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Expectant management of cystotomy at the time of midurethral sling placement: a retrospective case series

Tue, 05/12/2015 - 10:32pm

INTRODUCTION AND HYPOTHESIS: Cystotomy is one of the most common complications of retropubic midurethral sling placement. Some centers manage cystotomy with prolonged catheter drainage, and there are few published studies evaluating this practice. The purpose of this study is to review postoperative outcomes of patients who experienced cystotomy at the time of sling placement and did not undergo prolonged catheter drainage.

METHODS: This is a retrospective review of all patients undergoing midurethral sling placement complicated by a cystotomy at the University of Rochester between 2004 and 2009. Outpatient and inpatient records were reviewed and data collected include demographics, intraoperative details, voiding trial results, postoperative complications, and voiding function. Descriptive statistics were performed.

RESULTS: Between 2004 and 2009, 30 subjects experienced a cystotomy of the 374 subjects that had a midurethral sling placed, all by a suprapubic approach. There were 25 patients who underwent a voiding trial on the day of surgery and 20 (80 %) were discharged home without prolonged drainage. Five subjects (20 %) had urinary retention and were discharged with an indwelling catheter. All five successfully voided within 4 days of discharge. No subject required subsequent catheterization for any reason and at the 6-week postoperative evaluation all subjects denied voiding dysfunction or irritative bladder symptoms. No subject required additional intervention and postoperative complications were rare.

CONCLUSIONS: In this study, the majority of subjects experiencing a cystotomy during midurethral sling placement were successfully discharged home the day of surgery without catheter drainage. The results suggest that prolonged catheter drainage after a cystotomy during midurethral sling placement may be unnecessary.

Regional infant brain development: an MRI-based morphometric analysis in 3 to 13 month olds

Tue, 05/12/2015 - 10:32pm

Elucidation of infant brain development is a critically important goal given the enduring impact of these early processes on various domains including later cognition and language. Although infants' whole-brain growth rates have long been available, regional growth rates have not been reported systematically. Accordingly, relatively less is known about the dynamics and organization of typically developing infant brains. Here we report global and regional volumetric growth of cerebrum, cerebellum, and brainstem with gender dimorphism, in 33 cross-sectional scans, over 3 to 13 months, using T1-weighted 3-dimensional spoiled gradient echo images and detailed semi-automated brain segmentation. Except for the midbrain and lateral ventricles, all absolute volumes of brain regions showed significant growth, with 6 different patterns of volumetric change. When normalized to the whole brain, the regional increase was characterized by 5 differential patterns. The putamen, cerebellar hemispheres, and total cerebellum were the only regions that showed positive growth in the normalized brain. Our results show region-specific patterns of volumetric change and contribute to the systematic understanding of infant brain development. This study greatly expands our knowledge of normal development and in future may provide a basis for identifying early deviation above and beyond normative variation that might signal higher risk for neurological disorders.

Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes

Tue, 05/12/2015 - 10:32pm

The dilute plasma cytokine milieu associated with type 1 diabetes (T1D), while difficult to measure directly, is sufficient to drive transcription in a bioassay that uses healthy leukocytes as reporters. Previously, we reported disease-associated, partially IL-1 dependent, transcriptional signatures in both T1D patients and the BioBreeding (BB) rat model. Here, we examine temporal signatures in congenic BBDR.lyp/lyp rats that develop spontaneous T1D, and BBDR rats where T1D progresses only after immunological perturbation in young animals. After weaning, the BBDR temporal signature showed early coincident induction of transcription related to innate inflammation as well as IL-10- and TGF-beta-mediated regulation. BBDR plasma cytokine levels mirrored the signatures showing early inflammation, followed by induction of a regulated state that correlated with failure of virus to induce T1D in older rats. In contrast, the BBDR.lyp/lyp temporal signature exhibited asynchronous dynamics, with delayed induction of inflammatory transcription and later, weaker induction of regulatory transcription, consistent with their deficiency in regulatory T cells. Through longitudinal analyses of plasma-induced signatures in BB rats and a human T1D progressor, we have identified changes in immunoregulatory processes that attenuate a preexisting innate inflammatory state in BBDR rats, suggesting a mechanism underlying the decline in T1D susceptibility with age.

