Exogenous Administration of Recombinant MIF at Physiological Concentrations Failed to Attenuate Infarct Size in a Langendorff Perfused Isolated Mouse Heart Model

Purpose

Evidence suggests a two-pronged role of endogenous macrophage migration inhibitory factor (MIF) release in ischemia/reperfusion injury. We aimed to assess whether its exogenous administration confers cardioprotection.

Methods

Male C57/BL6 mice were randomly allocated to receive recombinant mouse MIF (rMIF) at physiological (ng/mL) concentrations in a dose–response fashion before or after a protocol of 35 min of ischemia and 2 h of reperfusion in an isolated Langendorff-perfused model with infarct size as endpoint. Isolated primary cardiomyocytes were also used for cell survival studies using rMIF at a supra-physiological concentration of 1 μg/mL. Pro-survival kinase activation was also studied using Western blot analyses.

Results

Exogenous MIF did not elicit a cardioprotective effect either when administered before the ischemic insult or when applied at reperfusion. rMIF did not confer protection when it was applied immediately before or after a hypoxia/reoxygenation insult in primary isolated cardiomyocytes. Consistently, hearts treated with MIF did not show a significant increase in phosphorylated Akt and ERK1/2.

Conclusion

The exogenous administration of rMIF in a physiological concentration range both before ischemia and at reperfusion did not show cardioprotective effects. Although these results do not address the role of endogenous MIF after an ischemic insult followed by reperfusion, they may limit the potential translational value of rMIF.

     

Treatment of acute hepatitis C: recommendations from an expert panel of the Italian Society of Infectious and Tropical Diseases

Aim

This paper is aimed at providing practical recommendations for the management of acute hepatitis C (AHC).

Methods

This is an expert position paper based on the literature revision. Final recommendations were graded by level of evidence and strength of the recommendations.

Results

Treatment of AHC with direct-acting antivirals (DAA) is safe and effective; it overcomes the limitations of INF-based treatments.

Conclusions

Early treatment with DAA should be offered when available.

     

Die Rolle der Selbsthilfegruppen in der Onkologie

Background

Little is known about self-help associations and their possibilities. Obstacles often prevent early contacts between affected people.

Objectives

The psychosocial support given by self-help associations in different phases is evaluated.

Materials and methods

Based on the experience of the Deutsche ILCO and from cooperation with other organizations and institutions, various dimensions of self-help groups are investigated.

Results

On the professional side, there is a lack of knowledge and of attitude. Suitable structures are rare.

Conclusions

The removal of barriers and development of effective structures are overdue.

     

Effects of a Video on Organ Donation Consent Among Primary Care Patients: A Randomized Controlled Trial

BACKGROUND

Low organ donation rates remain a major barrier to organ transplantation.

OBJECTIVE

We aimed to determine the effect of a video and patient cueing on organ donation consent among patients meeting with their primary care provider.

DESIGN

This was a randomized controlled trial between February 2013 and May 2014.

SETTING

The waiting rooms of 18 primary care clinics of a medical system in Cuyahoga County, Ohio.

PATIENTS

The study included 915 patients over 15.5 years of age who had not previously consented to organ donation.

INTERVENTIONS

Just prior to their clinical encounter, intervention patients (n?=?456) watched a 5-minute organ donation video on iPads and then choose a question regarding organ donation to ask their provider. Control patients (n?=?459) visited their provider per usual routine.

MAIN MEASURES

The primary outcome was the proportion of patients who consented for organ donation. Secondary outcomes included the proportion of patients who discussed organ donation with their provider and the proportion who were satisfied with the time spent with their provider during the clinical encounter.

KEY RESULTS

Intervention patients were more likely than control patients to consent to donate organs (22 % vs. 15 %, OR 1.50, 95%CI 1.10–2.13). Intervention patients were also more likely to have donation discussions with their provider (77 % vs. 18 %, OR 15.1, 95%CI 11.1–20.6). Intervention and control patients were similarly satisfied with the time they spent with their provider (83 % vs. 86 %, OR 0.87, 95%CI 0.61–1.25).

