood from Trauma Patients.
Trauma patients (TPs) are highly susceptible to infections, which often lead to sepsis. Among the numerous causative agents, Pseudomonas aeruginosa is especially important, as P. aeruginosa sepsis is often fatal. Understanding the mechanism of its pathogenesis in bloodstream infections is imperative; however, this mechanism has not been previously described. To examine the effect of trauma-induced changes in blood on the expression of P. aeruginosa genes, we grew strain UCBPP-PA14 (PA14) in blood samples from eight TPs and seven healthy volunteers (HVs). Compared with its growth in blood from HVs, the growth of PA14 in blood from TPs significantly altered the expression of 285 genes. Genes whose expression was significantly increased were related to carbon metabolism, especially malonate utilization and mannitol uptake, and efflux of heavy metals. Genes whose expression was significantly reduced included genes of the type VI secretion system, genes related to uptake and metabolism of amino acids, and genes related to biosynthesis and transport of the siderophores pyoverdine and pyochelin. These results suggest that during systemic infection in trauma patients, and to adapt to the trauma-induced changes in blood, P. aeruginosa adjusts positively and negatively the expression of numerous genes related to carbon metabolism and virulence, respectively. IMPORTANCE While a considerable body of knowledge regarding sepsis in trauma patients is available, the potential influence of trauma-induced changes in the blood of these patients on the pathogenesis of Pseudomonas aeruginosa is basically an unexplored area. Rather than using standard laboratory media, we grew P. aeruginosa in whole blood from either healthy volunteers or trauma patients. The specific changes in the P. aeruginosa transcriptome in response to growth in blood from trauma patients reflect the adaptation of this organism to the bloodstream environment. This knowledge is vital for understanding the strategies this pathogen uses to adapt and survive within the host during systemic infection. Such information will help researchers and clinicians to develop new approaches for treatment of sepsis caused by P. aeruginosa in trauma patients, especially in terms of recognizing the effects of specific therapies (e.g., iron, zinc, or mannitol) on the organism. Further, this information can most likely be extrapolated to all patients with P. aeruginosa septicemia.


How do scientists perceive the current publication culture? A qualitative focus group interview study among Dutch biomedical researchers.
To investigate the biomedical scientist's perception of the prevailing publication culture. Qualitative focus group interview study. Four university medical centres in the Netherlands. Three randomly selected groups of biomedical scientists (PhD, postdoctoral staff members and full professors). Main themes for discussion were selected by participants. Frequently perceived detrimental effects of contemporary publication culture were the strong focus on citation measures (like the Journal Impact Factor and the H-index), gift and ghost authorships and the order of authors, the peer review process, competition, the funding system and publication bias. These themes were generally associated with detrimental and undesirable effects on publication practices and on the validity of reported results. Furthermore, senior scientists tended to display a more cynical perception of the publication culture than their junior colleagues. However, even among the PhD students and the postdoctoral fellows, the sentiment was quite negative. Positive perceptions of specific features of contemporary scientific and publication culture were rare. Our findings suggest that the current publication culture leads to negative sentiments, counterproductive stress levels and, most importantly, to questionable research practices among junior and senior biomedical scientists.


EPISPOT: An epigenome-driven approach for detecting and interpreting hotspots in molecular QTL studies.
We present EPISPOT, a fully joint framework which exploits large panels of epigenetic annotations as variant-level information to enhance molecular quantitative trait locus (QTL) mapping. Thanks to a purpose-built Bayesian inferential algorithm, EPISPOT accommodates functional information for both cis and trans actions, including QTL hotspot effects. It effectively couples simultaneous QTL analysis of thousands of genetic variants and molecular traits with hypothesis-free selection of biologically interpretable annotations which directly contribute to the QTL effects. This unified, epigenome-aided learning boosts statistical power and sheds light on the regulatory basis of the uncovered hits; EPISPOT therefore marks an essential step toward improving the challenging detection and functional interpretation of trans-acting genetic variants and hotspots. We illustrate the advantages of EPISPOT in simulations emulating real-data conditions and in a monocyte expression QTL study, which confirms known hotspots and finds other signals, as well as plausible mechanisms of action. In particular, by highlighting the role of monocyte DNase-I sensitivity sites from >150 epigenetic annotations, we clarify the mediation effects and cell-type specificity of major hotspots close to the lysozyme gene. Our approach forgoes the daunting and underpowered task of one-annotation-at-a-time enrichment analyses for prioritizing cis and trans QTL hits and is tailored to any transcriptomic, proteomic, or metabolomic QTL problem. By enabling principled epigenome-driven QTL mapping transcriptome-wide, EPISPOT helps progress toward a better functional understanding of genetic regulation.


Antibacterial cannabinoids from Cannabis sativa: a structure-activity study.
Marijuana (Cannabis sativa) has long been known to contain antibacterial cannabinoids, whose potential to address antibiotic resistance has not yet been investigated. All five major cannabinoids (cannabidiol (1b), cannabichromene (2), cannabigerol (3b), Delta (9)-tetrahydrocannabinol (4b), and cannabinol (5)) showed potent activity against a variety of methicillin-resistant Staphylococcus aureus (MRSA) strains of current clinical relevance. Activity was remarkably tolerant to the nature of the prenyl moiety, to its relative position compared to the n-pentyl moiety (abnormal cannabinoids), and to carboxylation of the resorcinyl moiety (pre-cannabinoids). Conversely, methylation and acetylation of the phenolic hydroxyls, esterification of the carboxylic group of pre-cannabinoids, and introduction of a second prenyl moiety were all detrimental for antibacterial activity. Taken together, these observations suggest that the prenyl moiety of cannabinoids serves mainly as a modulator of lipid affinity for the olivetol core, a per se poorly active antibacterial pharmacophore, while their high potency definitely suggests a specific, but yet elusive, mechanism of activity.


Kidney biopsy findings in primary Sjögren syndrome.
Renal involvement is rare in primary Sjögren syndrome (PSS). In this study, we examined renal biopsy findings in patients with PSS and correlated them with their clinical and renal findings. Twenty-five patients with PSS who underwent renal biopsies from two renal units in Scotland between 1978 and 2013 were identified from renal biopsy database. We examined the renal morphologic, clinical and renal findings at the time of renal biopsy, renal and patient outcomes. The diagnosis of PSS preceded renal biopsy in 18/25 patients. In this group, the median duration of the disease was 5.5 years. Significant proteinuria, combined microscopic haematuria and proteinuria and reduced renal excretory function were found in 76, 56 and 84% of patients, respectively. The 3-year actuarial patient survival was significantly lower in patients with glomerulonephritis as compared with tubulointerstitial nephritis (66 versus 100%, P = 0.02). There was no difference in 3-year actuarial renal survival between these two groups (92 versus 92%, P = 1.0). Renal biopsy is rare in PSS and often reveals diverse pathological findings. Glomerulonephritis, as compared with tubulointerstitial nephritis, is associated with higher early mortality. Further studies are needed to evaluate the utility of renal biopsy and its impact on disease management.


