Donkey pericardium compares favorably with commercial xenopericardia used in the manufacture of transcatheter heart valves.

Transcatheter aortic valve implantation (TAVI) has gained considerable acceptance in the past decade due to its lower risks than conventional open-heart surgery. However, the deformation and delamination of the leaflets during the crimping procedure have raised questions about the durability and long-term serviceability of the pericardium tissue from which the leaflets are made. The collagen architecture, wall thickness and mechanical properties of donkey pericardium were investigated to assess its suitability as an alternative material for the manufacture of heart valves. Coupons sampled from different locations of donkey pericardium were investigated. Bovine, equine, and porcine pericardium specimens served as controls. The donkey pericardium had a similar surface morphology to that of the control pericardia except for the wavy topology on both the fibrous and serous sides. The average thickness of donkey pericardium (ca. 120 µm) was significantly lower than that from bovine (375 µm) and equine (410 µm), but slightly higher than that from porcine (99 µm) specimens. The interlaced wavy collagen bundles in the pericardium were composed of collagen fibers about 100 nm in diameter. This unique structure ensures that the donkey pericardium has a comparable ultimate tensile strength (UTS) and a much higher failure strain than the commercial pericardia used for the manufacture of heart valves. The donkey pericardium has an organized wavy collagen bundle architecture similar to that of bovine pericardium and has a satisfactory UTS and high failure strain. The thin and strong donkey pericardium might be a good candidate valve leaflet material for TAVI.

Post-Mortem Evaluation of Potentially Survivable Hemorrhagic Death in a Civilian Population.

BACKGROUND: Although the survivability of military extremity hemorrhage is well documented, equivalent civilian data are limited. We analyzed statewide autopsy records in Maryland to determine the number of hemorrhagic deaths that might have been potentially survivable with prompt hemorrhage control. Similar analyses of battlefield deaths led to life-saving changes in military medical practice. STUDY DESIGN: This is a retrospective study of decedent records. The objective is to estimate the number of hemorrhagic deaths that might have been prevented by prompt placement of an extremity tourniquet. Maryland autopsy records from 2002 to 2016 were selected using the following search terms: amputation, arm/arms, avulsion, exsanguination, extremity/extremities, leg/legs. The records were analyzed by applying a checklist of previously developed military criteria to characterize deaths as potentially survivable or nonsurvivable with prompt use of a tourniquet. Suicides and decedents less than 18 years old were excluded. The study did not use information about living participants. Two expert reviewers independently evaluated and scored the death records. Deaths were classified as either potentially survivable or nonsurvivable. A third reviewer broke any ties. RESULTS: There were 288 full autopsy records included in the final analysis. Of the eligible decedents reviewed during the 14-year period, 124 of 288 had potentially survivable wounds; 164 had nonsurvivable wounds. CONCLUSIONS: Over the 14-year study interval, 124 Maryland decedents-an average of 9 per year-might have been saved with prompt placement of a tourniquet. If extrapolated, approximately 480 people in the US might be saved per year. These results provide evidence to support educating and equipping the public to provide bleeding control.

T2 relaxation effects on apparent N-acetylaspartate concentration in proton magnetic resonance studies of schizophrenia.

Over the past two decades, many magnetic resonance spectroscopy (MRS) studies reported lower N-acetylaspartate (NAA) in key brain regions of patients with schizophrenia (SZ) compared to healthy subjects. A smaller number of studies report no difference in NAA. Many sources of variance may contribute to these discordant results including heterogeneity of the SZ subject populations and methodological differences such as MRS acquisition parameters, and post-acquisition analytic methods. The current study reviewed proton MRS literature reporting measurements of NAA in SZ with a focus on methodology. Studies which reported lower NAA were significantly more likely to have used longer echo times (TEs), while studies with shorter TEs reported no concentration difference. This suggests that NAA quantitation using MRS was affected by the choice of TE, and that published MRS literature reporting NAA in SZ using a long TE is confounded by apparent differential T2 relaxation effects between SZ and healthy control groups. Future MRS studies should measure T2 relaxation times. This would allow for spectral concentration measurements to be appropriately corrected for these relaxation effects. In addition, as metabolite concentration and T2 relaxation times are completely independent variables, this could offer distinct information about the metabolite of interest.

Tenofovir (TDF)-selected or abacavir (ABC)-selected low-frequency HIV type 1 subpopulations during failure with persistent viremia as detected by ultradeep pyrosequencing.