LIMITATION

How the observed increases in organ donation consent might translate into a greater organ supply is unclear.

CONCLUSION

Watching a brief video regarding organ donation and being cued to ask a primary care provider a question about donation resulted in more organ donation discussions and an increase in organ donation consent. Satisfaction with the time spent during the clinical encounter was not affected.

TRIAL REGISTRATION

clinicaltrials.gov Identifier: NCT01697137

     

Attenuated GABAergic Signaling in Intestinal Epithelium Contributes to Pathogenesis of Ulcerative Colitis

Background

Neuromediators produced by enteric nervous system regulate inflammatory processes via interacting with enteric immune system. Role of γ-aminobutyric acid (GABA), which is also a neuromediator, has been implicated in autoimmune diseases like multiple sclerosis, type 1 diabetes, and rheumatoid arthritis, where they modulate the immune responses. However, its role in ulcerative colitis (UC) has not been defined.

Aims

This study was carried out to investigate the role of GABA and its signaling components in pathogenesis of UC.

Methods

Peripheral blood, colon mucosal biopsy, and fecal specimens were collected from UC and control groups. Quantification of GABA was done using ELISA. Expression of GABAergic signal system components was analyzed through RT-PCR analysis. Enumeration of GABA-producing bacteria was done by qPCR analysis. Activity of p38 MAPK and expression of proinflammatory cytokines were determined by immunohistochemistry and RT-PCR analysis, respectively.

Results

GABA levels were significantly reduced in patients with UC as compared to control group when measured in serum and colon biopsy. Altered expression of GABAergic signal system was observed in UC patients. Reduced abundance of selected GABA-producing bacteria was detected in stool samples of UC patients as compared to control. p38 MAPK activity and expression of its downstream effector cytokines were found to be increased in UC patients as compared to control.

Conclusions

Reduced levels of GABA were observed in patients with UC, and this leads to hyperactivation of p38 MAPK and overexpression of downstream effector cytokines suggesting a role of GABA in pathogenesis of UC.

     

Fecal microbiota transplantation in a kidney transplant recipient with recurrent urinary tract infection

Purpose

We report on a kidney transplant recipient treated with fecal microbiota transplantation (FMT) for recurrent urinary tract infections.

Methods

FMT was administered via frozen capsulized microbiota. Before and after FMT, urinary, fecal and vaginal microbiota compositions were analyzed.

Results

The patient remained without symptoms after FMT.

Conclusions

Underlying mechanisms of action need to be addressed in depth by future research.

     

BMI Trajectories as a Harbinger of Pre-Diabetes or Underdiagnosed Diabetes: an 18-Year Retrospective Cohort Study in Taiwan

Background

Although prior studies have examined BMI trajectories in Western populations, little is known regarding how BMI trajectories in Asian populations vary between adults with and without diabetes.

Objective

To examine how BMI trajectories vary between those developing and not developing diabetes over 18 years in an Asian cohort.

Design

Multilevel modeling was used to depict levels and rates of change in BMI for up to 18 years for participants with and without self-reported physician-diagnosed diabetes.

Participants

We used 14,490 data points available from repeated measurements of 3776 participants aged 50+ at baseline without diabetes from a nationally representative survey of the Taiwan Longitudinal Study on Aging (TLSA1989-2007).

Main Measures

We defined development of diabetes as participants who first reported diabetes diagnoses in 2007 but had no diabetes diagnoses at baseline. We defined the reference group as those participants who reported the absence of diabetes at baseline and during the entire follow-up period.

Key Results

When adjusted for time-varying comorbidities and behavioral factors, higher level and constant increases in BMI were present more than 6.5 years before self-reported diabetes diagnosis. The higher BMI level associating with the development of diabetes was especially evident in females. Within 6.5 years prior to self-reported diagnosis, however, a wider range of decreases in BMI occurred (β_diabetes?=?1.294, P?=?0.0064; β_{diabetes*time}?=?0.150, P?=?0.0327; β_{diabetes*time} ²?=??0.008, P?=?0.0065). The faster rate of increases in BMI followed by a greater decline was especially prominent in males and individuals with BMI ≧24.