A 3-month-old child with COVID-19: A case report.
Coronavirus disease 2019 (COVID-19) is pandemic and is a medical issue. However, children account for a small portion of those with the disease, and there are few published reports of COVID-19 in children. The patient reported in this case report is the youngest case reported in Chengdu, China to date. A 3-month-old male infant presented with cough and rhinorrhea. Family members from Wuhan, the epicenter of the epidemic came to stay in the patient's home 16 days before the onset of his disease, and his mother had been diagnosed with COVID-19. He was diagnosed with COVID-19 based on a history of exposure and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), detected using reverse transcription polymerase chain reaction (RT-PCR). The patient was admitted to hospital and treated symptomatically with oral medication. The patient recovered completely and was discharged after one month of hospitalization. He tested negative for SARS-CoV-2 using RT-PCR and a chest CT performed 4 weeks after admission showed marked improvement prior to discharge. Clinicians must be aware of the presentation of COVID-19 in children because it differs from that in adults.


Serum apolipoprotein AI and B are stronger biomarkers of diabetic retinopathy than traditional lipids.
To describe and compare the associations of serum lipoproteins and apolipoproteins with diabetic retinopathy. This was a cross-sectional study of 224 diabetic patients (85 type 1 and 139 type 2) from a diabetes clinic. Diabetic retinopathy was graded from fundus photographs according to the Airlie House Classification system and categorized into mild, moderate, and vision-threatening diabetic retinopathy (VTDR). Serum traditional lipids (total, LDL, non-HDL, and HDL cholesterol and triglycerides) and apolipoprotein AI (apoAI), apolipoprotein B (apoB), and the apoB-to-apoAI ratio were assessed. Diabetic retinopathy was present in 133 (59.4%) individuals. After adjustment for age, sex, diabetes duration, A1C, systolic blood pressure, and diabetes medications, the HDL cholesterol level was inversely associated with diabetic retinopathy (odds ratio 0.39 [95% CI 0.16-0.94], highest versus lowest quartile; P(trend) = 0.017). The ApoAI level was inversely associated with diabetic retinopathy (per SD increase, 0.76 [95% CI 0.59-0.98]), whereas apoB (per SD increase, 1.31 [1.02-1.68]) and the apoB-to-apoAI ratio (per SD increase, 1.48 [1.13-1.95]) were positively associated with diabetic retinopathy. Results were similar for mild to moderate diabetic retinopathy and VTDR. Traditional lipid levels improved the area under the receiver operating curve by 1.8%, whereas apolipoproteins improved the area by 8.2%. ApoAI and apoB and the apoB-to-apoAI ratio were significantly and independently associated with diabetic retinopathy and diabetic retinopathy severity and improved the ability to discriminate diabetic retinopathy by 8%. Serum apolipoprotein levels may therefore be stronger biomarkers of diabetic retinopathy than traditional lipid measures.


Spouse criticism and support: their association with coping and psychological adjustment among women with rheumatoid arthritis.
Examined whether psychological adjustment of women with rheumatoid arthritis would be related to the support and criticism the patient received from the husband. Interviews were conducted with the husbands of 103 women with rheumatoid arthritis. Spouse interviews were content coded for critical remarks. Wives completed a revised version of the Ways of Coping Scale and a scale of the perceived supportiveness of the spouse. Husbands completed rating scales assessing their perceived vulnerability to illness and the degree of burden they experienced in providing assistance to their wives. Path analyses revealed that patient adjustment was significantly related to the attitude of the spouse. Patients with a highly critical spouse engaged in more maladaptive coping behaviors and reported a poorer psychological adjustment. Independent of spousal criticism, patients who perceived their spouse as being supportive engaged in more adaptive coping. A path model was fit to the data that suggested that the spouse may affect adjustment indirectly through influencing the patient's selection of adaptive or maladaptive coping responses.


Deriving SF-12v2 physical and mental health summary scores: a comparison of different scoring algorithms.
Summary scores for the SF-12, version 2 (SF-12v2) health status measure are based on scoring coefficients derived for version 1 of the SF-36, despite changes in item wording and response scales and despite the fact that SF-12 scales only contain a subset of SF-36 items. This study derives new summary scores based directly on SF-12v2 data from a recent U.S. sample and compares the new summary scores to the standard ones. Due to controversy regarding methods for developing scoring coefficients for the summary score, we compare summary scores produced by different methods. We analyzed nationally representative U.S. data, which provided 53,399 observations for the SF-12v2 in 2003-2005. In addition to the standard SF-12V2 scoring algorithm, summary scores were generated using exploratory factor analysis (EFA), principal components analysis (PCA), and confirmatory factor analysis (CFA), with orthogonal and oblique rotation. We examined correlations among different summary scores, their associations with demographic and clinical variables, and the consistency between changes in scale scores and in summary scores over time. The 8 scale means in the current data were similar to the 1998 SF-12v2 means, with the exception of the vitality scale. Correlations among the scales based on SF-12v2 data differed slightly from correlations derived from scales based on the SF-36 data. Correlations among summary scores derived using different methods were high (≥0.84). However, changes in summary scores derived using orthogonal rotation of components or factors were not consistent with changes in sub-scales, whereas changes in summary scores derived using oblique rotation were more consistent with patterns of change in sub-scales. Although the basic structure of the SF-12 is stable, summary scores derived from oblique rotation are preferable and more consistent with changes in individual scales. On empirical and conceptual grounds, we suggest using summary scores based on oblique CFA.


Pro-arrhythmic potential of oral antihistamines (H1): combining adverse event reports with drug utilization data across Europe.
There is appreciable utilisation of antihistamines (H1) in European countries, either prescribed by physician and purchased by patients for self-medication. Terfenadine and astemizole underwent regulatory restrictions in '90 because of their cardiac toxicity, but only scarce clinical data are available on other antihistamines. To investigate the pro-arrhythmic potential of antihistamines by combining safety reports of the FDA Adverse Event Reporting System (FAERS) with drug utilization data from 13 European Countries. We identified signals of antihistamine arrhythmogenic potential by analyzing FAERS database for all cases of Torsades de Pointes (TdP), QT abnormalities (QTabn), ventricular arrhythmia (VA) and sudden cardiac death/cardiac arrest (SCD/CA). Number of cases ≥3 and disproportionality were used to define alert signals: TdP and QTabn identified stronger signals, whereas SCD/CA identified weaker signals. Drug utilization data from 2005 to 2010 were collected from administrative databases through health authorities and insurance. Antihistamines were reported in 109 cases of TdP/QT prolongation, 278 VA and 610 SCD/CA. Five agents resulted in stronger signals (cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine) and 6 in weaker signals (alimemazine, carbinoxamine, cyclizine, cyproeptadine, dexchlorpheniramine and doxylamine). Exposure to antihistamines with stronger signal was markedly different across European countries and was at least 40% in each Country. Cetirizine was >29 Defined Daily Doses per 1000 inhabitants per day (DID) in Norway, desloratadine >11 DID in France and loratadine >9 DID in Sweden and Croatia. Drugs with weaker signals accounted for no more than 10% (in Sweden) and in most European countries their use was negligible. Some second-generation antihistamines are associated with signal of torsadogenicity and largely used in most European countries. Although confirmation by analytical studies is required, regulators and clinicians should consider risk-minimisation activities. Also antihistamines without signal but with peculiar use in a few Countries (e.g., levocetirizine) or with increasing consumption (e.g., rupatadine) deserve careful surveillance.