APOA-I: a possible novel biomarker for metabolic side effects in first episode schizophrenia

Wed, 05/06/2015 - 1:57pm

The purpose of this study was to investigate the change in plasma protein expression in first episode schizophrenia after an 8-week treatment with risperidone, and to explore potential biomarkers for metabolic side effects associated with risperidone treatment. Eighty first-episode schizophrenia patientswere enrolled in the study. Fifteen of the 80 patients were randomly selected to undergo proteomic analysis. Plasma proteins were obtained before and after the 8-week risperidone treatment, and measured using two-dimensional gel electrophoresis (2-DE), Matrix-Assisted Laser Desorption/Ionization Time of Flight Mass Spectrometry(MALDI-TOF/TOF) and peptide mass fingerprinting.Proteins with the highest fold changes after risperidone treatment were then measured for all 80 patients using enzyme linked immunosorbent assay (ELISA). The relationship between changes in plasma protein levels and changes in metabolic parameters after risperidone treatment was examined. In 15 randomly selected patients, approximately 1,500 protein spots were detected in each gel by 2-DE. Of those proteins, 22 spots showed significant difference in abundance after risperidone treatment (p's < 0.05). After MALDI-TOF peptide mass fingerprinting, apolipoprotein A-I (APOA-I) and Guanine Nucleotide Binding Protein, Alpha Stimulating (GNAS), were found to have the highest fold changes.The content of APOA-I was significantly increased, and the content of GNAS was significantly decreased after risperidone treatment (p's<0.05). The analysis in the entire study sample showed similar findings in changes of APOA-I and GNAS after risperidone treatment. Further analysis showed significant relationships between changesin APOA-1 and changes in triglyceride, total cholesterol, and body mass index after controlling for age, gender and family history of diabetes. Similar analysis showed a trend positive relationship between changes in GNAS and changes in BMI. Using proteomic analysis, the study suggested that APOA-I might be a novel biomarkers related to metabolic side effects in first episode schizophrenia treated with risperidone.

Surgical site infections and other postoperative complications following prophylactic anticoagulation in total joint arthroplasty

Wed, 05/06/2015 - 1:57pm

BACKGROUND: Anticoagulants reduce the risk of venous thromboembolism (VTE) after total joint replacement. However, concern remains that pharmacologic VTE prophylaxis can lead to bleeding, which may impact on postoperative complications such as infections and reoperations.

METHODS AND FINDINGS: From the Global Orthopedic Registry (GLORY), we reviewed 3,755 patients in US who elected for primary total hip or knee arthroplasty, received either warfarin or low molecular weight heparin (LMWH) as VTE prophylactics, and had up-to-90-day follow-up after discharge. We compared incidence rates of VTE, infections and other complications between LMWH and warfarin groups, and used multivariate analyses with propensity score weighting to generate the odds ratio (OR). Patients receiving LMWH tended to be older and higher in the American Society of Anesthesiologists grade scores. In contrast, warfarin was used more frequently for hip arthroplasty with longer duration among patients with more pre-existing comorbidity (all P < 0.02). A weight variable was created with propensity score to account for differences in covariate distributions. Propensity score-weighted analyses showed no differences in VTE complications. However, compared to warfarin, LMWH was associated with significantly higher rates of bleeding (6.2% vs. 2.1%; OR = 3.82, 95% confidence interval [CI], 2.64 to 5.52), blood transfusion (29.4% vs. 22.0%; OR = 1.75, 95% CI, 1.51 to 2.04), reoperations (2.4% vs. 1.3%; OR = 1.77, 95% CI, 1.07 to 2.93) and infections (1.6% vs. 0.6%; OR = 2.79, 95% CI, 1.42 to 5.45). Similar results were obtained from compliant uses of warfarin (26%) and LMWH (62%) according to clinical guidelines. While surgical site infections were mostly superficial, current study was underpowered to compare incidence rates of deep infections ( < 1.0%).

CONCLUSIONS: Surgical site infections and reoperations in 3 months following primary total joint arthroplasty may be associated with anticoagulant use that exhibited higher bleeding risk. Long-term complications and deep wound infections remain to be studied.