Conclusions

An unintentional decrease in BMI in sharp contrast to the gradually rising BMI preceding that time may be an alarm for undiagnosed diabetes or a precursor to developing diabetes.

     

Effects of the Wars on Smoking Among Veterans

BACKGROUND

Educating medical students about health disparities may be one step in diminishing the disparities in health among different populations. According to adult learning theory, learners’ opinions are vital to the development of future curricula.

DESIGN

Qualitative research using focus group methodology.

OBJECTIVES

Our objectives were to explore the content that learners value in a health disparities curriculum and how they would want such a curriculum to be taught.

PARTICIPANTS

Study participants were first year medical students with an interest in health disparities (n?=?17).

APPROACH

Semi-structured interviews consisting of 12 predetermined questions, with follow-up and clarifying questions arising from the discussion. Using grounded theory, codes were initially developed by the team of investigators, applied, and validated through an iterative process.

MAIN RESULTS

The students perceived negative attitudes towards health disparities education as a potential barrier towards the development of a health disparities curriculum and proposed possible solutions. These solutions centered around the learning environment and skill building to combat health disparities.

CONCLUSIONS

While many of the students’ opinions were corroborated in the literature, the most striking differences were their opinions on how to develop good attitudes among the student body. Given the impact of the provider on health disparities, how to develop such attitudes is an important area for further research.

     

Cost of Transformation among Primary Care Practices Participating in a Medical Home Pilot

Background

Medical home initiatives encourage primary care practices to invest in new structural capabilities such as patient registries and information technology, but little is known about the costs of these investments.

Objectives

To estimate costs of transformation incurred by primary care practices participating in a medical home pilot.

Design

We interviewed practice leaders in order to identify changes practices had undertaken due to medical home transformation. Based on the principles of activity-based costing, we estimated the costs of additional personnel and other investments associated with these changes.

Setting

The Pennsylvania Chronic Care Initiative (PACCI), a statewide multi-payer medical home pilot.

Participants

Twelve practices that participated in the PACCI.

Measurements

One-time and ongoing yearly costs attributed to medical home transformation.

Results

Practices incurred median one-time transformation-associated costs of $30,991 per practice (range, $7694 to $117,810), equivalent to $9814 per clinician ($1497 to $57,476) and $8 per patient ($1 to $30). Median ongoing yearly costs associated with transformation were $147,573 per practice (range, $83,829 to $346,603), equivalent to $64,768 per clinician ($18,585 to $93,856) and $30 per patient ($8 to $136). Care management activities accounted for over 60% of practices’ transformation-associated costs. Per-clinician and per-patient transformation costs were greater for small and independent practices than for large and system-affiliated practices.

Limitations

Error in interviewee recall could affect estimates. Transformation costs in other medical home interventions may be different.

Conclusions

The costs of medical home transformation vary widely, creating potential financial challenges for primary care practices—especially those that are small and independent. Tailored subsidies from payers may help practices make these investments.

Primary Funding Source

Agency for Healthcare Research and Quality

     

Reduced Effectiveness of Interruptive Drug-Drug Interaction Alerts after Conversion to a Commercial Electronic Health Record

Background

Drug-drug interaction (DDI) alerts in electronic health records (EHRs) can help prevent adverse drug events, but such alerts are frequently overridden, raising concerns about their clinical usefulness and contribution to alert fatigue.

Objective

To study the effect of conversion to a commercial EHR on DDI alert and acceptance rates.

Design

Two before-and-after studies.

Participants

3277 clinicians who received a DDI alert in the outpatient setting.

Intervention

Introduction of a new, commercial EHR and subsequent adjustment of DDI alerting criteria.

Main Measures

Alert burden and proportion of alerts accepted.