The effects of freeze drying and freeze drying additives on the prothrombin time and the international sensitivity index.
To determine whether freezing, freeze drying protective additives, or freeze drying of plasma samples from patients on coumarin treatment and from normal individuals affects prothrombin times or the international sensitivity index (ISI) calibration. The effect of the addition of the protective additives singly and combined on the prothrombin time of coumarin samples and normal samples before and after freeze drying was observed using high and low ISI reference thromboplastins. ISI values were also determined. Freezing caused a prolongation of prothrombin time in the normal plasma samples with both reagents, which was significant with the low ISI human. Prolongation (non-significant) of the prothrombin time in coumarin plasma samples occurred with the human reagent only. Significant prolongation of normal prothrombin time by some of the protective additives before and after freeze drying was observed with both thromboplastins but to a greater extent with the human. Significant prolongation of prothrombin time in coumarin plasma samples was observed, but again was more marked with human thromboplastin. An approximate ISI was determined on the 20 coumarin samples. The only marked ISI change was with the WHO human thromboplastin after freeze drying of plasma, where a decrease from 0.95 to 0.90 was observed, corresponding to a marked prothrombin ratio increase. Freeze drying additives and the freeze drying procedure prolong normal and coumarin prothrombin times, with low ISI thromboplastin. Less marked prolongations occurred with a high ISI rabbit reagent, coumarin samples showing more significant prolongations. Marked ISI change in freeze dried plasma was only recorded with the low ISI ECAA human reagent. Frozen normal plasma samples cannot be used with confidence for ISI calibrations.


Genes, maternal smoking, and the offspring brain and body during adolescence: design of the Saguenay Youth Study.
The search for genes of complex traits is aided by the availability of multiple quantitative phenotypes collected in geographically isolated populations. Here we provide rationale for a large-scale study of gene-environment interactions influencing brain and behavior and cardiovascular and metabolic health in adolescence, namely the Saguenay Youth Study (SYS). The SYS is a retrospective study of long-term consequences of prenatal exposure to maternal cigarette smoking (PEMCS) in which multiple quantitative phenotypes are acquired over five sessions (telephone interview, home, hospital, laboratory, and school). To facilitate the search for genes that modify an individual's response to an in utero environment (i.e. PEMCS), the study is family-based (adolescent sibships) and is carried out in a relatively geographically isolated population of the Saguenay Lac-Saint-Jean (SLSJ) region in Quebec, Canada. DNA is acquired in both biological parents and in adolescent siblings. A genome-wide scan will be carried out with sib-pair linkage analyses, and fine mapping of identified loci will be done with family-based association analyses. Adolescent sibships (12-18 years of age; two or more siblings per family) are recruited in high schools throughout the SLSJ region; only children of French-Canadian origin are included. Based on a telephone interview, potential participants are classified as exposed or nonexposed prenatally to maternal cigarette smoking; the two groups are matched for the level of maternal education and the attended school. A total of 500 adolescent participants in each group will be recruited and phenotyped. The following types of datasets are collected in all adolescent participants: (1) magnetic resonance images of brain, abdominal fat, and kidneys, (2) standardized and computer-based neuropsychological tests, (3) hospital-based cardiovascular, body-composition and metabolic assessments, and (4) questionnaire-derived measures (e.g. life habits such as eating and physical activity; drug, alcohol use and delinquency; psychiatric symptoms; personality; home and school environment; academic and vocational attitudes). Parents complete a medical questionnaire, home-environment questionnaire, a handedness questionnaire, and a questionnaire about their current alcohol and drug use, depression, anxiety, and current and past antisocial behavior. To date, we have fully phenotyped a total of 408 adolescent participants. Here we provide the description of the SYS and, using the initial sample, we present information on ascertainment, demographics of the exposed and nonexposed adolescents and their parents, and the initial MRI-based assessment of familiality in the brain size and the volumes of grey and white matter.


A systematic review of experimental infections with enterotoxigenic Escherichia coli (ETEC).
Volunteer challenge with enterotoxigenic Escherichia coli (ETEC) has been used for four decades to elucidate the pathogenesis and immune responses and assess efficacy of various interventions. We performed a systematic review of these studies and a meta-analysis of individual patient-level data (IPD) from a subset of studies using standard methodology. We identified 27 studies of 11 ETEC strains administered to 443 naive subjects at doses from 1×10(6) to 1×10(10) colony forming units (cfu). Diarrhea attack rates varied by strain, dose and enterotoxin. Similar rates were seen at doses of 5×10(8) to 1×10(10)cfu with the three most commonly used strains B7A, E24377A, H10407. In IPD analysis, the highest diarrhea attack rates were seen with strains B7A, H10407 and E24377A. The H10407 induced significantly higher stool output than the other strains. Additionally, the rate of output was different across strains. The risk of diarrhea, abdominal cramps, nausea and headaches differed significantly by ETEC strain. An increased risk of nausea, abdominal cramps and headaches was seen for females. Baseline anti-LT IgG titers appeared to be associated with a decrease risk of diarrhea outcomes, a trend not seen with anti-LT IgA or seen consistently with anti-colonization factor antibodies. Neither early antibiotic treatment nor diarrhea duration significantly affected the frequency or magnitude of serologic responses. These studies have served as an invaluable tool in understanding disease course, pathogenicity, innate immune responses and an early assessment of product efficacy. When designing and planning experimental ETEC infection studies in this age of increased ethical scrutiny and growing appreciation of post-infectious sequelae, better understanding of available data is essential.


Differentiating Post-Digital Nannying Autism Syndrome from Autism Spectrum Disorders in Young Children: A Comparative Cross-Sectional Study.
Excessive exposure of young children to digital devices has increased in recent years. Much research has shown that early excessive screentime is associated with autistic-like symptoms. This study aimed to differentiate children with Post-Digital Nannying Autism Syndrome (PDNAS) from children with autism spectrum disorders (ASD) and typically developing children (TDC), both behaviorally and cognitively. This study is comparative and cross-sectional and included three groups of children. The first group consisted of 15 young children with subthreshold autism symptoms. They had not received a formal diagnosis of ASD and had been exposed to digital devices for more than half of their waking time. The second group consisted of 15 young children with ASD, and the third group consisted of 15 young TDC. A lifestyle checklist, a modified checklist for autism in toddlers (M-CHAT), a behavioral flexibility rating scale-revised (BFRS-R), the Gilliam autism rating scale (GARS-2), and a behavior rating inventory of executive functioning-preschool version (BRIEF-P) were used to compare the three groups. The results showed that executive functions and behavioral flexibility were more impaired in children with ASD than in children with PDNAS and in TDC. Also, we found that there was no significant difference in the severity of autism symptoms between the children with ASD and the children with PDNAS. Early excessive exposure to digital devices may cause autism-like symptoms in children (PDNAS). Children with PDNAS are different from children with ASD in executive functions and behavioral flexibility. Further research is needed in this area.


