Relationship between LDL-C reduction after coronary revascularization and prevention of recurrence of cardiovascular events.
The purpose of our study was to optimize lipid-lowering therapy in patients undergoing coronary revascularization and to determine whether the percentage change in low-density lipoprotein-cholesterol (LDL-C) level in the 3 months after coronary revascularization could be used as a predictor of the time to recurrence of coronary artery disease (CAD). Biochemical values of patients undergoing lipid-lowering therapy after receiving coronary revascularization at the Nippon Medical School Chiba Hokusoh Hospital, Japan, were retrospectively investigated. Recurrence of a cardiovascular event (CVE) was defined by death, myocardial infarction, or angina caused by coronary revascularization more than 3 months after the first event. Of 171 patients under secondary preventive care who had at least one recurrence of a CVE, 75 showed evidence of objective stenotic lesions on coronary angiography. Among these 75 patients, exclusion of those in whom coronary revascularization had not been performed at disease onset, balloon dilatation had been used, serum lipid levels had not been measured, or coronary revascularization had been applied to restenosis left 44 patients suitable for inclusion in the study group. Although the mean value of high density lipoprotein-cholesterol did not change in the 3 months after coronary revascularization, that of (LDL-C) significantly decreased. A significant positive correlation was identified between % decrease in LDL-C and number of days to CVE recurrence. The average LDL-C value (102.8+/-21.7 mg/dL) in the group of patients with no recurrence within 5 years was significantly lower than that (135.3+/-46.1 mg/dL) in the recurrence group (P = 0.0088). The % of patients achieving the LDL-C target level (non-recurrence group vs. recurrence group: 50.0% vs. 16.7%; P = 0.032) and the % decrease in LDL-C (31.0%+/-12.6% vs. 9.6+/-21.0%, P = 0.0012) were significantly greater in the non-recurrence group than in the recurrence group. From our present study, a decrease in LDL-C 3 months after revascularization surgery reduces the rate of CVE relapse. The % LDL-C decrease could serve as a useful predictor of CVE recurrence, in addition to LDL-C values and achievement of the LDL-C target level.


Negative complementation at the notch locus of Drosophila melanogaster.
Four Abruptex alleles (AxE1, AxE2, Ax9B2, and Ax16172) have been mapped within the Notch locus. Based on their visible phenotypes and their interactions with one another and with N mutations, the Ax alleles can be divided into two groups. Heterozygous combinations of members of the same group are intermediate in phenotype compared to the respective homozygotes, whereas heterozygotes of Ax alleles from different groups exhibit negative heterosis, being much less viable and more extremely mutant than either homozygote. It is suggested that the Notch locus is a multi-functional regulator ("integrator") gene, whose product possesses both "repressor" and "activator" functions for the processes it regulates.


Blood products and procoagulants in traumatic bleeding: use and evidence.
Death from uncontrolled haemorrhage is one of the leading causes of trauma-related mortality and is potentially preventable. Advances in understanding the mechanisms of trauma-induced coagulopathy (TIC) have focused attention on the role of blood products and procoagulants in mitigating the sequelae of TIC and how these therapies can be improved. A host of preclinical and clinical studies have evaluated blood product availability and efficacy in trauma. Recently published randomized controlled trials have investigated the ratio of platelet:plasma:red cell transfusion and the role of early cryoprecipitate in trauma. Demand for readily available plasma has led to changes particularly in the use of thawed group A plasma. Furthermore, ex-vivo and early clinical work has demonstrated variations in the haemostatic activity of different plasma, platelet and whole blood products. A number of multicentre trials are in progress aiming to answer key questions regarding tranexamic acid, procoagulant factor and fibrinogen concentrates and their effect on trauma outcomes. There are promising results from ex-vivo studies in manufacturing and storage of blood products to optimize haemostatic activity and availability, particularly with alternative plasma and platelet products and whole blood. There is an urgent need for these products needs to be tested prospectively.


Solanum Incanum Extract Downregulates Aldehyde Dehydrogenase 1-Mediated Stemness and Inhibits Tumor Formation in Ovarian Cancer Cells.
Solanum incanum extract (SR-T100), containing the active ingredient solamargine, can induce apoptosis via upregulation of tumor necrosis factor receptor expression and activation of the mitochondrial apoptosis pathway, and has therapeutic effects in patients with actinic keratosis. Here, we evaluate the novel molecular mechanisms underlying SR-T100-regulated stemness and chemoresistance. The concentration of SR-T100 that inhibited 50% cell viability (IC50) was lower in ovarian cancer cells than in nonmalignant cells. Furthermore, the SR-T100 IC50 in chemoresistant cells was similar to the IC50 in chemosensitive cells. Additionally, SR-T100 increased cisplatin and paclitaxel sensitivity in chemoresistant cells. SR-T100 downregulated the expression of stem cell markers, including aldehyde dehydrogenase 1 (ALDH1), Notch1, and FoxM1, and reduced sphere formation in ovarian cancer cells. Using microarray analyses, immunoblotting, luciferase activity, and chromatin immunoprecipitation (ChIP) assays, we showed that SR-T100 suppressed the expression of c/EBPβ and COL11A1, and its promoter activity, in resistant cells, but not sensitive cells. SR-T100, paclitaxel, and cisplatin inhibited the growth of A2780CP70 cells in mouse xenografts, as compared to the vehicle control, and the combination of cisplatin and SR-T100 was more effective than either treatment alone. SR-T100 may represent a potential therapeutic adjunct to chemotherapy for ovarian cancer treatment.


A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene.
Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.


Cost-effectiveness of therapeutic hypothermia to treat neonatal encephalopathy.
To estimate the cost-effectiveness (CE) of total body hypothermia plus intensive care versus intensive care alone to treat neonatal encephalopathy. Decision analytic modeling was used to synthesize mortality and morbidity data from three randomized controlled trials, the Total Body Hypothermia for Neonatal Encephalopathy Trial (TOBY), National Institute of Child Health and Human Development (NICHD), and CoolCap trials. Cost data inputs were informed by TOBY, the sole source of prospectively collected resource utilization data for encephalopathic infants. CE was expressed in terms of incremental cost per disability-free life year (DFLY) gained. Probabilistic sensitivity analysis was performed to generate CE acceptability curves (CEACs). Cooling led to a cost increase of £3787 (95% confidence interval [CI]: -2516, 12,360) (€5115; 95% CI: -3398-16,694; US$5344; 95% CI: -3598, 26,356; using 2006 Organisation for Economic Co-operation and Development (OECD) purchasing power parities) and a DFLY gain of 0.19 (95%CI: 0.07-0.31) over the first 18 months after birth. The incremental cost per DFLY gained was £19,931 (€26,920; US$28,124). The baseline CEAC showed that if decision-makers are willing to pay £30,000 for an additional DFLY, there is a 69% probability that cooling is cost-effective. The probability of CE exceeded 99% at this threshold when the throughput of infants was increased to reflect the national incidence of neonatal encephalopathy or when the time horizon of the economic evaluation was extended to 18 years after birth. The probability that cooling is a cost-effective treatment for neonatal encephalopathy is finely balanced over the first 18 months after birth but increases substantially when national incidence data or an extended time horizon are considered.


Analysis of the stoichiometric metal activation of methionine aminopeptidase.
Methionine aminopeptidase (MetAP) is a ubiquitous enzyme required for cell survival and an attractive target for antibacterial and anticancer drug development. The number of a divalent metal required for catalysis is under intense debate. E. coli MetAP was shown to be fully active with one equivalent of metal by graphical analysis, but it was inferred to require at least two metals by a Hill equation model. Herein, we report a mathematical model and detailed analysis of the stoichiometric activation of MetAP by metal cofactors. Because of diverging results with significant implications in drug discovery, the experimental titration curve for Co2+ activating MetAP was analyzed by fitting with a multiple independent binding sites (MIBS) model, and the quality of the fitting was compared to that of the Hill equation. The fitting by the MIBS model was clearly superior and indicated that complete activity is observed at a one metal to one protein ratio. The shape of the titration curve was also examined for activation of metalloenzymes in general by one or two metals. Considering different scenarios of MetAP activation by one or two metal ions, it is concluded that E. coli MetAP is fully active as a monometalated enzyme. Our approach can be of value in proper determination of the number of cations needed for catalysis by metalloenzymes.


Cellular and molecular investigations into the development of the pectoral girdle.
The forelimbs of higher vertebrates are composed of two portions: the appendicular region (stylopod, zeugopod and autopod) and the less prominent proximal girdle elements (scapula and clavicle) that brace the limb to the main trunk axis. We show that the formation of the muscles of the proximal limb occurs through two distinct mechanisms. The more superficial girdle muscles (pectoral and latissimus dorsi) develop by the "In-Out" mechanism whereby migration of myogenic cells from the somites into the limb bud is followed by their extension from the proximal limb bud out onto the thorax. In contrast, the deeper girdle muscles (e.g. rhomboideus profundus and serratus anterior) are induced by the forelimb field which promotes myotomal extension directly from the somites. Tbx5 inactivation demonstrated its requirement for the development of all forelimb elements which include the skeletal elements, proximal and distal muscles as well as the sternum in mammals and the cleithrum of fish. Intriguingly, the formation of the diaphragm musculature is also dependent on the Tbx5 programme. These observations challenge our classical views of the boundary between limb and trunk tissues. We suggest that significant structures located in the body should be considered as components of the forelimb.


Data-Driven Soft Decoding of Compressed Images in Dual Transform-Pixel Domain.
In the large body of research literature on image restoration, very few papers were concerned with compression-induced degradations, although in practice, the most common cause of image degradation is compression. This paper presents a novel approach to restoring JPEG-compressed images. The main innovation is in the approach of exploiting residual redundancies of JPEG code streams and sparsity properties of latent images. The restoration is a sparse coding process carried out jointly in the DCT and pixel domains. The prowess of the proposed approach is directly restoring DCT coefficients of the latent image to prevent the spreading of quantization errors into the pixel domain, and at the same time, using online machine-learned local spatial features to regulate the solution of the underlying inverse problem. Experimental results are encouraging and show the promise of the new approach in significantly improving the quality of DCT-coded images.