Circulating irisin levels are not affected by coffee intake: a randomized controlled trial

Wed, 05/06/2015 - 1:57pm

Irisin, secreted by skeletal muscle and possibly fat, is hypothesized to play an important role in modulating energy expenditure, obesity and metabolism. Coffee consumption also increases energy expenditure and leads to positive metabolic effects, but whether these effects are mediated by irisin remains unknown. The objective of this study was to determine the association between baseline irisin levels and the metabolic profile in humans and to investigate whether consumption of caffeinated coffee alters irisin levels. To this end, a secondary analysis was performed investigating irisin levels at baseline and after eight weeks in 32 healthy, overweight coffee drinkers who were randomized to consumption of 5 cups per day of instant caffeinated coffee, decaffeinated coffee, or water. Spearman correlation and analysis of covariance analyses were performed to identify possible associations. Irisin levels were positively correlated with waist circumference (r = 0.41, p = 0.02), fat mass (r = 0.44, p = 0.01) and CRP (r = 0.47, p = 0.007). Though there was a trend towards increased levels of irisin over time in the caffeinated coffee group (+1.8%) when compared to the placebo group (24%) this did not reach statistical significance (p = 0.75 for the trend). This first randomized trial failed to reveal any effects of coffee consumption on irisin levels, but a larger trial, appropriately sized on the basis of data provided by this study, is needed to conclusively investigate such a relationship. TRIAL REGISTRATION: Clinicaltrials.gov NCT00305097.

Metalloproteinase-dependent TLR2 ectodomain shedding is involved in soluble toll-like receptor 2 (sTLR2) production

Wed, 05/06/2015 - 1:57pm

Toll-like receptor (TLR) 2, a type I membrane receptor that plays a key role in innate immunity, recognizes conserved molecules in pathogens, and triggering an inflammatory response. It has been associated with inflammatory and autoimmune diseases. Soluble TLR2 (sTLR2) variants have been identified in human body fluids, and the TLR2 ectodomain can negatively regulate TLR2 activation by behaving as a decoy receptor. sTLR2 generation does not involve alternative splicing mechanisms, indicating that this process might involve a post-translational modification of the full-length receptor; however, the specific mechanism has not been studied. Using CD14+ peripheral human monocytes and the THP-1 monocytic leukemia-derived cell line, we confirm that sTLR2 generation increases upon treatment with pro-inflammatory agents and requires a post-translational mechanism. We also find that the constitutive and ligand-induced release of sTLR2 is sensitive to pharmacological metalloproteinase activator and inhibitors leading us to conclude that metalloproteinase TLR2 shedding contributes to soluble receptor production. By expressing human TLR2 in ADAM10- or ADAM17-deficient MEF cells, we find both enzymes to be implicated in TLR2 ectodomain shedding. Moreover, using a deletion mutant of the TLR2 juxtamembrane region, we demonstrate that this domain is required for sTLR2 generation. Functional analysis suggests that sTLR2 generated by metalloproteinase activation inhibitsTLR2-induced cytokine production by this monocytic leukemia-derived cell line. The identification of the mechanisms involved in regulating the availability of soluble TLR2 ectodomain and cell surface receptors may contribute further research on TLR2-mediated processes in innate immunity and inflammatory disorders.

A human type 5 adenovirus-based Trypanosoma cruzi therapeutic vaccine re-programs immune response and reverses chronic cardiomyopathy