Optimal management of allergic rhinitis.
Allergic rhinitis (AR), the most common chronic disease in childhood is often ignored, misdiagnosed and/or mistreated. Undertreated AR impairs quality of life, exacerbates asthma and is a major factor in asthma development. It can involve the nose itself, as well as the organs connected with the nose manifesting a variety of symptoms. Evidence-based guidelines for AR therapy improve disease control. Recently, paediatric AR guidelines have been published by the European Academy of Allergy and Clinical Immunology and are available online, as are a patient care pathway for children with AR and asthma from the Royal College of Paediatrics and Child Health. Management involves diagnosis, followed by avoidance of relevant allergens, with additional pharmacotherapy needed for most sufferers. This ranges, according to severity, from saline sprays, through non-sedating antihistamines, oral or topical, with minimally bioavailable intranasal corticosteroids for moderate/severe disease, possibly plus additional antihistamine or antileukotriene. The concept of rhinitis control is emerging, but there is no universally accepted definition. Where pharmacotherapy fails, allergen-specific immunotherapy, which is uniquely able to alter long-term disease outcomes, should be considered. The subcutaneous form (subcutaneous immunotherapy) in children has been underused because of concerns regarding safety and acceptability of injections. Sublingual immunotherapy is both efficacious and safe for grass pollen allergy. Further studies on other allergens in children are needed. Patient, carer and practitioner education into AR and its treatment are a vital part of management.


Chromosome inversions, local adaptation and speciation.
We study the evolution of inversions that capture locally adapted alleles when two populations are exchanging migrants or hybridizing. By suppressing recombination between the loci, a new inversion can spread. Neither drift nor coadaptation between the alleles (epistasis) is needed, so this local adaptation mechanism may apply to a broader range of genetic and demographic situations than alternative hypotheses that have been widely discussed. The mechanism can explain many features observed in inversion systems. It will drive an inversion to high frequency if there is no countervailing force, which could explain fixed differences observed between populations and species. An inversion can be stabilized at an intermediate frequency if it also happens to capture one or more deleterious recessive mutations, which could explain polymorphisms that are common in some species. This polymorphism can cycle in frequency with the changing selective advantage of the locally favored alleles. The mechanism can establish underdominant inversions that decrease heterokaryotype fitness by several percent if the cause of fitness loss is structural, while if the cause is genic there is no limit to the strength of underdominance that can result. The mechanism is expected to cause loci responsible for adaptive species-specific differences to map to inversions, as seen in recent QTL studies. We discuss data that support the hypothesis, review other mechanisms for inversion evolution, and suggest possible tests.


Enriching lanthanide single-ion magnetism through symmetry and axiality.
Rapidly growing modern information technology demands energy and cost efficient tools that can efficiently store and process a large amount of data. However, the miniaturization technology that was being used to boost the performance of the electronic devices, keeping up with the pace as estimated by Moore's law, is reaching its limit. To overcome these challenges, several alternative routes that can eventually mimic the modern electronics fabrication using silicon have been proposed. Single molecule magnets (SMMs), being considered as one of the potential alternatives, have gone through significant progress and the focus has shifted from the use of polynuclear clusters to mononuclear complexes in the last few years. The recent frenzy in the field of SMMs is driven by a better understanding of the effects of crystal field (CF) and molecular symmetry on the magnetic properties, especially in the case of mononuclear paramagnetic complexes, apart from other controlling factors. This has led to the advent of highly anisotropic single-ion magnets (SIMs) with magnetic blocking temperatures as high as 60 K and anisotropic energy barriers over 1800 K. This article overviews our recent research in the light of the emergence of the importance of CF and symmetry in 4f ion based single-ion magnets (SIMs), especially in the context of SIMs with D5h symmetry, apart from commenting on the synthetic efforts adopted to place these metal ions in unusual coordination geometries.


Bioassay of 3-sulfolene for possible carcinogenicity (CAS No. 77-79-2).
A bioassay of 3-sulfolene for possible carcinogenicity was conducted using Osborne-Mendel rats and B6C3F1 mice. 3-Sulfolene in corn oil was administered by gavage, at either of two dosages, to groups of 50 male and 50 female animals of each species. The 78-week period of chemical administration was followed by an observation period of 33 weeks for the high dose female rats and low dose rats of both sexes. The last high dose male rat died in week 60. All treated groups of mice were observed for an additional 13 weeks following chemical administration. Initial dosage levels for the chronic bioassay were selected on the basis of a preliminary subchronic toxicity test. Subsequent dosage adjustments were made during the course of the chronic bioassay. The time-weighted average high and low doses of 3-sulfolene in the chronic study were respectively, 372 and 197 mg/kg/day for male rats, 240 and 120 mg/kg/day for female rats, 622 and 311 mg/kg/day for male mice and 768 and 384 mg/kg/day for the female mice. For each species, 20 animals of each sex were placed on test as vehicle controls. These animals were gavaged with corn oil at the same time that dosed animals were gavaged with the 3-sulfolene mixtures. Twenty animals of each sex were placed on test as untreated controls for each species. These animals were not intubated. There was a significant positive association between the administered dosages of 3-sulfolene and mortality in both sexes of rats and mice. In all groups, except the high dose male rats and the high dose male and female mice, adequate numbers of animals survived sufficiently long to be at risk from late-developing tumors. There were no tumors in either sex of rats or mice for which a significant positive association could be established between chemical administration and incidence. Under the conditions of this bioassay, there was no evidence for the carcinogenicity of 3-sulfolene to Osborne-Mendel rats or B6C3F1 mice.


Accuracy of sonographically guided posterior subtalar joint injections: comparison of 3 techniques.
The primary purpose of this investigation was to determine the accuracy of 3 different sonographically guided posterior subtalar joint (PSTJ) injection techniques in an unembalmed cadaveric model. A single experienced examiner injected the PSTJs of 12 unembalmed cadaveric ankle-foot specimens using the anterolateral, posterolateral, and posteromedial approaches. The injection order for each specimen was randomized, and each technique was completed with a different-color diluted latex solution. Coinvestigators blinded to the injection technique dissected each specimen and graded the colored latex location as accurate (in the PSTJ), accurate with overflow (within the PSTJ but also in other regions), or inaccurate (no latex in the joint). All 3 sonographically guided PSTJ injection approaches accurately placed latex into the PSTJ (100% accuracy). Latex was also found in adjacent regions in 19.4% (7 of 36) of injections: 8.3% (3 of 36) within the tibiotalar joint, 8.3% (3 of 36) in the peroneal (fibularis) tendon sheath, and 2.8% (1 of 36) in the flexor hallucis longus tendon sheath. The anterolateral approach placed latex outside the PSTJ 25% of the time (3 of 12 injections: 1 tibiotalar and 2 peroneal [fibularis] sheath), the posterolateral approach 25% of the time (3 of 12 injections: 1 tibiotalar, 1 peroneal [fibularis] sheath, and 1 flexor hallucis longus tendon sheath), and the posteromedial approach 8.3% of the time (1 tibiotalar). This cadaveric investigation suggests that all 3 sonographically guided PSTJ techniques may be used to access the PSTJ with a high degree of accuracy. Clinicians should consider sonographically guided PSTJ injections as a favorable alternative to fluoroscopy and computed tomographic guidance when diagnostic or therapeutic image-guided PSTJ injections are indicated.