Priorities for addressing the impact of the COVID-19 pandemic on college student mental health.
The COVID-19 pandemic has already produced profound impacts on college students, with unprecedented directives for student relocation from their college campuses and dormitories mid-semester and coursework that took place through virtual learning. The current disruptions and anticipated potential long-term changes call for immediate prioritization regarding next steps for addressing college mental health and well-being. This viewpoint article highlights two urgent priorities for addressing current college mental health needs: the development of strategies for ensuring mental health service access, and intentional outreach to college students with special circumstances. The current crisis also represents an opportunity for campus administrators, mental health professionals, researchers, and policymakers to leverage innovative models of care as well as identity-related student assets, strengths, and resilience-promoting factors to support students' eventual return to campus and to respond more effectively to future massive disruptions.


Exploring multiple trees through DAG representations.
We present a Directed Acyclic Graph visualisation designed to allow interaction with a set of multiple classification trees, specifically to find overlaps and differences between groups of trees and individual trees. The work is motivated by the need to find a representation for multiple trees that has the space-saving property of a general graph representation and the intuitive parent-child direction cues present in individual representation of trees. Using example taxonomic data sets, we describe augmentations to the common barycenter DAG layout method that reveal shared sets of child nodes between common parents in a clearer manner. Other interactions such as displaying the multiple ancestor paths of a node when it occurs in several trees, and revealing intersecting sibling sets within the context of a single DAG representation are also discussed.


Preventing unintended pregnancy: the cost-effectiveness of three methods of emergency contraception.
This study examined the cost-effectiveness of emergency contraceptive pills, minipills, and the copper-T intrauterine device (IUD) as emergency contraception. Cost savings were modeled for both (1) a single contraceptive treatment following unprotected intercourse and (2) emergency contraceptive pills provided in advance. In a managed care (public payer) setting, a single treatment of emergency contraception after unprotected intercourse saves $142 ($54) with emergency contraceptive pills and $119 ($29) with minipills. The copper-T IUD is not cost-effective as an emergency contraceptive alone, but savings quickly accrue as use continues. Advance provision of emergency contraceptive pills to women using barrier contraceptives, spermicides, withdrawal, or periodic abstinence saves from $263 to $498 ($99 to $205) annually. Emergency contraception is cost-effective whether provided when the emergency arises or in advance to be used as needed. Greater use of emergency contraception could reduce the considerable medical and social costs of unintended pregnancies.


Public Health Law Modernization 2.0: Rebalancing Public Health Powers And Individual Liberty In The Age Of COVID-19.
Public health emergency powers laws in the US underwent a profound stress test during the COVID-19 pandemic. Designed with bioterrorism in mind, they struggled to meet the challenges of a multiyear pandemic. Public health legal powers in the US are both too limited, in that they don't clearly permit officials to implement measures necessary to combat epidemics, and too broad, in that their accountability mechanisms fall short of public expectations. Recently, some courts and state legislatures have cut deeply into emergency powers, jeopardizing future emergency response. Instead of this curtailment of essential powers, the states and Congress should modernize emergency powers laws to balance powers and individual rights in more productive ways. In this analysis we propose reforms including meaningful legislative checks on executive power, stronger substantive standards for executive orders, mechanisms for public and legislative input, and clearer authority to issue orders affecting groups of people.


Rationale, design, and baseline characteristics of the CArdiovascular safety and Renal Microvascular outcomE study with LINAgliptin (CARMELINA®): a randomized, double-blind, placebo-controlled clinical trial in patients with type 2 diabetes and high cardio-renal risk.
Cardiovascular (CV) outcome trials in type 2 diabetes (T2D) have underrepresented patients with chronic kidney disease (CKD), leading to uncertainty regarding their kidney efficacy and safety. The CARMELINA® trial aims to evaluate the effects of linagliptin, a DPP-4 inhibitor, on both CV and kidney outcomes in a study population enriched for cardio-renal risk. CARMELINA® is a randomized, double-blind, placebo-controlled clinical trial conducted in 27 countries in T2D patients at high risk of CV and/or kidney events. Participants with evidence of CKD with or without CV disease and HbA1c 6.5-10.0% (48-86 mmol/mol) were randomized 1:1 to receive linagliptin once daily or matching placebo, added to standard of care adjusted according to local guidelines. The primary outcome is time to first occurrence of CV death, non-fatal myocardial infarction, or non-fatal stroke. The key secondary outcome is a composite of time to first sustained occurrence of end-stage kidney disease, ≥ 40% decrease in estimated glomerular filtration rate (eGFR) from baseline, or renal death. CV and kidney events are prospectively adjudicated by independent, blinded clinical event committees. CARMELINA® was designed to continue until at least 611 participants had confirmed primary outcome events. Assuming a hazard ratio of 1.0, this provides 90% power to demonstrate non-inferiority of linagliptin versus placebo within the pre-specified non-inferiority margin of 1.3 at a one-sided α-level of 2.5%. If non-inferiority of linagliptin for the primary outcome is demonstrated, then its superiority for both the primary outcome and the key secondary outcome will be investigated with a sequentially rejective multiple test procedure. Between July 2013 and August 2016, 6980 patients were randomized and took ≥ 1 dose of study drug (40.6, 33.1, 16.9, and 9.4% from Europe, South America, North America, and Asia, respectively). At baseline, mean ± SD age was 65.8 ± 9.1 years, HbA1c 7.9 ± 1.0%, BMI 31.3 ± 5.3 kg/m2, and eGFR 55 ± 25 mL/min/1.73 m2. A total of 5148 patients (73.8%) had prevalent kidney disease (defined as eGFR < 60 mL/min/1.73 m2 or macroalbuminuria [albumin-to-creatinine ratio > 300 mg/g]) and 3990 patients (57.2%) had established CV disease with increased albuminuria; these characteristics were not mutually exclusive. Microalbuminuria (n = 2896 [41.5%]) and macroalbuminuria (n = 2691 [38.6%]) were common. CARMELINA® will add important information regarding the CV and kidney disease clinical profile of linagliptin by including an understudied, vulnerable cohort of patients with T2D at highest cardio-renal risk. Trial registration ClinicalTrials.gov identifier-NCT01897532; registered July 9, 2013.


Dietary and management factors influence the equine gastric microbiome.
The purpose of this study was to characterize the relationship of diet and management factors with the glandular gastric mucosal microbiome. We hypothesize that the gastric mucosal microbial community is influenced by diet and management factors. Our specific objective is to characterize the gastric mucosal microbiome in relation to these factors. 57 client-owned horses in the southern Louisiana region with and without equine glandular gastric disease. Diet and management data were collected via a questionnaire. Gastroscopy was used for evaluation of equine gastric ulcer syndrome and collection of glandular mucosal pinch biopsies. 16S rRNA amplicon sequencing was used for microbiome analysis. Similarity and diversity indices and sequence read counts of individual taxa were compared between diet and management factors. Differences were detected in association with offering hay, type of hay, sweet feed, turnout, and stalling. Offering hay and stalling showed differences in similarity indices, whereas hay type, sweet feed, and turnout showed differences in similarity and diversity indices. Offering hay, hay type, and sweet feed were also associated with differences in individual sequence read counts. This study provides preliminary characterization of the complex relationship between the glandular gastric microbiome and diet/management factors. The ideal microbiome to promote a healthy glandular gastric environment remains unknown.


Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome.
Elderly patients (age > or = 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I-II studies, low-intensity regimens, or 'targeted' therapies. However, baseline expectations for outcomes of elderly AML with 'standard' AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated. A total of 998 patients age > or = 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods. The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age > or = 75 years, unfavorable karyotypes (often complex), poor performance (3-4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50-55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25-30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%. Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups.


Raman-like light scattering from acoustic phonons in photonic crystal fiber.
Raman and Brillouin scattering are normally quite distinct processes that take place when light is resonantly scattered by, respectively, optical and acoustic phonons. We show how few-GHz acoustic phonons acquire many of the same characteristics as optical phonons when they are tightly trapped, transversely and close to modal cut-off, inside the wavelength-scale core of an air-glass photonic crystal fiber (PCF). The result is an optical scattering effect that closely resembles Raman scattering, though at much lower frequencies. We use photoacoustic techniques to probe the effect experimentally and finite element modelling to explain the results. We also show by numerical modelling that the cladding structure supports two phononic band gaps that contribute to the confinement of sound in the core.


Infective endocarditis in South Africa.
Infective endocarditis (IE) is defined by infection of either a native or prosthetic heart valve, endocardial surface or any cardiac prosthetic device. It is a disease of both the developed and developing world, although IE has evolved in the developed world to a disease markedly different to the disease encountered in the developing world. IE in developed nations is mainly a disease of older patients with degenerative heart valve disease or cardiac prosthetic material, with virulent Staphylococci the most common causative organism. Data regarding the epidemiology of IE in South Africa, a developing country, is limited. The available data suggest it is still a disease of younger patients with rheumatic heart disease (RHD), associated with penicillin-sensitive Streptococcal infection. Although novel diagnostic techniques and improved therapeutic options has emerged, the 1-year mortality rate has remained high in both the developed and developing world at around 30%.


Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis.
Tyrosine kinases play a central role in the activation of signal transduction pathways and cellular responses that mediate the pathogenesis of rheumatoid arthritis. Imatinib mesylate (imatinib) is a tyrosine kinase inhibitor developed to treat Bcr/Abl-expressing leukemias and subsequently found to treat c-Kit-expressing gastrointestinal stromal tumors. We demonstrate that imatinib potently prevents and treats murine collagen-induced arthritis (CIA). We further show that micromolar concentrations of imatinib abrogate multiple signal transduction pathways implicated in RA pathogenesis, including mast cell c-Kit signaling and TNF-alpha release, macrophage c-Fms activation and cytokine production, and fibroblast PDGFR signaling and proliferation. In our studies, imatinib attenuated PDGFR signaling in fibroblast-like synoviocytes (FLSs) and TNF-alpha production in synovial fluid mononuclear cells (SFMCs) derived from human RA patients. Imatinib-mediated inhibition of a spectrum of signal transduction pathways and the downstream pathogenic cellular responses may provide a powerful approach to treat RA and other inflammatory diseases.