Wed, 05/06/2015 - 1:57pm

Chagas disease (CD), caused by the protozoan Trypanosoma cruzi, is a prototypical neglected tropical disease. Specific immunity promotes acute phase survival. Nevertheless, one-third of CD patients develop chronic chagasic cardiomyopathy (CCC) associated with parasite persistence and immunological unbalance. Currently, the therapeutic management of patients only mitigates CCC symptoms. Therefore, a vaccine arises as an alternative to stimulate protective immunity and thereby prevent, delay progression and even reverse CCC. We examined this hypothesis by vaccinating mice with replication-defective human Type 5 recombinant adenoviruses (rAd) carrying sequences of amastigote surface protein-2 (rAdASP2) and trans-sialidase (rAdTS) T. cruzi antigens. For prophylactic vaccination, naive C57BL/6 mice were immunized with rAdASP2+rAdTS (rAdVax) using a homologous prime/boost protocol before challenge with the Colombian strain. For therapeutic vaccination, rAdVax administration was initiated at 120 days post-infection (dpi), when mice were afflicted by CCC. Mice were analyzed for electrical abnormalities, immune response and cardiac parasitism and tissue damage. Prophylactic immunization with rAdVax induced antibodies and H-2Kb-restricted cytotoxic and interferon (IFN)gamma-producing CD8+ T-cells, reduced acute heart parasitism and electrical abnormalities in the chronic phase. Therapeutic vaccination increased survival and reduced electrical abnormalities after the prime (analysis at 160 dpi) and the boost (analysis at 180 and 230 dpi). Post-therapy mice exhibited less heart injury and electrical abnormalities compared with pre-therapy mice. rAdVax therapeutic vaccination preserved specific IFNgamma-mediated immunity but reduced the response to polyclonal stimuli (anti-CD3 plus anti-CD28), CD107a+ CD8+ T-cell frequency and plasma nitric oxide (NO) levels. Moreover, therapeutic rAdVax reshaped immunity in the heart tissue as reduced the number of perforin+ cells, preserved the number of IFNgamma+ cells, increased the expression of IFNgamma mRNA but reduced inducible NO synthase mRNA. Vaccine-based immunostimulation with rAd might offer a rational alternative for re-programming the immune response to preserve and, moreover, recover tissue injury in Chagas' heart disease.

Figure-associated text summarization and evaluation

Wed, 05/06/2015 - 1:57pm

Biomedical literature incorporates millions of figures, which are a rich and important knowledge resource for biomedical researchers. Scientists need access to the figures and the knowledge they represent in order to validate research findings and to generate new hypotheses. By themselves, these figures are nearly always incomprehensible to both humans and machines and their associated texts are therefore essential for full comprehension. The associated text of a figure, however, is scattered throughout its full-text article and contains redundant information content. In this paper, we report the continued development and evaluation of several figure summarization systems, the FigSum+ systems, that automatically identify associated texts, remove redundant information, and generate a text summary for every figure in an article. Using a set of 94 annotated figures selected from 19 different journals, we conducted an intrinsic evaluation of FigSum+. We evaluate the performance by precision, recall, F1, and ROUGE scores. The best FigSum+ system is based on an unsupervised method, achieving F1 score of 0.66 and ROUGE-1 score of 0.97. The annotated data is available at figshare.com (http://figshare.com/articles/Figure_Associated_Text_Summarization_and_Evaluation /858903).

FHL1 reduces dystrophy in transgenic mice overexpressing FSHD muscular dystrophy region gene 1 (FRG1)

Wed, 05/06/2015 - 1:57pm

Facioscapulohumeral muscular dystrophy (FSHD) is an autosomal-dominant disease with no effective treatment. The genetic cause of FSHD is complex and the primary pathogenic insult underlying the muscle disease is unknown. Several disease candidate genes have been proposed including DUX4 and FRG1. Expression analysis studies of FSHD report the deregulation of genes which mediate myoblast differentiation and fusion. Transgenic mice overexpressing FRG1 recapitulate the FSHD muscular dystrophy phenotype. Our current study selectively examines how increased expression of FRG1 may contribute to myoblast differentiation defects. We generated stable C2C12 cell lines overexpressing FRG1, which exhibited a myoblast fusion defect upon differentiation. To determine if myoblast fusion defects contribute to the FRG1 mouse dystrophic phenotype, this strain was crossed with skeletal muscle specific FHL1-transgenic mice. We previously reported that FHL1 promotes myoblast fusion in vitro and FHL1-transgenic mice develop skeletal muscle hypertrophy. In the current study, FRG1 mice overexpressing FHL1 showed an improvement in the dystrophic phenotype, including a reduced spinal kyphosis, increased muscle mass and myofiber size, and decreased muscle fibrosis. FHL1 expression in FRG1 mice, did not alter satellite cell number or activation, but enhanced myoblast fusion. Primary myoblasts isolated from FRG1 mice showed a myoblast fusion defect that was rescued by FHL1 expression. Therefore, increased FRG1 expression may contribute to a muscular dystrophy phenotype resembling FSHD by impairing myoblast fusion, a defect that can be rescued by enhanced myoblast fusion via expression of FHL1.

