Citations

BackgroundQuantifying craving longitudinally during the course of withdrawal, early abstinence, and relapse is essential for optimal management of alcohol use disorder (AUD). In an effort to identify biological correlates of craving, we used proton magnetic resonance spectroscopy (1H‐MRS) to investigate the correlation between craving and glutamate levels in the left dorsolateral prefrontal cortex (LDLPFC) of patients with AUD.MethodsParticipants underwent 1H‐MRS of the LDLPFC with 2‐dimensional J‐resolved (2DJ) averaged PRESS. MRS data were processed with LCModel and cerebrospinal fluid (CSF)‐corrected to generate metabolite concentrations. The Penn Alcohol Craving Scale (PACS) and the 30‐day time line follow‐back (TLFB 30) were used to quantify craving for alcohol and drinking patterns, respectively.ResultsThere was a statistically significant positive correlation between CSF‐corrected glutamate ([Glu]) levels and PACS scores (n = 14; p = 0.005). When PACS scores were dichotomized (< or ≥median = 16), [Glu] levels were significantly higher in the high‐ versus low‐craving group (p = 0.007). In addition, there was a significant negative correlation between CSF‐corrected N‐acetyl aspartic acid ([NAA]) levels and mean number of drinks per drinking day in the past month (n = 13; TLFB 30; p = 0.012). When mean TLFB 30 was dichotomized (< or ≥median = 7.86), [NAA] levels were significantly lower in subjects that consumed more alcoholic beverages. There was no significant correlation between [Glu] and [NAA] levels with other measures of drinking behavior and or depression symptom severity.ConclusionsWhile limited by small sample size, these data suggest that glutamate levels in LDLPFC are associated with alcohol craving intensity in patients with AUD. Further study with larger sample size is needed to replicate this finding and evaluate the merits of glutamate spectroscopy as a biological correlate of alcohol craving intensity and a guide to treatment interventions.

Bioprosthetic valve thrombosis is an uncommon complication. We report two young women with prior uncomplicated percutaneous pulmonary valve replacement (Melody®, Medtronic, Inc. Minneapolis, MN) who later developed symptomatic pulmonary emboli and pulmonary valve dysfunction without evidence of infection. Thrombophilia risk factors included oral contraceptive use and mild thrombophilia. Both experienced recovery of valve function following anticoagulation. Acute changes in Melody® valve function should prompt a thorough investigation for and treatment of potential thrombotic causes. © 2016 Wiley Periodicals, Inc.

AbstractExtracellular vesicles (EVs) are membrane‐bound vesicles released from cells into the extracellular environment. There is emerging interest in the use of EVs as potential therapeutic interventions. We sought to evaluate the safety of EVs that may be therapeutically used by performing in vitro toxicological assessments. EVs were obtained from mesenchymal stem cells (MSC‐EV) or from bovine milk (BM‐EV) by differential ultracentrifugation, and quantitated using nanoparticle tracking analysis. Genotoxic effects, hematological effects, immunological effects and endotoxin production were evaluated at two dose levels. Neither MSC‐EVs nor BM‐EVs elicited detectable genotoxic effects using either the alkaline comet assay or micronucleus assay. Hemolysis was observed with BM‐EVs but not with MSC‐EVs. MSC‐EVs did not have any significant effect on either spontaneous or collagen‐induced platelet aggregation. In contrast, BM‐EVs were noted to increase collagen‐induced platelet aggregation, even though no spontaneous increase in platelet aggregation was noted. Both types of EVs induced leukocyte proliferation, which was greater with BM‐EV. Neither MSC‐EVs nor BM‐EVs induced HL‐60 phagocytosis, although BM‐EVs decreased zymosan‐induced phagocytosis. Furthermore, neither MSC‐EVs nor BM‐EVs induced nitric oxide production. Unlike MSC‐EVs, BM‐EVs tested positive for endotoxin and induced complement activation. There are significant differences in toxicological profiles between MSC‐EVs and BM‐EVs that may reflect variations in techniques for EV isolation, EV content or cross‐species differences. The safety of MSC‐EV supports their use for disease therapeutics, whereas detailed safety and toxicological assessment will be necessary before the use of BM‐EVs. Copyright © 2016 John Wiley & Sons, Ltd.

Volume regulation, assessment, and management remain basic issues in patients with heart failure. The discussion presented here is directed at opening a reassessment of the pathophysiology of congestion in congestive heart failure and the methods by which we determine volume overload status. Peer-reviewed historical and contemporary literatures are reviewed. Volume overload and fluid congestion remain primary issues for patients with chronic heart failure. The pathophysiology is complex, and the simple concept of intravascular fluid accumulation is not adequate. The dynamics of interstitial and intravascular fluid compartment interactions and fluid redistribution from venous splanchnic beds to central pulmonary circulation need to be taken into account in strategies of volume management. Clinical bedside evaluations and right heart hemodynamic assessments can alert clinicians of changes in volume status, but only the quantitative measurement of total blood volume can help identify the heterogeneity in plasma volume and red blood cell mass that are features of volume overload in patients with chronic heart failure and help guide individualized, appropriate therapy—not all volume overload is the same.