Honokiol protects pulmonary microvascular endothelial barrier against lipopolysaccharide-induced ARDS partially via the Sirt3/AMPK signaling axis.
Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia with diffuse alveolar damage and increased pulmonary microvascular permeability. Honokiol (HKL), the principal active ingredient of Chinese herb magnolia officinalis, protected the lung of experimental ARDS models via attenuation of inflammation and oxidative stress. However, whether HKL has protective effects against the dysfunction of pulmonary microvascular endothelial barrier and the potential mechanisms remain unclear. In the present study, we examined the levels of plasma Angiopoietin-2 (Ang-2) in ARDS patients, explored the effects of HKL on the vascular endothelial barrier at the ARDS animal and cell levels. Our data showed that compared with the healthy controls, circulating Ang-2 level was higher in the patients with ARDS, and were usually supposed to be positively related to the severity of ARDS. Moreover, HKL effectively inhibited lung inflammatory injury and microvascular leakage, and improved ARDS mice survival. HKL also inhibited the expression of Ang-2, ICAM-1 and VCAM-1, and restored the expression of Sirt3, β-Catenin and VE-Cadherin. Furthermore, HKL improved ECs survival and inhibited the apoptosis of ECs. The inhibition of Ang-2 expression in vitro by HKL is accompanied by the upregulation of Sirt3 and AMPK phosphorylation. Our data demonstrated that HKL protected pulmonary microvascular endothelial barrier against LPS-induced ARDS at least in part through activating the Sirt3/AMPK signaling and inhibiting the Ang-2 expression. Thus, our findings show that the activation of Sirt3 signaling is a potential mechanism for the protective effects of HKL on vascular barrier.


Vinblastine induces an interaction between FtsZ and tubulin in mammalian cells.
The Escherichia coli cell division protein FtsZ was expressed in Chinese hamster ovary cells, where it formed a striking array of dots that were independent of the mammalian cytoskeleton. Although FtsZ appears to be a bacterial homolog of tubulin, its expression had no detectable effects on the microtubule network or cell growth. However, treatment of the cells with vinblastine at concentrations that caused microtubule disassembly rapidly induced a network of FtsZ filaments that grew from and connected the dots, suggesting that the dots are an active storage form of FtsZ. Cells producing FtsZ also exhibited vinblastine- and calcium-resistant tubulin polymers that colocalized with the FtsZ network. The FtsZ polymers could be selectively disassembled, indicating that the two proteins were not copolymerized. The vinblastine effects were readily reversible by washing out the drug or by treating the cells with the vinblastine competitor, maytansine. These results demonstrate that FtsZ assembly can occur in the absence of bacterial chaperones or cofactors, that FtsZ and tubulin do not copolymerize, and that tubulin-vinblastine complexes have an enhanced ability to interact with FtsZ.


C-type natriuretic peptide plasma levels are elevated in subjects with achondroplasia, hypochondroplasia, and thanatophoric dysplasia.
C-type natriuretic peptide (CNP) is a crucial regulator of endochondral bone growth. In a previous report of a child with acromesomelic dysplasia, Maroteaux type (AMDM), caused by loss-of-function of the CNP receptor (natriuretic peptide receptor-B [NPR-B]), plasma levels of CNP were elevated. In vitro studies have shown that activation of the MAPK kinase (MEK)/ERK MAPK pathway causes functional inhibition of NPR-B. Achondroplasia, hypochondroplasia, and thanatophoric dysplasia are syndromes of short-limbed dwarfism caused by activating mutations of fibroblast growth factor receptor-3, which result in overactivation of the MEK/ERK MAPK pathway. The purpose of this study was to determine whether these syndromes exhibit evidence of CNP resistance as reflected by increases in plasma CNP and its amino-terminal propeptide (NTproCNP). This was a prospective, observational study. Participants were 63 children and 20 adults with achondroplasia, 6 children with hypochondroplasia, 2 children with thanatophoric dysplasia, and 4 children and 1 adult with AMDM. Plasma levels of CNP and NTproCNP were higher in children with achondroplasia with CNP SD scores (SDSs) of 1.0 (0.3-1.4) (median [interquartile range]) and NTproCNP SDSs of 1.4 (0.4-1.8; P < .0005). NTproCNP levels correlated with height velocity. Levels were also elevated in adults with achondroplasia (CNP SDSs of 1.5 [0.7-2.1] and NTproCNP SDSs of 0.5 [0.1-1.0], P < .005). In children with hypochondroplasia, CNP SDSs were 1.3 (0.7-1.5) (P = .08) and NTproCNP SDSs were 1.9 (1.8-2.3) (P < .05). In children with AMDM, CNP SDSs were 1.6 (1.4-3.3) and NTproCNP SDSs were 4.2 (2.7-6.2) (P < .01). In these skeletal dysplasias, elevated plasma levels of proCNP products suggest the presence of tissue resistance to CNP.


Is There Variation in Procedural Utilization for Lumbar Spine Disorders Between a Fee-for-Service and Salaried Healthcare System?
Whether compensation for professional services drives the use of those services is an important question that has not been answered in a robust manner. Specifically, there is a growing concern that spine care practitioners may preferentially choose more costly or invasive procedures in a fee-for-service system, irrespective of the underlying lumbar disorder being treated. (1) Were proportions of interbody fusions higher in the fee-for-service setting as opposed to the salaried Department of Defense setting? (2) Were the odds of interbody fusion increased in a fee-for-service setting after controlling for indications for surgery? Patients surgically treated for lumbar disc herniation, spinal stenosis, and spondylolisthesis (2006-2014) were identified. Patients were divided into two groups based on whether the surgery was performed in the fee-for-service setting (beneficiaries receive care at a civilian facility with expenses covered by TRICARE insurance) or at a Department of Defense facility (direct care). There were 28,344 patients in the entire study, 21,290 treated in fee-for-service and 7054 treated in Department of Defense facilities. Differences in the rates of fusion-based procedures, discectomy, and decompression between both healthcare settings were assessed using multinomial logistic regression to adjust for differences in case-mix and surgical indication. TRICARE beneficiaries treated for lumbar spinal disorders in the fee-for-service setting had higher odds of receiving interbody fusions (fee-for-service: 7267 of 21,290 [34%], direct care: 1539 of 7054 [22%], odds ratio [OR]: 1.25 [95% confidence interval 1.20-1.30], p < 0.001). Purchased care patients were more likely to receive interbody fusions for a diagnosis of disc herniation (adjusted OR 2.61 [2.36-2.89], p < 0.001) and for spinal stenosis (adjusted OR 1.39 [1.15-1.69], p < 0.001); however, there was no difference for patients with spondylolisthesis (adjusted OR 0.99 [0.84-1.16], p = 0.86). The preferential use of interbody fusion procedures was higher in the fee-for-service setting irrespective of the underlying diagnosis. These results speak to the existence of provider inducement within the field of spine surgery. This reality portends poor performance for surgical practices and hospitals in Accountable Care Organizations and bundled payment programs in which provider inducement is allowed to persist. Level III, economic and decision analysis.