Deep breast pain during lactation: a case-control study in Sweden investigating the role of Candida albicans.
Deep breast pain during lactation, with or without accompanying nipple pain and soreness continues to be anecdotally linked to infection by Candia albicans despite lack of robust evidence in the literature that Candida albicans is the cause of women's breast symptoms. A case-control study of breastfeeding women in Sweden with (n 35) and without (n 35) symptoms that may be attributable to Candida albicans was carried out. The symptoms were radiating, burning and penetrating or non-penetrating breast pain with or without associated nipple pain during or after breastfeeding. The primary aim of the study was to test the hypothesis that breastfeeding women with symptoms commonly associated with Candida albicans infection will have a growth of Candida albicans in their breast milk significantly more often than women without these symptoms. A secondary aim was comparison of breastfeeding self-efficacy, measured by the BSES-SF (Breastfeeding Self Efficacy Scale -Short Form), between cases and controls. None of the women in the control group and eight of the women in the case group showed a growth of Candida albicans in their breast milk (p < 0.01), which confirms the hypothesis. There were no statistically significant differences in severity or type of symptoms between those in the case group with and without growth of Candida albicans in their breast milk. Results of the BSES-SF measurement showed no statistically significant differences between cases and controls. However, when analyses were stratified for parity, multiparous controls showed statistically significant higher scores for breastfeeding self-efficacy than multiparous cases. Neither clinical symptoms nor microbial cultivation appear to be reliable means for making a diagnosis of Candida albicans infection of the breast. Skilled breastfeeding consultants should offer support and help with positioning, attachment and identification of physical impediments to successful breastfeeding. Professionals should be aware that it is possible that uncertainty in the breastfeeding situation may to some extent account for mothers' breast symptoms. The ISRCTN (International Standard Randomised Controlled Trial Number) identity for this case-control study is ISRCTN88839993. The study was retrospectively registered on 30 November 2016.


Role of Resultant Dipole Moment in Mechanical Dissociation of Biological Complexes.
Protein-peptide interactions play essential roles in many cellular processes and their structural characterization is the major focus of current experimental and theoretical research. Two decades ago, it was proposed to employ the steered molecular dynamics (SMD) to assess the strength of protein-peptide interactions. The idea behind using SMD simulations is that the mechanical stability can be used as a promising and an efficient alternative to computationally highly demanding estimation of binding affinity. However, mechanical stability defined as a peak in force-extension profile depends on the choice of the pulling direction. Here we propose an uncommon choice of the pulling direction along resultant dipole moment (RDM) vector, which has not been explored in SMD simulations so far. Using explicit solvent all-atom MD simulations, we apply SMD technique to probe mechanical resistance of ligand-receptor system pulled along two different vectors. A novel pulling direction-when ligand unbinds along the RDM vector-results in stronger forces compared to commonly used ligand unbinding along center of masses vector. Our observation that RDM is one of the factors influencing the mechanical stability of protein-peptide complex can be used to improve the ranking of binding affinities by using mechanical stability as an effective scoring function.


Impact of Hyperglycemia and Low Oxygen Tension on Adipose-Derived Stem Cells Compared with Dermal Fibroblasts and Keratinocytes: Importance for Wound Healing in Type 2 Diabetes.
Adipose-derived stem cells (ASC) are currently proposed for wound healing in those with type 2 diabetes mellitus (T2DM). Therefore, this study investigated the impact of diabetes on adipose tissue in relation to ASC isolation, proliferation, and growth factor release and the impact of hyperglycemia and low oxygen tension (found in diabetic wounds) on dermal fibroblasts, keratinocytes, and ASC in vitro. Different sequences of hypoxia and hyperglycemia were applied in vitro to ASC from nondiabetic (n = 8) or T2DM patients (n = 4) to study cell survival, proliferation, and growth factor release. Comparisons of dermal fibroblasts (n = 8) and keratinocytes (primary lineage) were made. No significant difference of isolation and proliferation capacities was found in ASC from nondiabetic and diabetic humans. Hypoxia and hyperglycemia did not impact cell viability and proliferation. Keratinocyte Growth Factor release was significantly lower in diabetic ASC than in nondiabetic ASC group in each condition, while Vascular Endothelial Growth Factor release was not affected by the diabetic origin. Nondiabetic ASC exposition to hypoxia (0.1% oxygen) combined with hyperglycemia (25mM glucose), resulted in a significant increase in VEGF secretion (+64%, p<0.05) with no deleterious impact on KGF release in comparison to physiological conditions (5% oxygen and 5 mM glucose). Stromal cell-Derived Factor-1α (-93%, p<0.001) and KGF (-20%, p<0.05) secretion by DF decreased in these conditions. A better profile of growth factor secretion (regarding wound healing) was found in vitro for ASC in hyperglycemia coupled with hypoxia in comparison to dermal fibroblasts and keratinocytes. Interestingly, ASC from T2DM donors demonstrated cellular growth rates and survival (in hypoxia and hyperglycemic conditions) similar to those of healthy ASC (from normoglycemic donors); however, KGF secretion was significantly depleted in ASC obtained from T2DM patients. This study demonstrated the impact of diabetes on ASC for regenerative medicine and wound healing.


Angioedema due to C1 inhibitor deficiency in 2010.
Angioedema is a recurrent, non-pitting, non-pruritic, self-limiting swelling due to transient increase of endothelial permeability in the capillaries of the deep cutaneous and mucosal layers. Two main groups of angioedema should be distinguished based on the response to treatment: those responding to antihistamine and those that do not. Among the last ones, angioedema due to inherited (hereditary angioedema) and acquired (acquired angioedema) C1 inhibitor deficiency are the best defined, and are known to be mediated by bradykinin. The clinical picture is characterized by cutaneous, abdominal, and laryngeal symptoms that are highly disabling, and can be lethal when they affect the larynx, or if they are not promptly and adequately treated. Important advances in diagnosis and treatment of C1 inhibitor deficiency have been made in recent years, and today, we can rely on different therapeutic options to prevent symptoms or to treat those already present. Because of these advances, in patients properly diagnosed and treated, the mortality for the disease has dropped close to zero, and the quality of life for patients approaches that of normal subjects.


Characterization of MgFe2O4 nanoparticles as a novel electrochemical sensor: application for the voltammetric determination of ciprofloxacin.
A new sensor containing MgFe2O4 nanoparticles in modified multiwall carbon nanotubes (MgFe2O4-MWCNTs) was prepared, and its electrochemical behavior was investigated. MgFe2O4-MWCNTs were used as a voltammetric sensor for the electrocatalytic determination of ciprofloxacin. The synthesized materials were characterized by different methods such as transmission electron microscopy (TEM), X-ray diffraction (XRD), cyclic voltammetry, and electrochemical impedance spectroscopy. The MgFe2O4-MWCNTs electrode showed an oxidation peak potential at around 250 mV. The immobilized composite films facilitate interfacial electron transfer and electrocatalytic activity on the oxidation of ciprofloxacin. The oxidation peak current was dependent on the ciprofloxacin concentration, which was linear over the range of 0.10 - 1000 µmol L(-1) with a detection limit and quantification limit of 0.01 and 0.08 µmol L(-1), respectively. The relative standard deviation for the determination of 1.0 µmol L(-1) ciprofloxacin was 1.1%. The repeatability of the sensor was investigated by preparing nine similar electrodes. The proposed sensor is a selective and fast tool for the determination of ciprofloxacin in tablet, plasma, and urine samples.


Correlates of Agreement between Accelerometry and Self-reported Physical Activity.
Understanding factors that influence accurate assessment of physical activity (PA) and sedentary behavior (SB) is important to measurement development, epidemiologic studies, and interventions. This study examined agreement between self-reported (International Physical Activity Questionnaire-Long Form [IPAQ-LF]) and accelerometry-based estimates of PA and SB across six countries and identified correlates of between-method agreement. Self-report and objective (accelerometry-based) PA and SB data were collected in 2002-2011 from 3865 adult participants in eight cities from six countries (Belgium, Czech Republic, Denmark, Spain, United Kingdom, and United States). Between-method relative agreement (correlation) and absolute disagreement (mean difference between conceptually and intensity-matched IPAQ-LF and accelerometry-based PA and SB variables) were estimated. Also, sociodemographic characteristics and PA patterns were examined as correlates of between-method agreement. Observed relative agreement (relationships of IPAQ-LF with accelerometry-based PA and SB variables) was small to moderate (r = 0.05-0.37) and was moderated by sociodemographic (age, sex, weight status, and education) and behavioral (PA-type) factors. The absolute disagreement was large, with participants self-reporting higher PA intensity and total time in moderate-to-vigorous-intensity PA than accelerometry. Also, self-reported sitting time was lower than accelerometry-based sedentary behavior. After adjusting for sociodemographic and behavioral factors, the absolute disagreement between pairs of IPAQ-LF and accelerometry-based PA variables remained significantly different across cities/countries. Present findings suggest systematic cultural and/or linguistic and sociodemographic differences in absolute agreement between the IPAQ-LF and the accelerometry-based PA and SB variables. These results have implications for the interpretation of international PA and SB data and correlate/determinant studies. They call for further efforts to improve such measures.