Recognition of Aspergillus fumigatus hyphae by human plasmacytoid dendritic cells is mediated by dectin-2 and results in formation of extracellular traps

Wed, 05/06/2015 - 1:57pm

Plasmacytoid dendritic cells (pDCs) were initially considered as critical for innate immunity to viruses. However, our group has shown that pDCs bind to and inhibit the growth of Aspergillus fumigatus hyphae and that depletion of pDCs renders mice hypersusceptible to experimental aspergillosis. In this study, we examined pDC receptors contributing to hyphal recognition and downstream events in pDCs stimulated by A. fumigatus hyphae. Our data show that Dectin-2, but not Dectin-1, participates in A. fumigatus hyphal recognition, TNF-alpha and IFN-alpha release, and antifungal activity. Moreover, Dectin-2 acts in cooperation with the FcRgamma chain to trigger signaling responses. In addition, using confocal and electron microscopy we demonstrated that the interaction between pDCs and A. fumigatus induced the formation of pDC extracellular traps (pETs) containing DNA and citrullinated histone H3. These structures closely resembled those of neutrophil extracellular traps (NETs). The microarray analysis of the pDC transcriptome upon A. fumigatus infection also demonstrated up-regulated expression of genes associated with apoptosis as well as type I interferon-induced genes. Thus, human pDCs directly recognize A. fumigatus hyphae via Dectin-2; this interaction results in cytokine release and antifungal activity. Moreover, hyphal stimulation of pDCs triggers a distinct pattern of pDC gene expression and leads to pET formation.

Declining Long-term Risk of Adverse Events after First-time Community-presenting Venous Thromboembolism: The Population-based Worcester VTE Study (1999 to 2009)

Wed, 05/06/2015 - 1:55pm

INTRODUCTION: Contemporary trends in health-care delivery are shifting the management of venous thromboembolism (VTE) events (deep vein thrombosis [DVT] and/or pulmonary embolism [PE]) from the hospital to the community, which may have implications for its prevention, treatment, and outcomes.

MATERIALS AND METHODS: Population-based surveillance study monitoring trends in clinical epidemiology among residents of the Worcester, Massachusetts, metropolitan statistical area (WMSA) diagnosed with an acute VTE in all 12 WMSA hospitals. Patients were followed for up to 3years after their index event. Total of 2334 WMSA residents diagnosed with first-time community-presenting VTE (occurring in an ambulatory setting or diagnosed within 24hours of hospitalization) from 1999 through 2009.

RESULTS: While PE patients were consistently admitted to the hospital for treatment over time, the proportion diagnosed with DVT-alone admitted to the hospital decreased from 67% in 1999 to 37% in 2009 (p value for trend

CONCLUSIONS: A decade of change in VTE management was accompanied by improved long-term outcomes. However, rates of adverse events remained fairly high in our population-based surveillance study, implying that new risk-assessment tools to identify individuals at increased risk for developing major adverse outcomes over the long term are needed.

Anti-Inflammatory Diet for Inflammatory Bowel Disease (IBD-AID)

Wed, 05/06/2015 - 9:53am

Background: Inflammatory Bowel Disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), are chronic, immune-mediated inflammatory conditions of the gastrointestinal tract, which have increasingly been linked to dysbiosis, or an imbalance in the gut microbiome. Standard of care for IBD involves an often-evolving combination of anti-inflammatory, antibiotic, and immunomodulatory medications; however, the pharmacological approach is never curative, and medications routinely become ineffective for individual patients. Partially fueled by the increasing inadequacy of pharmacologic treatment regimens, there is emerging interest from patients regarding diet and its role in the pathogenesis and treatment of inflammatory diseases, demanding more in-depth and substantiating research from the medical community.