Effect of domperidone on the composition of preterm human breast milk.
Domperidone is increasingly prescribed to improve breast milk volume despite a lack of evidence regarding its effects on breast milk composition. We examined the effect of domperidone on the nutrient composition of breast milk. Forty-six mothers who had delivered infants at <31 weeks' gestation, who experienced lactation failure, were randomly assigned to receive domperidone or placebo for 14 days. Protein, energy, fat, carbohydrate, sodium, calcium, and phosphate levels in breast milk were measured on days 0, 4, 7, and 14, serum prolactin levels were measured on days 0, 4, and 14, and total milk volume was recorded daily. Mean within-subject changes in nutrients and milk volumes were examined. Maternal and infant characteristics, serum prolactin level, and breast milk volume and composition were not significantly different between domperidone and placebo groups on day 0. By day 14, breast milk volumes increased by 267% in the domperidone-treated group and by 18.5% in the placebo group (P = .005). Serum prolactin increased by 97% in the domperidone group and by 17% in the placebo group (P = .07). Mean breast milk protein declined by 9.6% in the domperidone group and increased by 3.6% in the placebo group (P = .16). Changes in energy, fat, carbohydrate, sodium, and phosphate content were also not significantly different between groups. Significant increases were observed in breast milk carbohydrate (2.7% vs -2.7%; P = .05) and calcium (61.8% vs -4.4%; P = .001) in the domperidone versus placebo groups. No significant adverse events were observed among mothers or infants. Domperidone increases the volume of breast milk of preterm mothers experiencing lactation failure, without substantially altering the nutrient composition.


The Wnt pathway controls cell death engulfment, spindle orientation, and migration through CED-10/Rac.
Wnt signalling pathways have extremely diverse functions in animals, including induction of cell fates or tumours, guidance of cell movements during gastrulation, and the induction of cell polarity. Wnt can induce polar changes in cellular morphology by a remodelling of the cytoskeleton. However, how activation of the Frizzled receptor induces cytoskeleton rearrangement is not well understood. We show, by an in depth 4-D microscopy analysis, that the Caenorhabditis elegans Wnt pathway signals to CED-10/Rac via two separate branches to regulate modulation of the cytoskeleton in different cellular situations. Apoptotic cell clearance and migration of the distal tip cell require the MOM-5/Fz receptor, GSK-3 kinase, and APC/APR-1, which activate the CED-2/5/12 branch of the engulfment machinery. MOM-5 (Frizzled) thus can function as an engulfment receptor in C. elegans. Our epistatic analyses also suggest that the two partially redundant signalling pathways defined earlier for engulfment may act in a single pathway in early embryos. By contrast, rearrangement of mitotic spindles requires the MOM-5/Fz receptor, GSK-3 kinase, and beta-catenins, but not the downstream factors LIT-1/NLK or POP-1/Tcf. Taken together, our results indicate that in multiple developmental processes, CED-10/Rac can link polar signals mediated by the Wnt pathway to rearrangements of the cytoskeleton.


The presentation of hypoactive sexual desire disorder in premenopausal women.
Little is known about the clinical presentation of hypoactive sexual desire disorder (HSDD) in premenopausal women or their perceptions of sexual problems. Describe characteristics of premenopausal women with clinically diagnosed acquired, generalized HSDD, and investigate factors perceived to contribute to desire problems. Cross-sectional analysis of baseline data from premenopausal women with clinically diagnosed and confirmed HSDD enrolled during the first year of the HSDD Registry for Women (N=400). Relationship, demographic, and clinical characteristics were assessed by clinician's medical history review and self-administered questionnaire. Sexual desire function was measured by the validated Female Sexual Function Index (FSFI). Over 85% of women cited multiple factors that contributed to ongoing decreased desire (mean 2.9± 2.3 factors, range 0-12). Most commonly cited contributing factors were "stress or fatigue" (60.0%), "dissatisfaction with my physical appearance" (40.8%), and other sexual difficulties (e.g., inability to reach orgasm) (33.5%). Exploratory analyses of the FSFI score confirmed that self-image (P=0.002) and other sexual problems (P<0.001) were significantly associated with decreased desire. Almost all (96%) participants were currently in a partner relationship. Antidepressant medication was currently used by 18.0% of women, hormonal contraceptives by 28.5%, and hormonal medications (for noncontraceptive reasons) by 7.3%. Physical functioning was consistent with general population norms (SF-36 mean±standard deviation, 53.3±7.6 vs. norm of 50±10), while overall mental functioning was slightly lower (SF-36, 44.7±10.6). Within this sample of premenopausal women with clinically diagnosed HSDD, decreased sexual desire was associated with multiple factors, including poor self-image and stress or fatigue. Clinicians presented with premenopausal women expressing sexual desire problems should assess patients' perceptions of their condition to develop a comprehensive, patient-oriented management plan. Therapy may need to address issues with low self-esteem and mood and offer practical coping mechanisms for stress and fatigue.


Effect of antidepressants and psychological therapies, including hypnotherapy, in irritable bowel syndrome: systematic review and meta-analysis.
Irritable bowel syndrome (IBS) is a chronic functional gastrointestinal disorder. Evidence relating to the treatment of this condition with antidepressants and psychological therapies continues to accumulate. We performed an updated systematic review and meta-analysis of randomized controlled trials (RCTs). MEDLINE, EMBASE, and the Cochrane Controlled Trials Register were searched (up to December 2013). Trials recruiting adults with IBS, which compared antidepressants with placebo, or psychological therapies with control therapy or "usual management," were eligible. Dichotomous symptom data were pooled to obtain a relative risk (RR) of remaining symptomatic after therapy, with a 95% confidence interval (CI). The search strategy identified 3,788 citations. Forty-eight RCTs were eligible for inclusion: thirty-one compared psychological therapies with control therapy or "usual management," sixteen compared antidepressants with placebo, and one compared both psychological therapy and antidepressants with placebo. Ten of the trials of psychological therapies, and four of the RCTs of antidepressants, had been published since our previous meta-analysis. The RR of IBS symptom not improving with antidepressants vs. placebo was 0.67 (95% CI=0.58-0.77), with similar treatment effects for both tricyclic antidepressants and selective serotonin reuptake inhibitors. The RR of symptoms not improving with psychological therapies was 0.68 (95% CI=0.61-0.76). Cognitive behavioral therapy, hypnotherapy, multicomponent psychological therapy, and dynamic psychotherapy were all beneficial. Antidepressants and some psychological therapies are effective treatments for IBS. Despite the considerable number of studies published in the intervening 5 years since we last examined this issue, the overall summary estimates of treatment effect have remained remarkably stable.