Key Results

Overall interruptive DDI alert burden increased by a factor of 6 from the legacy EHR to the commercial EHR. The acceptance rate for the most severe alerts fell from 100 to 8.4%, and from 29.3 to 7.5% for medium severity alerts (P?<?0.001). After disabling the least severe alerts, total DDI alert burden fell by 50.5%, and acceptance of Tier 1 alerts rose from 9.1 to 12.7% (P?<?0.01).

Conclusions

Changing from a highly tailored DDI alerting system to a more general one as part of an EHR conversion decreased acceptance of DDI alerts and increased alert burden on users. The decrease in acceptance rates cannot be fully explained by differences in the clinical knowledge base, nor can it be fully explained by alert fatigue associated with increased alert burden. Instead, workflow factors probably predominate, including timing of alerts in the prescribing process, lack of differentiation of more and less severe alerts, and features of how users interact with alerts.

     

Application of the qSOFA score to predict mortality in patients with suspected infection in a resource-limited setting in Malawi

Purpose

To determine the predictive value of qSOFA (quick Sequential Organ Failure Assessment) in Malawian patients with suspected infection.

Methods

Prospective observational study in a tertiary referral hospital in Malawi.

Results

Predictive ability of qSOFA was reasonable [AUROC 0.73 (95% CI 0.68–0.78)], increasing to 0.77 (95% CI 0.72–0.82) when classifying all patients with altered mental status as high risk. Adding HIV status as a variable to the qSOFA score did not improve predictive value.

Conclusion

qSOFA is a simple tool that can aid risk stratification in resource-limited settings.

     

Overexpression of Protein Phosphatase 1γ (PP1γ) Is Associated with Enhanced Cell Proliferation and Poor Prognosis in Hepatocellular Carcinoma

Background

Protein phosphatase 1γ (PP1γ), as a member of the protein phosphatase 1 family, may be involved in regulation of multiple cellular processes, such as mitosis, cell survival, and apoptosis. However, little is known about the underlying mechanisms by which PP1γ regulates hepatocellular carcinoma development.

Aim

We investigated the expression profile of PP1γ in hepatocellular carcinoma (HCC) cell lines and human HCC specimens, as well as its potential prognostic significance in HCC.

Methods

PP1γ expression profile was detected in 94 HCC specimens using immunohistochemistry. PP1γ levels in HCC cells were downregulated by small interfering RNA (siRNA) transfection. Cell cycle progression and proliferation status of HCC cells and the effectiveness of doxorubicin were evaluated by flow cytometry and CCK-8 assay. The levels of PP1γ, CyclinD1, PCNA, Mdmx, p53, p21, and active caspase-3 were evaluated by Western blot analysis.

Results

PP1γ was upregulated in tumorous specimens, compared with adjacent nontumorous tissues. Univariate and multivariate survival analyses were conducted to determine the prognostic significance of PP1γ in HCC. The expression pattern of PP1γ was positively correlated with tumor size, histological grade, Ki-67 expression, and poor prognosis in HCC. In addition, depletion of PP1γ by siRNA could inhibit cell proliferation, resulted in G1 phase arrest, and attenuated resistance to doxorubicin in Huh7 cells.

Conclusions

PP1γ is upregulated in HCC cell lines and HCC specimens, promotes cancer cell proliferation through regulation of p53, and may be a potential target for treatment of HCC.

     

Prediction Model for Two-Year Risk of Opioid Overdose Among Patients Prescribed Chronic Opioid Therapy

Background

Naloxone is a life-saving opioid antagonist. Chronic pain guidelines recommend that physicians co-prescribe naloxone to patients at high risk for opioid overdose. However, clinical tools to efficiently identify patients who could benefit from naloxone are lacking.

Objective

To develop and validate an overdose predictive model which could be used in primary care settings to assess the need for naloxone.

Design

Retrospective cohort.

Setting

Derivation site was an integrated health system in Colorado; validation site was a safety-net health system in Colorado.

Participants

We developed a predictive model in a cohort of 42,828 patients taking chronic opioid therapy and externally validated the model in 10,708 patients.