Kilohertz pulse repetition frequency slab Ti:sapphire lasers with high average power (10 W).
High-average-power broadband 780-nm slab Ti:sapphire lasers, pumped by a kilohertz pulse repetition frequency copper vapor laser (CVL), were demonstrated. These lasers are designed for damage-free power scaling when pumped by CVL's configured for maximum output power (of order 100 W) but with poor beam quality (M(2) approximately 300). A simple Brewster-angled slab laser side pumped by a CVL produced 10-W average power (1.25-mJ pulses at 8 kHz) with 4.2-ns FWHM pulse duration at an absolute efficiency of 15% (68-W pump power). Thermal lensing in the Brewster slab laser resulted in multitransverse mode output, and pump absorption was limited to 72% by the maximum doping level for commercially available Ti:sapphire (0.25%). A slab laser with a multiply folded zigzag path was therefore designed and implemented that produced high-beam-quality (TEM(00)-mode) output when operated with cryogenic cooling and provided a longer absorption path for the pump. Excessive scattering of the Ti:sapphire beam at the crystal surfaces limited the efficiency of operation for the zigzag laser, but fluorescence diagnostic techniques, gain measurement, and modeling suggest that efficient power extraction (>15 W TEM(00), >23% efficiency) from this laser would be possible for crystals with an optical quality surface polish.


Persistence of rhombomeric organisation in the postsegmental hindbrain.
Rhombomeres are morphological varicosities of the neural tube that are present between embryonic day (E) 1.5 and E5 and are characterised by compartment organisation, segmentally neuronal organisation and spatially restricted patterns of gene expression. After E5, the segmented origins of the hindbrain become indistinct, while the adult hindbrain has an longitudinal columnar nuclear organisation. In order to assess the impact of the early transverse pattern on later longitudinal organisation, we have used orthotopic quail grafts and in situ hybridisation to investigate the long-term fate of rhombomeres in the embryonic chick hindbrain. The uniformity of mixing between quail and chick cells was first verified using short-term aggregation cultures. The dispersal of the progeny of individual rhombomeres (r) was then assessed by the unilateral, isochronic and orthotopic transplantation of either r2, r3, r4, r5 or r6 from quail to chick at embryonic day E2. In addition, orthotopic, partial rhombomere grafts, encompassing an inter-rhombomere boundary and adjacent rhombomere bodies were used to assess cell mixing within rhombomeres. Operated embryos were incubated to either E7 or E10 when chimaeric brains were removed. Quail cells were identified in whole mounts or serial sections using the quail-specific antibody QCPN. Subsequently, radial glia morphology was assessed either by immunohistochemistry or DiI labelling. A series of fixed hindbrains between E6 and E9 were probed for transcripts of Hoxa-2 and Hoxb-1. Fate-mapping reveals that the progeny of individual rhombomeres form stripes of cells running dorsoventrally through the hindbrain. This pattern of dispersal precisely parallels the array of radial glia. Although the postmitotic progeny of adjacent rhombomeres spread to some extent into each others' territory in intermediate and marginal zones, there is little or no mixing between rhombomeres in the ventricular zone, which thus remains compartmentalised long after the rhombomeric morphology disappears. Segmental gene expression within this layer is also maintained after E5. A more detailed analysis of mixing between proliferating cells, using partial rhombomere grafts, reveals that both mixing and growth are non-uniform within the ventricular layer, suggesting, in particular, that longitudinal expansion within this layer is restricted. Together, these observations suggest that rhombomeres do not disappear at E5, as has previously been supposed, rather they persist in the ventricular zone to at least E9, ensuring a continuity in the presumed segmental cues that specify neuroepithelial cells in the hindbrain.


Single-molecule fluorescence lifetime and anisotropy measurements of the red fluorescent protein, DsRed, in solution.
Fluorescence lifetime and anisotropy measurements were made on the red fluorescent protein (DsRed) from tropical coral of the Discosoma genus, both at single-molecule and bulk concentrations. As expected from previous work, the fluorescence lifetime of DsRed in solution is dependent on laser power, decreasing from an average fluorescence lifetime in the beam of about 3.3 ns at low power (3.5 ns if one extrapolates to zero power) to about 2.1 ns at 28 kW/cm2. At the single-molecule level, exciting with 532 nm, 10 ps laser pulses at 80 MHz repetition rate, DsRed particles entering the laser beam initially have a lifetime of about 3.6 ns and convert to a form having a lifetime of about 3.0 ns with a quantum yield of photoconversion on the order of 10(-3) (calculated in terms of photons per DsRed tetramer). The particles then undergo additional photoconversion with a quantum yield of roughly 10(-5), generating a form with an average lifetime of 1.6 ns. These results may be explained by rapid photoconversion of one DsRed monomer in a tetramer, which acts as an energy transfer sink, resulting in a lower quantum yield for photoconversion of subsequent monomers. Multiparameter correlation and selective averaging can be used to identify DsRed in a mixture of fluorophores, in part exploiting the fact that fluorescent lifetime of DsRed changes as a function of excitation intensity.


Chemosensory cues affect amygdaloid neurogenesis and alter behaviors in the socially monogamous prairie vole.
The current study examined the effects of pheromonal exposure on adult neurogenesis and revealed the role of the olfactory pathways on adult neurogenesis and behavior in the socially monogamous prairie vole (Microtus ochrogaster). Subjects were injected with a cell proliferation marker [5-bromo-2'-deoxyuridine (BrdU)] and then exposed to their own soiled bedding or bedding soiled by a same- or opposite-sex conspecific. Exposure to opposite-sex bedding increased BrdU labeling in the amygdala (AMY), but not the dentate gyrus (DG), of female, but not male, voles, indicating a sex-, stimulus-, and brain region-specific effect. The removal of the main olfactory bulbs or lesioning of the vomeronasal organ (VNOX) in females reduced BrdU labeling in the AMY and DG, and inhibited the male bedding-induced BrdU labeling in the AMY, revealing the importance of an intact olfactory pathway for amygdaloid neurogenesis. VNOX increased anxiety-like behavior and altered social preference, but it did not affect social recognition memory in female voles. VNOX also reduced the percentage of BrdU-labeled cells that co-expressed the neuronal marker TuJ1 in the AMY, but not the DG. Together, our data indicate the importance of the olfactory pathway in mediating brain plasticity in the limbic system as well as its role in behavior.


Does type 2 diabetes confer higher relative rates of cardiovascular events in women compared with men?
To investigate whether diabetes confers higher relative rates of cardiovascular events in women compared with men using contemporary data, and whether these sex-differences depend on age. All Danish residents aged 40-89 years without a history major adverse cardiovascular events, including heart failure, as of 1 January 2012 until 31 December 2016 were categorized by diabetes-status and characterized by individual-level linkage of Danish nationwide administrative registers. We used Poisson regression to calculate overall and age-dependent incidence rates, incidence rate ratios, and women-to-men ratios for myocardial infarction, heart failure, ischaemic stroke, or cardiovascular death (MACE-HF). Among 218 549 (46% women) individuals with diabetes, the absolute rate of MACE-HF was higher in men than in women (24.9 vs. 19.9 per 1000 person-years). Corresponding absolute rates in men and women without diabetes were 10.1 vs. 7.0 per 1000 person-years. Comparing individuals with and without diabetes, women had higher relative rates of MACE-HF than men [2.8 (confidence interval, CI 2.9-2.9) in women vs. 2.5 (CI 2.4-2.5) in men] with a women-to-men ratio of 1.15 (CI 1.11-1.19, P < 0.001). The relative rates of MACE-HF were highest in the youngest and decreased with advancing age for both men and women, but the relative rates were higher in women across all ages, with the highest women-to-men ratio between age 50 and 60 years. Although men have higher absolute rates of cardiovascular complications, the relative rates of cardiovascular complications associated with diabetes are higher in women than in men across all ages in the modern era.


Ataxin-3 interactions with rad23 and valosin-containing protein and its associations with ubiquitin chains and the proteasome are consistent with a role in ubiquitin-mediated proteolysis.
Machado-Joseph disease is caused by an expansion of a trinucleotide CAG repeat in the gene encoding the protein ataxin-3. We investigated if ataxin-3 was a proteasome-associated factor that recognized ubiquitinated substrates based on the rationale that (i) it is present with proteasome subunits and ubiquitin in cellular inclusions, (ii) it interacts with human Rad23, a protein that may translocate proteolytic substrates to the proteasome, and (iii) it shares regions of sequence similarity with the proteasome subunit S5a, which can recognize multiubiquitinated proteins. We report that ataxin-3 interacts with ubiquitinated proteins, can bind the proteasome, and, when the gene harbors an expanded repeat length, can interfere with the degradation of a well-characterized test substrate. Additionally, ataxin-3 associates with the ubiquitin- and proteasome-binding factors Rad23 and valosin-containing protein (VCP/p97), findings that support the hypothesis that ataxin-3 is a proteasome-associated factor that mediates the degradation of ubiquitinated proteins.


Possible role of aerosol transmission in a hospital outbreak of influenza.
We examined the role of aerosol transmission of influenza in an acute ward setting. We investigated a seasonal influenza A outbreak that occurred in our general medical ward (with open bay ward layout) in 2008. Clinical and epidemiological information was collected in real time during the outbreak. Spatiotemporal analysis was performed to estimate the infection risk among patients. Airflow measurements were conducted, and concentrations of hypothetical virus-laden aerosols at different ward locations were estimated using computational fluid dynamics modeling. Nine inpatients were infected with an identical strain of influenza A/H3N2 virus. With reference to the index patient's location, the attack rate was 20.0% and 22.2% in the "same" and "adjacent" bays, respectively, but 0% in the "distant" bay (P = .04). Temporally, the risk of being infected was highest on the day when noninvasive ventilation was used in the index patient; multivariate logistic regression revealed an odds ratio of 14.9 (95% confidence interval, 1.7-131.3; P = .015). A simultaneous, directional indoor airflow blown from the "same" bay toward the "adjacent" bay was found; it was inadvertently created by an unopposed air jet from a separate air purifier placed next to the index patient's bed. Computational fluid dynamics modeling revealed that the dispersal pattern of aerosols originated from the index patient coincided with the bed locations of affected patients. Our findings suggest a possible role of aerosol transmission of influenza in an acute ward setting. Source and engineering controls, such as avoiding aerosol generation and improving ventilation design, may warrant consideration to prevent nosocomial outbreaks.