The Anti-Inflammatory Diet for IBD (IBD-AID), which is derived and augmented from The Specific Carbohydrate Diet (SCD), is a nutritional regimen that restricts the intake of pro-inflammatory carbohydrates such as refined sugar, lactose, and most grains, while maximizing anti-inflammatory foods including those with prebiotic and probiotic properties. We have previous results from a case series of 11 patients with IBD showing symptomatic improvement (by Harvey Bradshaw Index scores) and downscaling of medication regimens in all 11 patients after 4 weeks on the IBD-AID.

Objectives: The purpose of this small prospective study was to further assess the efficacy and feasibility of the IBD-AID intervention for the treatment of CD, and to provide pilot data for a larger application.

Methods: The sample included 17 patients with biopsy-confirmed Crohn’s disease. Participants were offered the treatment diet (IBD-AID) (n=12) or standard medical care alone (control) (n=5). Patients in the IBD-AID group were required to attend one individual nutrition counseling session and three IBD-AID-specific cooking classes at the University of Massachusetts Medical School’s Shaw Building teaching kitchen. The control group continued with usual care. For all participants, demographic, clinical, and symptom data were obtained from baseline and follow-up questionnaires; dietary composition was monitored by weekly dietary recalls and food journals. All participants continued to follow with their gastroenterologists throughout the study duration. Study duration was 2 months after 70% adherence to the diet for IBD-AID participants, and 2 months after baseline for control participants.

Consistent with the goals for any treatment used for CD, efficacy measures included: 1) reduction in symptomology, as measured by the validated Harvey Bradshaw Index (HBI); 2) reduction in the need of immunomodulatory and anti-inflammatory medications; and 3) normalizing trend in circulating inflammatory markers (i.e., CRP and ESR), albumin, and hematocrit. Feasibility measures included participant retention, dietary compliance, and participants’ self-assessments of difficulty in maintaining the diet.

Results: A total of 15 enrolled patients with confirmed diagnosis of Crohn’s Disease, 5 in observation arm, 10 in intervention arm. Significant trends in dietary composition included significant increases in prebiotic and favorable dietary components, and decrease in adverse foods for the group as a whole (paired t-test values 0.0016, 0.0344, 0.0085, and 0.0014, respectively). For those patients on medication at baseline and with complete follow-up (n=9), one-third were able to decrease doses of or discontinue these medications. In addition, lab values reflected symptomatic improvements in two of our intervention patients, with changes in CRP, ESR, and hematocrit levels of -55.9 and -1.4, -30.0 and -15.0, and +5.4 and +0.3, respectively, with corresponding symptomatic improvements (HBI scores 1à7 and 8à0, respectively). No significance can be assigned, however, due to low sample size and loss to follow-up. Feasibility measures include a significant loss to follow-up rate of 33.3%, as well as an average “difficulty score” of 3.1, reflecting participants’ views on the difficult nature of “sticking with” the IBD-AID (scored on scale of 1-5, very easy to very difficult).

Conclusion: Despite the study’s limitations, as well as because of them, several conclusions can be drawn. The trends noticed in the participants’ dietary component reports, and supported by participants’ self-evaluation, reveal that it is relatively easy to eliminate problem foods from the diet, but adding unfamiliar foods, particularly from the probiotic category such as plain yogurt, kimchi, miso, sauerkraut, etc., is a huge barrier to maintaining compliance. This trend may be a partial reflection of the Western food and dieting culture in which our daily meals are relatively homogenous. We are also brought up from a young age learning that “dieting” and “healthy eating” means cutting out the bad, but not necessarily bringing in the good and/or new. Despite lack of statistical significance, the two patients who exhibited normalizing lab values, in combination with their improved HBI scores, suggest the possibility of a real and meaningful benefit from IBD-AID for those able to comply with the dietary and lifestyle changes.

In terms of the diet’s feasibility, the considerable loss to follow-up in this study may reflect a variety of issues, one of which may be the well-established medical and psychosocial complexity of IBD patients. This element is important for clinicians to keep in mind, and reflects the need for additional support and close follow-up when it comes to facilitating lifestyle change in this population. It also has implications for the diet itself, which should be re-examined to simplify or reframe in order to maximize generalizability and access for a greater percentage of IBD patients. Overall, this small study highlights the need for larger-scale research to draft clinical nutrition guidelines and further legitimize the utility of preventive clinical nutrition in Western medicine.