Phylogenetic distribution of symbiotic bacteria from Panamanian amphibians that inhibit growth of the lethal fungal pathogen Batrachochytrium dendrobatidis.
The introduction of next-generation sequencing has allowed for greater understanding of community composition of symbiotic microbial communities. However, determining the function of individual members of these microbial communities still largely relies on culture-based methods. Here, we present results on the phylogenetic distribution of a defensive functional trait of cultured symbiotic bacteria associated with amphibians. Amphibians are host to a diverse community of cutaneous bacteria and some of these bacteria protect their host from the lethal fungal pathogen Batrachochytrium dendrobatidis (Bd) by secreting antifungal metabolites. We cultured over 450 bacterial isolates from the skins of Panamanian amphibian species and tested their interactions with Bd using an in vitro challenge assay. For a subset of isolates, we also completed coculture experiments and found that culturing isolates with Bd had no effect on inhibitory properties of the bacteria, but it significantly decreased metabolite secretion. In challenge assays, approximately 75% of the bacterial isolates inhibited Bd to some extent and these inhibitory isolates were widely distributed among all bacterial phyla. Although there was no clear phylogenetic signal of inhibition, three genera, Stenotrophomonas, Aeromonas and Pseudomonas, had a high proportion of inhibitory isolates (100%, 77% and 73%, respectively). Overall, our results demonstrate that antifungal properties are phylogenetically widespread in symbiotic microbial communities of Panamanian amphibians and that some functional redundancy for fungal inhibition occurs in these communities. We hope that these findings contribute to the discovery and development of probiotics for amphibians that can mitigate the threat of chytridiomycosis.


Medical management of Cushing disease.
Although transsphenoidal excision of the adrenocorticotropic hormone (ACTH)-producing neoplasm is often the treatment of choice in patients with Cushing disease, medical management is itself a useful preoperative temporizing measure, an option for long-term management in nonsurgical candidates, and an option for patients in whom surgery and/or radiotherapy have failed. Three pathophysiologically based approaches exist in the research literature--neuro-modulation to limit ACTH levels, adrenal enzyme inhibition, and glucocorticoid receptor antagonism. Unfortunately, the neuromodulatory approach involving agents such as bromocriptine, cyproheptadine, octreotide, and valproate has yielded only suboptimal results. Glucocorticoid receptor antagonism remains in its infancy but may overall be limited by side effects and a resultant increase in ACTH and cortisol levels. Adrenal enzyme inhibitors, however, offer substantial future promise in the management of Cushing disease but are limited by the potential need to use them indefinitely and by dose-tolerance effects. Although etomidate is a potential intravenous alternative for acute cortisol level control, ketoconazole has shown efficacy in the long-term treatment of patients with the disease. Metyrapone and/or aminoglutethimide can be added to ketoconazole if additional control is needed. If success is still not achieved, the potent adrenolytic agent often used for adrenocortical carcinomas, mitotane, is another alternative.


New 1,3-oxathianes derived from myrtenal: synthesis and reactivity.
2-Methyl- and 2-phenyl-substituted oxathianes derived from Myrtenal have been synthesized in satisfying yields. Lithiation of 2-methyl-substituted oxathiane could not be done, but lithiation of 2-phenyl-substituted and non-substituted oxathianes could be performed with s-BuLi. Quenching with D(2)O, TMSCl, and/or a carbonyl compound always provides the equatorial product in consistency with a prefered equatorial orientation of the lithium in the lithiated derivatives. A model is proposed to rationalize the diastereoselectivities observed at C5' during reaction of aldehydes with lithiated non-substituted oxathiane. The model is based on the hypothesis that the lithium, being linked simultaneously to the carbon and the oxygen, is shifted toward the oxygen side, making the steric hindrance of this side more effective. Dimeric side products were observed during formation of these oxathianes (condensation of various aldehydes with the corresponding hydroxythiol), which had not been reported for other oxathianes (derived from pulegone and/or camphorsulfonic acid).


Occupational Therapy Fall Prevention Interventions for Community-Dwelling Older Adults: A Systematic Review.
Accidental falls among community-dwelling older adults are preventable and increase the risk of morbidity, hospitalization, and institutionalization. We updated and broadened a 2008 systematic review examining the evidence for the effectiveness of fall prevention interventions in improving fall-related outcomes, occupational performance, quality of life, and health care facility readmissions for community-dwelling older adults. We searched and analyzed literature published from 2008 to 2015 from five electronic databases. Fifty articles met the inclusion criteria and were critically appraised and synthesized-37 provided Level I; 5, Level II; and 8, Level III evidence. Analysis was organized into four intervention themes: single component, multicomponent, multifactorial, and population based. Mixed evidence was found for single-component and multifactorial interventions, strong evidence was found for multicomponent interventions, and moderate evidence was found for population-based interventions. These findings can inform the delivery and integration of fall prevention interventions from acute care to community discharge.


Cell adhesion to borate glasses by colloidal probe microscopy.
The adhesion of osteoblast-like cells to silicate and borate glasses was measured in cell growth medium using colloidal probe microscopy. The probes consisted of silicate and borate glass spheres, 25-50 μm in diameter, attached to atomic force microscope cantilevers. Variables of the study included glass composition and time of contact of the cell to the glasses. Increasing the time of contact from 15 to 900 s increased the force of adhesion. The data could be plotted linearly on a log-log plot of adhesive force versus time. Of the seven glasses tested, five had slopes close to 0.5, suggesting a square root dependence of the adhesive force on the contact time. Such behavior can be interpreted as a diffusion limited process occurring during the early stages of cell attachment. We suggest that the rate limiting step in the adhesion process is the diffusion of integrins resident in the cell membrane to the area of cell attachment. Data presented in this paper support the hypothesis of Hench et al. that strong adhesion depends on the formation of a calcium phosphate reaction layer on the surfaces of the glass. Glasses that did not form a calcium phosphate layer exhibited a weaker adhesive force relative to those glasses that did form a calcium phosphate layer.


Comparative evaluation of effects of chlorhexidine and tetracycline on neutrophil viability and functions in vitro.
Chlorhexidine (CHX) and Tetracycline (TET) are the two antimicrobial agents used in the management of periodontal infections, due to their antimicrobial potency and substantivity. The benefits and limitations of an antimicrobial agent can only be assessed by determining their relative toxicity to microbes and host cells. (1) To detect the effects of CHX and TET on neutrophil viability and functions in vitro. (2) To compare the effects of CHX and TET on crevicular blood neutrophils. Crevicular blood was collected using 5-μl pipette, stored in EDTA-containing vacutainers and sent for evaluation of Cell Viability- Neutrophils would be mixed with 0.25 volume of 0.4% trypan blue in Hank's balanced salt solution (HBSS) and counted to assess the viability. Chemotaxis- Evaluated under agarose slides, a total of 100 μl crevicular blood Neutrophils-0.2% BSA or HBSS-0.2% containing concentration of CHX and TET. Oxidative Metabolism- would be assessed using nitro blue tetrazolium. In all experiments, three concentrations of TET (0.1%, 0.05%, 0.025%) and CHX (0.01%, 0.005%, 0.0025%) respectively were used. N-Formyl methionyl leucyl phenylalanine (1 μm) in the presence of 2 μg/ml cytochalasin B will be used as the activating agent. Neutrophils would be treated with CHX and TET similarly to that for chemotaxis. TET comparatively has less deleterious effects on neutrophil functions as compared with that of CHX with statistically significant results for all parameters tested. From this study, it is inferred that CHX and TET do cause certain changes in neutrophil functions.