Pre-departure and post-arrival management of P. falciparum malaria in refugees relocating from sub-Saharan Africa to the United States.
Plasmodium infection, often sub-clinical, is common in migrating sub-Saharan refugee populations. Refugees who subsequently develop clinical malaria suffer illness and exact a cost on state and local health care facilities. Untreated infection is also of public health concern because of the potential for local transmission. In response to increasing numbers of refugees originating in sub-Saharan Africa guidelines for the management of malaria in refugees migrating to the United States have been broadened and updated. The guidelines are based on available evidence-based literature and recent public health experience. These guidelines were critically reviewed, assessed, and approved by multiple National and State entities as well as outside experts. These consensus guidelines recommend that sub-Saharan African refugees relocating to the United States receive presumptive treatment of P. falciparum malaria before departure or during the domestic refugee medical screening after arrival. Presumptive therapy is not currently recommended for either non-falciparum malaria or for refugees relocating from areas outside sub-Saharan Africa.


Citrus flavanones prevent systemic inflammation and ameliorate oxidative stress in C57BL/6J mice fed high-fat diet.
The flavanones hesperidin, eriocitrin and eriodictyol were investigated for their prevention of the oxidative stress and systemic inflammation caused by high-fat diet in C57BL/6J mice. The mice received a standard diet (9.5% kcal from fat), high-fat diet (45% kcal from fat) or high-fat diet supplemented with hesperidin, eriocitrin or eriodictyol for a period of four weeks. Hesperidin, eriocitrin and eriodictyol increased the serum total antioxidant capacity, and restrained the elevation of interleukin-6 (IL-6), macrophage chemoattractant protein-1 (MCP-1), and C-reactive protein (hs-CRP). In addition, the liver TBARS levels and spleen mass (g per kg body weight) were lower for the flavanone-treated mice than in the unsupplemented mice. Eriocitrin and eriodictyol reduced TBARS levels in the blood serum, and hesperidin and eriodictyol also reduced fat accumulation and liver damage. The results showed that hesperidin, eriocitrin and eriodictyol had protective effects against inflammation and oxidative stress caused by high-fat diet in mice, and may therefore prevent metabolic alterations associated with the development of cardiovascular diseases in other animals.


Two new Eimeria species parasitic in corncrakes (Crex crex) (Gruiformes: Rallidae) in the United Kingdom.
In this study we describe 2 new species of coccidia (Apicomplexa: Eimeriidae) parasites isolated from the feces of corncrake (Crex crex) (Gruiformes: Rallidae), bred in captivity in the U.K. Oocysts of Eimeria crecis n. sp. were approximately spherical and measured 15.3 μm (13-18) × 14.3 (12-16), providing an oocyst shape index of 1.1. A micropyle and oocyst residuum were absent, but a polar granule was present. Oocysts of Eimeria nenei n. sp. were ellipsoidal and measured 23.6 (21-26) × 18.1 (17-20), providing an oocyst shape index of 1.3. A micropyle and polar granule were present. Surveying free-living, wild adult corncrakes in Scotland (U.K.) demonstrated both parasite species to be widespread. These are the first species described to infect the corncrake, and they are distinct from those previously found to infect members of the closely related crane family (Gruiformes: Gruidae). Partial amplification and sequencing of the 18S rRNA gene and internal transcribed spacer 2 indicated a close relationship between the 2 proposed new species as a group distinct from the Eimeria species known to infect cranes. These newly identified parasite species have been associated with enteric disease in corncrakes being prepared for reproduction in captivity and reintroduction into England (U.K.).


Keratan sulfates from bovine tracheal cartilage structural studies of intact polymer chains using H and 13C NMR spectroscopy.
Intact keratan sulfate chains derived from bovine tracheal cartilage have been examined using both one-dimensional methods and the two-dimensional experiments COSY-45 and TOCSY for homonuclear shift correlations and a modified COLOC (correlated spectroscopy for long-range couplings) approach for 13C-1H shift correlations. Partial 1H and 13C NMR signal assignments for residues within the intact polymer chain are reported; data derived from the repeat region signals and from chain cap residues are assigned by comparison with published data derived from oligosaccharides obtained through cleavage of keratan sulfate polymer chains using keratanase and keratanase II and are discussed in detail. The one-dimensional spectra for both 1H and 13C nuclei contain highly crowded signal clusters for which data analysis is not directly possible. COSY-45 analysis allow the correlation and assignment of many proton resonances located within the 3.4-4.8 p.p.m. chemical shift region while from the C/H correlation spectrum data are assignable for some signals within the complex set of carbon resonances which fall in the region between 68 and 86 p.p.m., This work using material from tracheal cartilage has permitted the first detailed combined 1H and 13C NMR examination of the primary keratan sulfate polymer structure; this sequence forms the basis for the more complex members of the keratan sulfate family present in other tissues such as articular cartilage and cornea where further residues such as (alpha1-3)-linked fucose and (alpha2-6)-linked N-acetylneuraminic acid are also present. This nondestructive method of analysis complements the currently available degradative methods for structure determination which may then subsequently be utilized.


Value of a new fixed-combination pack of bisphosphonate, calcium and vitamin D in the therapy of osteoporosis: results of two quantitative patient research studies.
Osteoporotic patients with insufficient calcium intake and/or vitamin D insufficiency need adequate calcium and vitamin D supplementation with their bisphosphonate treatment. However, consistent intake and, therefore, the effectiveness of calcium/vitamin D supplementation may be impaired by several factors in the individual patient: low prescription rate or lack of advice to purchase calcium/vitamin D; reduced compliance because of the complexity of the regimen; or incorrect intake. There is a need to provide patients with a better way of taking bisphosphonate treatment with their calcium/vitamin D supplementation. To this end, a fixed-combination pack to help patients take the combination of bisphosphonate, calcium and vitamin D correctly and regularly has been developed. To evaluate patients' understanding of administration instructions, preferences and their perceptions of compliance, convenience and completeness of a fixed-combination pack of bisphosphonate, calcium and vitamin D compared with those associated with separate packs. The new monthly fixed-combination pack of bisphosphonate, calcium and vitamin D contains four weekly boxes. Each box contains a blister pack with one swallowable risedronate 35 mg film-coated tablet and six sachets of calcium/vitamin D effervescent granules (calcium 1000 mg and vitamin D(3) [colecalciferol] 880 IU) for dissolution in water as an oral solution, together constituting 1 week of therapy, accompanied by a patient information leaflet. Two quantitative patient research survey studies were conducted using standard questionnaires in face-to-face interviews with 400 postmenopausal women in several French cities. Participants were given the combined pack and two separate packs (risedronate 35 mg once weekly and calcium/vitamin D effervescent granules in sachets). In the first study, participants' understanding of administration instructions and preferences were evaluated. In the second study, participants' perception of compliance, convenience and completeness of the new combination pack of risedronate 35 mg plus calcium/vitamin D compared with two separate packs were evaluated. Participants asked about the combined pack answered a significantly higher proportion of questions about intake instructions correctly (80.3%) than participants asked about the two separate packs (70.7%) [p = 0.0004]. The combined pack was preferred by 72% of participants (p < 0.0001) for several reasons. Compared with separate packs, the combined pack was considered easier to use by 63% and easier to remember to use by 67% of participants. Participants believed that use of the combined pack would be more likely to help them take their bisphosphonate regularly (66%) and correctly (67%), and to take their calcium/vitamin D supplementation more regularly and correctly (68%), than use of separate packs. Seventy percent of participants believed that use of the combination pack would help them to not forget to take calcium/vitamin D supplementation. Use of the fixed-combination pack of risedronate 35 mg plus calcium/vitamin D once weekly could increase the likelihood that postmenopausal osteoporotic patients will receive a complete bisphosphonate, calcium and vitamin D therapy course and is likely to enhance correct intake of combination therapy. Use of this fixed-combination product will provide patients with a tool for improving adherence to recommended osteoporosis therapy and optimize the effectiveness of such treatment.


The HESI exit exam: Progression benchmark and remediation guide.
Evidence exists indicating that remediation positively affects NCLEX success of students with known academic deficits. However, specific benchmarks that identify students who are at risk of NCLEX failure and in need of remediation have not been identified. Following publication of research findings that established the reliability and validity of the HESI Exit Exam (E2) as an accurate measure of students' NCLEX preparedness, nurse educators increasingly chose to administer the E2 to their senior students. This study investigated using the E2 as a benchmark for progression and as a guide for remediation.


Site-specific administration of antisense oligonucleotides using biodegradable polymer microspheres provides sustained delivery and improved subcellular biodistribution in the neostriatum of the rat brain.
Antisense oligonucleotides (ODNs) are being increasingly used in the central nervous system as biological tools, as drug-target validation agents and as potential therapeutic agents. Although the local delivery of naked ODNs to the brain can result in the desired biological effects, the duration of efficacy is relatively short lived due to the combined effects of rapid ODN degradation and elimination half-lives in vivo. In this study, we have examined the use of biodegradable polymer microspheres as a site-specific delivery system for targeting ODNs to the neostriatum of the rat brain. Model phosphorothioate backbone-modified ODNs were entrapped within poly(D,L-lactide-co-glycolide) (PLAGA) microspheres using a double emulsion-deposition method and the formulations characterised in terms of particle size, surface morphology, percent encapsulation efficiency, ODN loading and in vitro release profiles. For in vivo evaluation, PLAGA microspheres containing fluorescently-labelled ODNs were stereo-taxically administered to the neostriatum of the rat brain and biodistribution of ODNs monitored after 48 h. Administration of free fluorescently-labelled ODNs to the neostriatum resulted in a punctate cellular distribution of ODNs after 24 h with little or no ODN remaining in the neostriatum after 48 h. In comparison, fluorescently-labelled ODNs delivered using polymer microspheres were intensely visible in cells after 48 h post-administration and the fluorescence appeared to be diffuse covering both cytosolic and nuclear regions. Dual-label immunohistochemical analyses suggested that ODNs were mainly distributed to neuronal cells. These data indicate that site-specific administration of ODNs using biodegradable polymer microspheres will not only provide sustained delivery of nucleic acids but can also improve the cellular distribution of ODNs to brain cells. Sustained or controlled-release biodegradable polymer formulations, therefore, represent an attractive strategy for improved local delivery of ODNs to the CNS.