Main Measures

Potential predictors and outcomes (nonfatal pharmaceutical and heroin overdoses) were extracted from electronic health records. Fatal overdose outcomes were identified from state vital records. To match the approximate shelf-life of naloxone, we used Cox proportional hazards regression to model the 2-year risk of overdose. Calibration and discrimination were assessed.

Key Results

A five-variable predictive model showed good calibration and discrimination (bootstrap-corrected c-statistic?=?0.73, 95% confidence interval [CI] 0.69–0.78) in the derivation site, with sensitivity of 66.1% and specificity of 66.6%. In the validation site, the model showed good discrimination (c-statistic?=?0.75, 95% CI 0.70–0.80) and less than ideal calibration, with sensitivity and specificity of 82.2% and 49.5%, respectively.

Conclusions

Among patients on chronic opioid therapy, the predictive model identified 66–82% of all subsequent opioid overdoses. This model is an efficient screening tool to identify patients who could benefit from naloxone to prevent overdose deaths. Population differences across the two sites limited calibration in the validation site.

     

S100A4 and P53 in myocardial collagen fibers of hypertrophic cardiomyopathy

Objective

The purpose of this work is to investigate the expression of S100A4 and P53 and their correlation with myocardial collagen fibers in hypertrophic cardiomyopathy (HCM).

Patients and methods

Myocardial tissue obtained from 10 patients undergoing HCM surgery (HCM group) was compared to myocardial tissue obtained from 10 traffic accident deaths (healthy control group). Collagen volume fractions were visualized and compared using sirius red F3B(SR) staining. Immunohistochemistry S-P and in situ hybridization techniques were used to test the different expressions of S100A4, P53 proteins, and their mRNA. Imaging and statistical methods were used for quantitative analysis.

Results

The collagen volume fraction in the HCM group was significantly higher than that in the control group. The integral optical density values of S100A4 and P53 in cardiomyocytes of the HCM group were also significantly higher than in the control group.

Conclusion

The increased content of collagen fibers and overexpression of S100A4 and P53 may play an important role in myocardial fibrosis of HCM, and they can be used in future HCM research. Blockade of S100A4 may have therapeutic potential in HCM by attenuating cardiac fibrosis.

     

VLDL and apolipoprotein CIII induce ER stress and inflammation and attenuate insulin signalling via Toll-like receptor 2 in mouse skeletal muscle cells

Aim/hypothesis

Here, our aim was to examine whether VLDL and apolipoprotein (apo) CIII induce endoplasmic reticulum (ER) stress, inflammation and insulin resistance in skeletal muscle.

Methods

Studies were conducted in mouse C2C12 myotubes, isolated skeletal muscle and skeletal muscle from transgenic mice overexpressing apoCIII.

Results

C2C12 myotubes exposed to VLDL showed increased levels of ER stress and inflammatory markers whereas peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) and AMP-activated protein kinase (AMPK) levels were reduced and the insulin signalling pathway was attenuated. The effects of VLDL were also observed in isolated skeletal muscle incubated with VLDL. The changes caused by VLDL were dependent on extracellular signal-regulated kinase (ERK) 1/2 since they were prevented by the ERK1/2 inhibitor U0126 or by knockdown of this kinase by siRNA transfection. ApoCIII mimicked the effects of VLDL and its effects were also blocked by ERK1/2 inhibition, suggesting that this apolipoprotein was responsible for the effects of VLDL. Skeletal muscle from transgenic mice overexpressing apoCIII showed increased levels of some ER stress and inflammatory markers and increased phosphorylated ERK1/2 levels, whereas PGC-1α levels were reduced, confirming apoCIII effects in vivo. Finally, incubation of myotubes with a neutralising antibody against Toll-like receptor 2 abolished the effects of apoCIII on ER stress, inflammation and insulin resistance, indicating that the effects of apoCIII were mediated by this receptor.

Conclusions/interpretation

These results imply that elevated VLDL in diabetic states can contribute to the exacerbation of insulin resistance by activating ERK1/2 through Toll-like receptor 2.