Surgical management of effusive constrictive pericarditis.
The surgical approach for effusive constrictive pericarditis (ECP) has not been extensively studied. We present our institution's early and long-term results of pericardiectomy in our cohort of patients with ECP. Diagnosis was made primarily by echocardiography. Right heart catheterisation was performed in eight patients. Pre-operatively, 10 patients had undergone at least one previous attempt at therapeutic pericardiocentesis. Pericardiectomy was performed where appropriate (thickened or inflamed). Of our 12 patients (50% male, median age 48 years, range 17-72 years), the underlying aetiology included idiopathic in five (41.6%), tuberculosis in four (33%), and malignancy in three patients (25%). Elective surgery was performed in nine patients. Median values of both central venous pressure and pulmonary capillary wedge pressure decreased markedly postoperatively (from 16.5 to 11.0 mmHg, p = 0.02; 20.0-15.0 mmHg, p = 0.01, respectively). There was no in-hospital mortality. Follow up ranged from three months to nine years (median three years). Five (41.6%) patients died during the follow-up period, and cumulative two-year survival was 55.6 ± 1.5%. Pericardiectomy for ECP was effective, in terms of our early results, in patients unresponsive to medical therapy. Long-term survival depends on the underlying disease.


Eliminating chromatic aberration in Gauss-type lens design using a novel genetic algorithm.
Two different types of Gauss lens design, which effectively eliminate primary chromatic aberration, are presented using an efficient genetic algorithm (GA). The current GA has to deal with too many targets in optical global optimization so that the performance is not much improved. Generally speaking, achromatic aberrations have a great relationship with variable glass sets for all elements. For optics whose design is roughly convergent, glass sets for optics will play a significant role in axial and lateral color aberration. Therefore better results might be derived from the optimal process of eliminating achromatic aberration, which could be carried out by finding feasible glass sets in advance. As an alternative, we propose a new optimization process by using a GA and involving theories of geometrical optics in order to select the best optical glass combination. Two Gauss-type lens designs are employed in this research. First, a telephoto lens design is sensitive to axial aberration because of its long focal length, and second, a wide-angle Gauss design is complicated by lateral color aberration at the extreme corners because Gauss design is well known not to deal well with wide-angle problems. Without numbers of higher chief rays passing the element, it is difficult to correct lateral color aberration altogether for the Gauss design. The results and conclusions show that the attempts to eliminate primary chromatic aberrations were successful.


The predictable chaos of slow earthquakes.
Slow earthquakes, like regular earthquakes, result from unstable frictional slip. They produce little slip and can therefore repeat frequently. We assess their predictability using the slip history of the Cascadia subduction between 2007 and 2017, during which slow earthquakes have repeatedly ruptured multiple segments. We characterize the system dynamics using embedding theory and extreme value theory. The analysis reveals a low-dimensional (<5) nonlinear chaotic system rather than a stochastic system. We calculate properties of the underlying attractor like its correlation and instantaneous dimension, instantaneous persistence, and metric entropy. We infer that the system has a predictability horizon of the order of days weeks. For the better resolved segments, the onset of large slip events can be correctly forecasted by high values of the instantaneous dimension. Longer-term deterministic prediction seems intrinsically impossible. Regular earthquakes might similarly be predictable but with a limited predictable horizon of the order of their durations.


When Aspirations Exceed Expectations: Quixotic Hope Increases Depression among Students.
A paradox exists in modern schooling: students are simultaneously more positive about the future and more depressed than ever. We suggest that these two phenomena may be linked. Two studies demonstrated that students are more likely to be depressed when educational aspirations exceed expectations. In Study 1 (N = 85) aspiring to a thesis grade higher than one expected predicted greater depression at the beginning and end of the academic year. In Study 2 (N = 2820) aspiring to a level of education (e.g., attending college) higher than one expected to achieve predicted greater depression cross-sectionally and five years later. In both cases the negative effects of aspiring high while expecting low persisted even after controlling for whether or not students achieved their educational aspirations. These findings highlight the danger of teaching students to aspire higher without also investing time and money to ensure that students can reasonably expect to achieve their educational goals.


The impact of ethnicity on the natural history of autoimmune hepatitis.
The impact of ethnicity on the natural history of autoimmune hepatitis (AIH) has not been well characterized. The aim of this study was to assess the natural history of AIH in blacks in comparison with others (nonblacks). This was a 10-year (June 1996 to June 2006) retrospective analysis of patients with AIH from a single tertiary care center. The diagnosis of AIH was defined by the criteria established by the International Autoimmune Hepatitis Club. A poor outcome was defined as liver failure at presentation, failure to achieve remission, need for liver transplantation, and/or death. One hundred one patients with AIH were eligible for the study. Black patients were more likely to have cirrhosis (56.7% versus 37.5%, P = 0.061), have liver failure at the initial presentation (37.8% versus 9.3%, P = 0.001), and be referred for liver transplantation (51.3% versus 23.4%, P = 0.004). The overall mortality was also significantly higher in black patients (24.3% versus 6.2%, P = 0.009). Compared with nonblacks, blacks had more advanced hepatic fibrosis (3.6 +/- 2.7 versus 2.1 +/- 2.4, P = 0.013). A Kaplan-Meier analysis showed that the probability of developing a poor outcome was significantly higher in blacks (P = 0.003). Independent predictors of poor outcome were black ethnicity, the presence of cirrhosis, and the fibrosis stage at presentation. Black males were the group most likely to have a poor outcome (85.7%). Blacks, especially black men with AIH, have more aggressive disease at the initial presentation, are less likely to respond to conventional immunosuppression, and have a worse outcome than nonblacks.


Safety profile and clinical outcomes in a phase I, placebo-controlled study of siplizumab in acute graft-versus-host disease.
Acute graft-versus-host disease (GVHD) is a major complication of both bone marrow and hematologic stem cell allografts. T cells and natural killer (NK) cells have been linked to the development of GVHD. Modulation of these cells via the CD2 receptor may be a potentially important approach to the management of this disease. The safety profile and tolerability of siplizumab (MEDI-507), a humanized anti-CD2 IgG-1kappa monoclonal antibody, in the treatment of GVHD were evaluated in a phase I, double-blind, multiple-dose, placebo-controlled study. Thirty-four subjects with at least grade II acute GVHD were randomized to receive four doses of 0.012, 0.04, 0.12, or 0.4 mg/kg siplizumab or placebo intravenously every 3 days. Subjects received concurrent 2 mg/kg per day methylprednisolone for more than or equal to 10 days. No meaningful difference occurred between siplizumab and placebo groups in the incidence or severity of adverse events or laboratory test results. No increase in incidence of infection secondary to siplizumab treatment was observed. During 100 days postinitial infusion, a modest increase in resolution of GVHD, grade 0 (67% vs. 54%, P=0.0629), was reported for the siplizumab-treated group. Siplizumab administered with corticosteroid therapy for grade II or higher acute GVHD treatment exhibited an acceptable safety profile that would support further clinical development.