Experimental autoimmune encephalomyelitis repressed by microglial paralysis.
Although microglial activation occurs in inflammatory, degenerative and neoplastic central nervous system (CNS) disorders, its role in pathogenesis is unclear. We studied this question by generating CD11b-HSVTK transgenic mice, which express herpes simplex thymidine kinase in macrophages and microglia. Ganciclovir treatment of organotypic brain slice cultures derived from CD11b-HSVTK mice abolished microglial release of nitrite, proinflammatory cytokines and chemokines. Systemic ganciclovir administration to CD11b-HSVTK mice elicited hematopoietic toxicity, which was prevented by transfer of wild-type bone marrow. In bone marrow chimeras, ganciclovir blocked microglial activation in the facial nucleus upon axotomy and repressed the development of experimental autoimmune encephalomyelitis. We conclude that microglial paralysis inhibits the development and maintenance of inflammatory CNS lesions. The microglial compartment thus provides a potential therapeutic target in inflammatory CNS disorders. These results validate CD11b-HSVTK mice as a tool to study the impact of microglial activation on CNS diseases in vivo.


Snus undermines quit attempts but not abstinence: a randomised clinical trial among US smokers.
Observational studies and a few clinical trials suggest that use of low nitrosamine smokeless tobacco (snus) can facilitate smoking cessation. To better understand the real-world impact of snus on smoking behaviour, a large-scale, long-term clinical trial of naturalistic snus use among smokers is needed. A nationwide clinical trial compared abstinence outcomes among smokers who were randomised to receive free samples of snus versus not. Participants (N=1236) were recruited throughout the US and assessed for 1 year following a 6-week naturalistic sampling period, with high retention throughout. Primary outcomes included self-reported quit attempts, floating abstinence (any 7-day period of non-smoking) and 7-day point-prevalence abstinence at 6 months and 12 months. Secondary outcomes were changes in smoking, motivation and confidence to quit and adverse events. No tobacco industry support was provided. Within snus group, 82% used at least once, and 16% were using regularly at end of sampling period. Compared to control participants, smokers in the snus group were less likely to make any quit attempt (RR=0.83; 95% CI 0.70 to 1.00), and any 24 h quit attempt (RR=0.77; 95% CI 0.63 to 0.95). There were no group differences on any measure of abstinence. Provision of snus in a naturalistic context resulted in minimal uptake, and as a whole, undermined quit attempts and did not increase smoking abstinence. Results do not support the unguided, free provision of snus among smokers not motivated to quit as a means to facilitate quit attempts. NCT01509586, Results.


Primary hyperaldosteronism in a domestic ferret with an adrenocortical adenoma.
A 6-year-old spayed female domestic ferret was evaluated because of lethargy, alopecia, pruritus, and an abdominal mass. On initial examination, nonregenerative anemia, mild azotemia, and a large left adrenal gland mass were identified. However, deterioration of the ferret's general condition prevented excision of the mass, and dyspnea, weakness, hypertension, and severe hypokalemia developed. Plasma aldosterone concentration was >3329 pmol/L, confirming a provisional diagnosis of hyperaldosteronism. High concentrations of sex hormones were also observed, but baseline cortisol concentration was within reference limits. Medical treatment included oral administration of spironolactone, potassium gluconate, leuprolide acetate, amlodipine, and benazepril. Inhalation of albuterol proved effective in reducing the dyspnea. In the following weeks, serum potassium concentration returned to within reference limits and hypertension decreased, but dyspnea persisted. Two months after initial examination, the ferret became anorectic and was euthanized. Histologic examination revealed a large left adrenal gland adenoma, progressive chronic nephropathy, severe pulmonary edema, and focal fibrosis in the left ventricle. Immunohistochemical staining of the adrenal gland mass revealed aldosterone within neoplastic adrenocortical cells. Findings suggested that primary hyperaldosteronism should be considered as a possible cause in ferrets with hypokalemia, hypertension, and an adrenal gland mass. Early detection of aldosterone-secreting masses might allow for removal of the tumor before irreversible complications occur.


Lymph node evaluation for colon cancer in an era of quality guidelines: who improves?
In the 1990s, several organizations began recommending evaluation of > 12 lymph nodes during colon resection because of its association with improved survival. We examined practice implications of multispecialty quality guidelines over the past 20 years recommending evaluation of ≥ 12 lymph nodes during colon resection for adequate staging. We used the 1988 to 2009 Surveillance, Epidemiology, and End Results program to conduct a retrospective observational cohort study of 90,203 surgically treated patients with colon cancer. We used Cochran-Armitage tests to examine trends in lymph node examination over time and multivariate logistic regression to identify patient characteristics associated with guideline-recommended lymph node evaluation. The introduction of practice guidelines was associated with gradual increases in guideline-recommended lymph node evaluation. From 1988 to 1990, 34% of patients had > 12 lymph nodes evaluated, increasing to 38% in 1994 to 1996 and to > 75% from 2006 to 2009. Younger, white patients and those with more-extensive bowel penetration (T3/4 nonmetastatic) and high tumor grade saw more-rapid increases in lymph node evaluation (P < .001). Multivariate analyses demonstrated a significant interaction between year of diagnosis and both T stage and grade, indicating that those with higher T stage and higher grade were more likely to receive guideline-recommended care earlier. The implementation of lymph node evaluation guidelines was accepted gradually into practice but adopted more quickly among higher risk patients. By identifying patients who are least likely to receive guideline-recommended care, these findings present a starting point for promoting targeted improvements in cancer care and further understanding underlying contributors to these disparities.


Association analysis between variants of the interleukin-1beta and the interleukin-1 receptor antagonist gene and antidepressant treatment response in major depression.
This study investigated the possible association of the interleukin-1 beta (IL-1beta) C-511T promoter polymorphism and the interleukin-1 receptor antagonist (IL-1Ra) (86bp)(n) variable number of tandem repeats (VNTR) polymorphism with antidepressant response to paroxetine and mirtazapine treatment. The study group consisted of 101 patients suffering from DSM-IV major depression participating in a randomized double-blind controlled clinical trial. Patients homozygous for the IL-1beta-511T allele had a significantly faster and more pronounced response to paroxetine treatment than IL-1beta-511C allele carriers. No association was found for the IL-1beta C-511T polymorphism with mirtazapine treatment response. The IL-1Ra VNTR showed neither an association with paroxetine nor with mirtazapine treatment response. Our results provide further suggestive evidence that time course of response and antidepressant efficacy of paroxetine, but not of mirtazapine, is influenced in a clinically relevant manner by the IL-1beta C-511T gene variant. Our data do not support the hypothesis that the IL-1Ra (86bp)(n) VNTR affects antidepressant treatment response to paroxetine or mirtazapine. An independent replication of our finding is needed. If replicated, the IL-1beta C-511T promoter polymorphism could be considered useful for prospective confirmatory pharmacogenetic trials in patients with major depression.


Lack of myostatin alters intermyofibrillar mitochondria activity, unbalances redox status, and impairs tolerance to chronic repetitive contractions in muscle.
Loss of myostatin (mstn) function leads to a decrease in mitochondrial content, a reduced expression of cytochrome c oxidase, and a lower citrate synthase activity in skeletal muscle. These data suggest functional or ultrastructural mitochondrial abnormalities that can impact on muscle endurance characteristics in such phenotype. To address this issue, we investigated subsarcolemmal and intermyofibrillar (IMF) mitochondrial activities, skeletal muscle redox homeostasis, and muscle fiber endurance quality in mstn-deficient mice [mstn knockout (KO)]. We report that lack of mstn induced a decrease in the coupling of IMF mitochondria respiration, with significantly higher basal oxygen consumption. No lysis of mitochondrial cristae or excessive swelling were observed in mstn KO mice compared with wild-type (WT) mice. Concerning redox status, mstn KO gastrocnemius exhibited a significant decrease in lipid peroxidation levels (-56%; P < 0.01 vs. WT) together with a significant upregulation of the antioxidant glutathione system. In contrast, superoxide dismutase and catalase activities were altered in mstn KO, gastrocnemius and soleus with a reduction of up to 80% compared with WT animals. The force production observed after contractile endurance test was significantly lower in extensor digitorum longus and soleus muscles of mstn KO mice compared with the controls (17 ± 3 and 36 ± 5% vs. 28 ± 4 and 56 ± 5%, respectively, P < 0.05). Together, these findings indicate that, besides an increased skeletal muscle mass, genetic mstn inhibition has differential effects on redox homeostasis and mitochondrial function that would have functional consequences on muscle response to endurance exercise.