Insulin regulates skeletal muscle protein degradation, but the types of proteins being degraded in vivo remain to be determined due to methodological limitations. We present a method to assess the types of skeletal muscle proteins that are degraded by extracting their degradation products as low-molecular weight (LMW) peptides from muscle samples. High-resolution mass spectrometry was used to identify the original intact proteins that generated the LMW peptides, which we validated in rodents and then applied to humans. We deprived insulin from insulin-treated streptozotocin (STZ) diabetic mice for 6 and 96 h and for 8 h in type 1 diabetic humans (T1D) for comparison with insulin-treated conditions. Protein degradation was measured using activation of autophagy and proteasome pathways, stable isotope tracers, and LMW approaches. In mice, insulin deprivation activated proteasome pathways and autophagy in muscle homogenates and isolated mitochondria. Reproducibility analysis of LMW extracts revealed that ∼80% of proteins were detected consistently. As expected, insulin deprivation increased whole body protein turnover in T1D. Individual protein degradation increased with insulin deprivation, including those involved in mitochondrial function, proteome homeostasis, nDNA support, and contractile/cytoskeleton. Individual mitochondrial proteins that generated more LMW fragment with insulin deprivation included ATP synthase subunit-γ (+0.5-fold, P = 0.007) and cytochrome c oxidase subunit 6 (+0.305-fold, P = 0.03). In conclusion, identifying LMW peptide fragments offers an approach to determine the degradation of individual proteins. Insulin deprivation increases degradation of select proteins and provides insight into the regulatory role of insulin in maintaining proteome homeostasis, especially of mitochondria.

Inflammation plays a pivotal role in peripheral artery disease (PAD). Cellular adhesion proteins mediate the interaction of leukocytes with endothelial cells during inflammation. To determine the association of cellular adhesion molecules with ankle–brachial index (ABI) and ABI category (≤1.0 vs >1.0) in a diverse population, 15 adhesion proteins were measured in the Multi-Ethnic Study of Atherosclerosis (MESA). To assess multivariable associations of each protein with ABI and ABI category, linear and logistic regression was used, respectively. Among 2364 participants, 23 presented with poorly compressible arteries (ABI > 1.4) and were excluded and 261 had ABI ≤ 1.0. Adjusting for traditional risk factors, elevated levels of soluble P-selectin, hepatocyte growth factor, and secretory leukocyte protease inhibitor were associated with lower ABI ( P = .0004, .001, and .002, respectively). Per each standard deviation of protein, we found 26%, 20%, and 19% greater odds of lower ABI category ( P = .001, .01, and .02, respectively). Further investigation into the adhesion pathway may shed new light on biological mechanisms implicated in PAD.

Objectives: Approximately half of ICU admissions are comprised of patients older than 65 years old. Mild cognitive impairment is a common disorder affecting 10–20% of patients in the same age group. A need exists for exploring mild cognitive impairment and risk of critical illness. As mild cognitive impairment may be a contributor to poorer overall health or be a result of it, we sought to determine whether the presence of mild cognitive impairment independently increases the risk of critical illness admissions. Design: Data from the Mayo Clinic Study of Aging were analyzed. All study participants underwent prospective comprehensive cognitive testing and expert panel consensus diagnosis of both cognitive function and clinical state at baseline and subsequent visits. Comparisons were made between those with normal cognitive function and mild cognitive impairment regarding baseline health and frequency of critical illness. Setting: Single-center population-based cohort out of Olmsted County, MN. Participants: All individuals 70–89 years old were screened for prospective enrollment in the Mayo Clinic Study of Aging. Patients with preexisting dementia and ICU admission within 3 years of entry to the study were excluded from this analysis. Interventions: None. Measurements and Main Results: Of 2,425 patients analyzed from the Mayo Clinic Study of Aging, 1,734 patients (71%) were included in the current study. Clinical factors associated with baseline mild cognitive impairment included age, male gender, stroke, and poorer health self-rating. Using a Cox regression model adjusting for these and a priori variables of baseline health, the presence of mild cognitive impairment remained a significant predictor of ICU admission (hazard ratio, 1.50 [1.15–1.96]; p = 0.003). Conclusions and Relevance: The presence of mild cognitive impairment is independently associated with increased critical illness admission. Further prospective studies are needed to analyze the impact of critical illness on cognitive function.