Detection of human telomerase RNA gene in cervical cancer and precancerous lesions: comparison with cytological and human papillomavirus DNA test findings.
The aims of this study were to compare the findings of fluorescence in situ hybridization (FISH) detection of human telomerase RNA gene (hTERC) amplification with that of cytological and human papillomavirus (HPV) DNA tests and explore the possibility to improve the accuracy of the diagnoses of high-grade cervical intraepithelial neoplasia (CIN) and cervical cancer. A total of 201 specimens of liquid-based thin-layer cytological examination findings were collected and detected by HPV DNA test and hTERC detected by FISH. All women underwent colposcopy and histological examination of biopsy specimen if needed. The 3 screening methods were compared based on histological examination of colposcopic biopsies. The amplification of hTERC showed 6.06% in normal or inflammation cases, 10.00% in CIN 1, 66.67% in CIN 2, 72.50% in CIN 3, and 100.00% in carcinoma, with significant difference between the low- (<or=CIN 1 or <or=low-grade squamous intraepithelial lesion) and high-grade (>or=CIN 2 or >or=atypical squamous cells in which high-grade squamous intraepithelial lesion cannot be excluded) cervical lesions (P < 0.001). The hTERC amplification rate was consistent with abnormal rates of cytological and histological diagnoses. The detection of hTERC amplification had a much higher accuracy (87.56%) than the cytological (80.10%) and HPV DNA test (77.61%) findings. Using FISH to detect the amplification of hTERC had a much higher specificity and accuracy for the diagnoses of high-grade CIN and cervical cancer than cytological and HPV DNA test findings, suggesting that this detection might be a useful and specific screening method in cervical cancer and precancerous lesions.


Fetal and maternal candidate single nucleotide polymorphism associations with cerebral palsy: a case-control study.
Previous studies have suggested associations between certain genetic variants and susceptibility to cerebral palsy (CP). This study was designed to assess established and novel maternal and child genetic and epidemiologic risk factors for CP along with their interactions. DNA from 587 case and 1154 control mother-child pairs was analyzed. A panel of 35 candidate single nucleotide polymorphisms (SNPs) were examined and included SNPs in genes associated with (1) thrombophilia, (2) inflammation, and (3) risk factors for CP (eg, preterm birth). Comparisons were specified a priori and made by using a χ(2) test. There were 40 fetal and 28 maternal associations with CP when analyzed by CP subtype, gestational age, genotypes of apolipoprotein E, and haplotypes of mannose-binding-lectin. After Bonferroni correction for multiple testing, no fetal or maternal candidate SNP was associated with CP or its subtypes. Only fetal carriage of prothrombin gene mutation remained marginally associated with hemiplegia in term infants born to mothers with a reported infection during pregnancy. Odds ratio directions of fetal SNP associations were compared with previously reported studies and confirmed no trend toward association. Except for the prothrombin gene mutation, individual maternal and fetal SNPs in our candidate panel were not found to be associated with CP outcome. Past reported SNP associations with CP were not confirmed, possibly reflecting type I error from small numbers and multiple testing in the original reports.


'Effectiveness of Continuing Professional Development' project: a summary of findings.
This article reports on a study examining continuing professional development (CPD) for consultant doctors. The aim of the study was to identify what promotes or inhibits the effectiveness of CPD and met the following objectives: comparing and contrasting the experiences of CPD across the range of specialties; identifying and describing the range of different models of CPD employed across the different specialties and clinical contexts; considering the educational potential of reflective practice in CPD and its impact on professional practice and exploring how different professionals judge the effectiveness of current CPD practices. Using a mixture of qualitative (interviews, letters, observation) and quantitative (online questionnaire) methods, the views of CPD providers and users were surveyed. Findings suggested that the effectiveness of CPD, as inferred from the comments made by interviewees and questionnaire respondents, relates to the impact on knowledge, skills, values, attitudes, behaviours and changes in practice in the work place. The quality of CPD was seen as inextricably linked to any improvements in the quality of the professional practices required for service delivery. There was widespread consensus as to the value of learning in professional settings. There was recognition that there needs to be a move away from tick boxes to the in-depth identification of learning needs and how these can be met both within and external to the work place, with learning being adequately enabled and assessed in all locations. In conclusion, it can be said that CPD is valued and is seen as effective when it addresses the needs of individual clinicians, the populations they serve and the organisations within which they work. However, the challenge for CPD may lie in the dynamic interaction between educational opportunities and service delivery requirements, as there may be occasions where they vie with each other for resources.


Parental origin of mutation and the risk of breast cancer in a prospective study of women with a BRCA1 or BRCA2 mutation.
The objective is to estimate the risk of breast cancer in women who carry a deleterious BRCA1 or BRCA2 mutation, according to parental origin of mutation. We conducted a cohort study of women with a BRCA1 mutation (n = 1523) or BRCA2 mutation (n = 369) who had not been diagnosed with breast or ovarian cancer. For each woman, the pedigree was reviewed and the origin of the mutation was assigned as probable paternal or maternal. The hazard ratio (HR) for developing breast cancer in the follow-up period was estimated for women with a paternal mutation compared to a maternal mutation. The risk of breast cancer was modestly higher in women with a paternal BRCA1 mutation compared to women with a maternal BRCA1 mutation (HR = 1.46; 95% CI = 0.99-2.16) but the difference was not significant (p = 0.06). The parental mutation origin did not affect the risk in women with a BRCA2 mutation. Our results are consistent with the hypothesis that there is an increased risk of breast cancer among women with a paternally inherited BRCA1 mutation compared to a maternally inherited mutation. However, the data are not sufficiently compelling to justify different screening recommendations for the two subgroups.


Roundtable on Preseason Heat Safety in Secondary School Athletics: Heat Acclimatization.
To provide best-practice recommendations for developing and implementing heat-acclimatization strategies in secondary school athletics. An extensive literature review on topics related to heat acclimatization and heat acclimation was conducted by a group of content experts. Using the Delphi method, action-oriented recommendations were developed. A period of heat acclimatization consisting of ≥14 consecutive days should be implemented at the start of fall preseason training or practices for all secondary school athletes to mitigate the risk of exertional heat illness. The heat-acclimatization guidelines should outline specific actions for secondary school athletics personnel to use, including the duration of training, the number of training sessions permitted per day, and adequate rest periods in a cool environment. Further, these guidelines should include sport-specific and athlete-specific recommendations, such as phasing in protective equipment and reintroducing heat acclimatization after periods of inactivity. Heat-acclimatization guidelines should be clearly detailed in the secondary school's policy and procedures manual and disseminated to all stakeholders. Heat-acclimatization guidelines, when used in conjunction with current best practices surrounding the prevention, management, and care of secondary school student-athletes with exertional heat stroke, will optimize their health and safety.


Refractive aim and visual outcome after phacoemulsification: A 2-year review from a Tertiary Private Eye Hospital in Sub-Saharan Africa.
To review the short-term visual outcome of phacoemulsification in adults with uncomplicated cataracts in Eye Foundation Hospital, Lagos, Nigeria. A retrospective review of records of patients that had phacoemulsification between January 2012 and December 2013 in Eye Foundation Hospital, Lagos, Nigeria, was done. Preoperative visual acuity, refractive aim, intraoperative complications, postoperative unaided, and best-corrected visual acuity at 1 and 3 months were analyzed. Only eyes of adults that had phacoemulsification for uncomplicated cataracts were included in the study, all pediatric cataracts and eyes with ocular comorbidities were excluded. Common ocular comorbidities excluded were corneal opacity/corneal scar, glaucoma, uveitis, pseudo exfoliation syndrome, moderate and severe nonproliferative diabetic retinopathy, macula edema, proliferative diabetic retinopathy, eye trauma, age-related macular degeneration, previous corneal surgery, glaucoma surgery, and previous or simultaneous vitreoretinal surgery. A total of 157 eyes of 119 patients who met the inclusion criteria were analyzed. There were 60 (50.4%) females and 59 (49.6%) males, with age range from 31 to 91 years and a mean of 65.3 ± 11.10 years. Only eyes with available data were analyzed at 1 and 3 months postoperatively. In 112 eyes (85.7%), the refractive aim was met, 21 eyes (14.3%) did not meet their refractive aim, 20 eyes (12.7%) were excluded, the refractive aim could not be determined from the records as surgeons did not specify, and in 4 eyes, the required information was missing from the case files. An unaided visual acuity of 6/18 and better was achieved in 134 eyes (85.4%) at 1 month and 126 eyes (85.9%) at 3 months whereas best-corrected vision of 6/18 and better was achieved by 145 eyes (92.4%) at 1 month and 146 eyes (98.0%) at 3 months. Surgical outcomes after phacoemulsification are comparable with international benchmarks for good outcomes, with 85.4% of eyes achieving within 1 D of spherical equivalent of the refractive aim, 92.4% and 98.0% of eyes also achieving best-corrected visual acuities of 6/18 and better at 1 and 3 postoperative months, respectively. Unaided vision of 6/18 and better was also achieved in 85.4% and 85.9% at 1 and 3 postoperative months, respectively.


Potential Metabolomic Linkage in Blood between Parkinson's Disease and Traumatic Brain Injury.
The etiologic basis for sporadic forms of neurodegenerative diseases has been elusive but likely represents the product of genetic predisposition and various environmental factors. Specific gene-environment interactions have become more salient owing, in part, to the elucidation of epigenetic mechanisms and their impact on health and disease. The linkage between traumatic brain injury (TBI) and Parkinson's disease (PD) is one such association that currently lacks a mechanistic basis. Herein, we present preliminary blood-based metabolomic evidence in support of potential association between TBI and PD. Using untargeted and targeted high-performance liquid chromatography-mass spectrometry we identified metabolomic biomarker profiles in a cohort of symptomatic mild TBI (mTBI) subjects (n = 75) 3⁻12 months following injury (subacute) and TBI controls (n = 20), and a PD cohort with known PD (n = 20) or PD dementia (PDD) (n = 20) and PD controls (n = 20). Surprisingly, blood glutamic acid levels in both the subacute mTBI (increased) and PD/PDD (decreased) groups were notably altered from control levels. The observed changes in blood glutamic acid levels in mTBI and PD/PDD are discussed in relation to other metabolite profiling studies. Should our preliminary results be replicated in comparable metabolomic investigations of TBI and PD cohorts, they may contribute to an "excitotoxic" linkage between TBI and PD/PDD.


Factors affecting SP-A-mediated phagocytosis in human monocytic cell lines.
Surfactant protein-A enhances the phagocytosis and killing of many pathogens, although studying this effect in an assortment of models and different experimental protocols has sometimes yielded conflicting results. In this report, using the human THP-1 cell line as the primary phagocytic cell, we systematically examined several models where microspheres, Staphylococcus aureus and Escherichia coli were used for targets. We found that SP-A derived from human lavage appeared to enhance phagocytosis by two different mechanisms; by SP-A binding of the target to enhance its recognition and subsequent phagocytosis and by a direct SP-A stimulatory effect on the phagocyte itself. Both SP-A mechanisms occurred with different targets in the same experimental system and the SP-A effects were qualitatively (but not quantitatively) comparable in several human cell lines (THP-1, U937, Mono-Mac-6). We also found that the SP-A effects were abrogated when SP-A was combined with surfactant lipids, but the lipids did not affect the basal level of phagocytosis or phagocytosis by mechanisms not involving SP-A. Moreover, the stimulatory effect of SP-A was pH-dependent and appeared to be independent of several other phagocytic mechanisms, including those mediated by Fc receptors and mannose receptor.


Characterization of different alginate lyases for dissolving Pseudomonas aeruginosa biofilms.
Aggregates of Pseudomonas aeruginosa form a protective barrier against antibiotics and the immune system. These barriers, known as biofilms, are associated with several infectious diseases. One of the main components of these biofilms is alginate, a homo- and hetero-polysaccharide that consists of β-D-mannuronate (M) and α-L-guluronate (G) units. Alginate lyases degrade this sugar and have been proposed as biotherapeutic agents to dissolve P. aeruginosa biofilms. However, there are contradictory reports in the literature regarding the efficacy of alginate lyases against biofilms and their synergistic effect with antibiotics. We found that most positive reports used a commercial crude extract from Flavobacterium multivorum as the alginate lyase source. By using anion exchange chromatography coupled to nano LC MS/MS, we identified two distinct enzymes in this extract, one has both polyM and polyG (polyM/G) degradation activities and it is similar in sequence to a broad-spectrum alginate lyase from Flavobacterium sp. S20 (Alg2A). The other enzyme has only polyG activity and it is similar in sequence to AlyA1 from Zobellia galactanivorans. By characterizing both of these enzymes together with three recombinant alginate lyases (a polyM, a polyG and a polyM/G), we showed that only enzymes with polyM/G activity such as Alg2A and A1-II' (alginate lyase from Sphingomonas sp.) are effective in dissolving biofilms. Furthermore, both activities are required to have a synergistic effect with antibiotics.


Alfalfa Intervention Alters Rumen Microbial Community Development in Hu Lambs During Early Life.
The pre-weaning period is crucial for rumen developmental plasticity, which can have a long-term impact on animal performance. Understanding the rumen microbiota during early life is important to elucidate its potential role in rumen development. In this study, the rumen microbiota of 10-day-old Hu lambs fed either milk replacer (B-10), milk replacer and starter (STA) or milk replacer and starter supplemented with alfalfa (S-ALF) in the pre- (d17, 24, and 38) and post-weaning periods (d45 and 66) were assessed to characterize rumen microbial colonization during early life and its response to fiber intervention. In the rumens of B-10 lambs, 498 operational taxonomic units belonging to 33 predominant genera were observed, and the top six predicted functions included "Membrane transport," "carbohydrate metabolism," "amino acid metabolism," "replication and repair," "translation," and "energy metabolism." Prevotella, Succinivibrio, Bifidobacterium, and Butyrivibrio abundances were increased at d38 for both STA and S-ALF groups compared to the B-10 group, whereas fibrolytic bacteria of the taxa Lachnospiraceae and Treponema were only increased in the S-ALF group at d38. A number of saccharolytic bacteria (Bacteroidaceae), organic acid-producing bacteria (Coprococcus and Actinomyces), proteolytic and amino acid fermenters (Fusobacterium) and fibrolytic bacteria (unclassified Ruminococcaceae) were significantly decreased in the STA lambs but not in the S-ALF lambs at d38. After weaning and exposed to alfalfa, the rumen microbial composition in the STA group started to appear similar to that of the S-ALF lambs. The relative abundance of unclassified Clostridiales was higher in S-ALF lambs than STA lambs after weaning. Spearman's correlation analysis showed positive relationships between unclassified Lachnospiraceae, unclassified Clostridiales, Treponema, unclassified Bacteroidales, Coprococcus and crude protein intake, neutral detergent fiber intake, and plasma β-hydroxybutyrate. The unclassified Lachnospiraceae and Treponema were also positively correlated with average daily gain. Our results revealed that alfalfa stimulated changes in rumen microbiota during the pre- and post-weaning periods and was consistent with rumen development for better feed intake and animal performance before and after weaning. The findings of this study provide clues for strategies to improve rumen function through manipulation of the rumen microbiota during early life.


Quick reference guide to the new oral anticoagulants.
After the commissioning of new oral anticoagulants for the treatment and prevention of thrombosis, these medications are now widely used within clinical settings. Increasing numbers of patients present to the health services on anticoagulant medications, and it is therefore imperative for surgeons to be aware of the new therapeutic treatments available and how patients will benefit from such interventions. This review highlights the most pertinent learning points for surgeons regarding the indications, pharmacokinetics, and perioperative management of these new oral medications, as a quick reference guide.


Exercise programs for cancer-related fatigue: evidence and clinical guidelines.
This article provides an overview of the research literature and clinical recommendations on aerobic and resistance exercise programs for managing cancer-related fatigue (CRF). Current research evidence suggests that exercise improves CRF, with more recent evidence suggesting greater benefits when exercise programs are administered in the survivorship phase than in the active treatment phase. Moreover, positive changes in fitness from aerobic exercise programs have been shown to mediate the effects of exercise on CRF. Resistance exercise programs show promise in ameliorating CRF, especially in patients with prostate cancer, and should be considered a potential component of the exercise program. Future trials should examine the potential mechanisms through which exercise influences symptoms of CRF and the effect of exercise on CRF in the long-term. More research is needed evaluating exercise programs for cancer survivors with CRF, especially those with moderate-to-severe CRF.


Vesicular glutamate transporters 1 and 2 target to functionally distinct synaptic release sites.
Vesicular glutamate transporters (VGLUTs) 1 and 2 show a mutually exclusive distribution in the adult brain that suggests specialization for synapses with different properties of release. Consistent with this distribution, inactivation of the VGLUT1 gene silenced a subset of excitatory neurons in the adult. However, the same cell populations exhibited VGLUT1-independent transmission early in life. Developing hippocampal neurons transiently coexpressed VGLUT2 and VGLUT1 at distinct synaptic sites with different short-term plasticity. The loss of VGLUT1 also reduced the reserve pool of synaptic vesicles. Thus, VGLUT1 plays an unanticipated role in membrane trafficking at the nerve terminal.


The population genetics of crypsis in vertebrates: recent insights from mice, hares, and lizards.
By combining well-established population genetic theory with high-throughput sequencing data from natural populations, major strides have recently been made in understanding how, why, and when vertebrate populations evolve crypsis. Here, we focus on background matching, a particular facet of crypsis that involves the ability of an organism to conceal itself through matching its color to the surrounding environment. While interesting in and of itself, the study of this phenotype has also provided fruitful population genetic insights into the interplay of strong positive selection with other evolutionary processes. Specifically, and predicated upon the findings of previous candidate gene association studies, a primary focus of this recent literature involves the realization that the inference of selection from DNA sequence data first requires a robust model of population demography in order to identify genomic regions which do not conform to neutral expectations. Moreover, these demographic estimates provide crucial information about the origin and timing of the onset of selective pressures associated with, for example, the colonization of a novel environment. Furthermore, such inference has revealed crypsis to be a particularly useful phenotype for investigating the interplay of migration and selection-with examples of gene flow constraining rates of adaptation, or alternatively providing the genetic variants that may ultimately sweep through the population. Here, we evaluate the underlying evidence, review the strengths and weaknesses of the many population genetic methodologies used in these studies, and discuss how these insights have aided our general understanding of the evolutionary process.


Examining functional and social determinants of depression in community-dwelling older adults: implications for practice.
Coping with declining health, physical illnesses and complex medical regimens, which are all too common among many older adults, requires significant lifestyle changes and causes increasing self-management demands. Depression occurs in community-dwelling older adults as both demands and losses increase, but this problem is drastically underestimated and under-recognized. Depressive symptoms are often attributed to physical illnesses and thus overlooked, resulting in lack of appropriate treatment and diminished quality of life. The purpose of this study is to assess prevalence of depressive symptoms in community-dwelling older adults with high levels of co-morbidity and to identify correlates of depression. In this sample of 533 homebound older adults screened (76.1% female, 71.8% white, mean age 78.5 years) who were screened using the Geriatric Depression Scale (SF), 35.9% scored greater than 5. Decreased satisfaction with family support (p << 0.001) and functional status (p ≤ 0.001) and increased loneliness (p < 0.001) were significant independent predictors of depression status in this sample; thus, these factors should be considered when planning care.


Oral methotrexate for recurrent brain tumors in children: a Pediatric Oncology Group study.
Children with recurrent or progressive central nervous system (CNS) tumors have an unfavorable prognosis. Based on Pediatric Oncology Group (POG) institutional pilot data, low-dose oral methotrexate (MTX) was studied. Eight dosages of MTX 7.5 mg/m2 every 6 hours were administered on a weekly schedule for as long as 18 months. Patients in six different brain tumor strata were accrued. The response rates (complete or partial responses) were as follows: astrocytoma 2 of 10, malignant glioma 1 of 19, medulloblastoma 0 of 18, brainstem tumor 0 of 12, ependymoma 1 of 7, and miscellaneous histologic types 0 of 12. The main toxicities, mucositis, myelosuppression, and hepatic transaminase elevation were considered tolerable. Low-dose oral MTX showed no significant activity against malignant glioma, medulloblastoma, brainstem tumors, and miscellaneous histologic types. Indeterminate but low response rates were observed in children with astrocytoma and ependymoma. This regimen will not be recommended for front-line therapy.