Detection of drug resistance is critical for determining antiretroviral treatment options. Ultradeep pyrosequencing (UDPS; 454 Life Sciences) is capable of detecting virus variant subpopulations with much greater sensitivity than population sequencing, which typically has a detection limit around 20%. UDPS of the HIV-1 reverse transcriptase (RT) (amino acids 56-120) was performed to detect the key mutations K65R and L74V associated with tenofovir and abacavir use. Plasma specimens from subjects with persistent rebound viremia following suppression on tenofovir (n = 8) or abacavir (n = 9)-based therapy were studied. Samples from a subject treated with zidovudine/lamivudine/efavirenz with a similar loss of virologic response served as a control. HIV-1 plasma RNA was ≥3.68 log(10) copies/ml at all time points sequenced. The median number of UDPS sequences analyzed/time point was 33,246. Among the eight tenofovir-treated subjects, three showed high-frequency (>20%) RT K65R at the time of failure, whereas one showed low-frequency (<20%) L74V; no low-frequency K65R was detected in these subjects. Among the nine abacavir-treated subjects, three showed low-frequency K65R; no L74V was detected in these patients. No K65R or L74V was detected in the samples from the control subject. At failure, other RT mutations were detected, including low-frequency NNRTI-resistant species detected at ≥1 time point in nine subjects; the key NNRTI mutation K103N, however, was always observed at >20% frequency. Although UDPS is useful in the detection of low-frequency subpopulations with transmitted resistance in antiviral-naive patients, it may have less utility in treatment-experienced patients with persistent viremia on therapy.

In vivo proton magnetic resonance spectroscopic examination of benzodiazepine action in humans.

In an examination of the effect of benzodiazepines on brain chemistry, 44 healthy controls underwent a short echo-time proton magnetic resonance spectroscopy ((1)H MRS) session after induced sedation with intravenous midazolam (0.03mg/kg) plus fentanyl (2µg/kg). The regions of interest were the anterior cingulate cortex, right basal ganglia, right frontal lobe, and right hippocampus. Twenty-five of these subjects underwent the second (1)H MRS session while awake. The measured (1)H MRS metabolites included N-acetyl-aspartate, creatine-containing compounds (PCr+Cr), choline-containing compounds, myo-inositol, and glutamate plus glutamine, which were quantified both as absolute values and metabolite/PCr+Cr ratios. The results were analyzed using independent group t tests and repeated measures analysis of variance (ANOVA, with alpha values set at 0.025 to minimize the risk of false-positive findings arising from multiple comparisons. No significant difference between subjects under midazolam plus fentanyl induced sedation and awake could be detected with unpaired analyses. Paired comparisons by ANOVA with repeated measures found that neither drug (midazolam plus fentanyl) nor the drug by time (interval between two scan times) interaction had a significant effect on the quantified metabolites. These findings encourage utilization of benzodiazepine-induced brief sedation during in vivo (1)H MRS experiments of the brain, and may help with elucidation of state-dependent neurochemical alterations during the course of bipolar and schizoaffective disorders.

T2 relaxation time abnormalities in bipolar disorder and schizophrenia.

There are substantial abnormalities in the number, density, and size of cortical neurons and glial cells in bipolar disorder and schizophrenia. Because molecule-microenvironment interactions modulate metabolite signals characteristics, these cellular abnormalities may impact transverse (T2) relaxation times. We measured T2 relaxation times for three intracellular metabolites (N-acetylaspartate+N-acetylaspartylglutamate, creatine+phosphocreatine, and choline-containing compounds) in the anterior cingulate cortex and parieto-occipital cortex from 20 healthy subjects, 15 patients with bipolar disorder, and 15 patients with schizophrenia at 4 T. Spectra used in T2 quantification were collected from 8-cc voxels with varying echo times (30 to 500 ms, in 10-ms steps). Both bipolar disorder and schizophrenia groups had numerically shorter T2 relaxation times than the healthy subjects group in both regions; these differences reached statistical significance for creatine+phosphocreatine and choline-containing compounds in bipolar disorder and for choline-containing compounds in schizophrenia. Metabolite T2 relaxation time shortening is consistent with reduced cell volumes and altered macromolecule structures, and with prolonged water T2 relaxation times reported in bipolar disorder and schizophrenia. These findings suggest that metabolite concentrations reported in magnetic resonance spectroscopy studies of psychiatric conditions may be confounded by T2 relaxation and highlight the importance of measuring and correcting for this variable.

Sensitivity of phenotypic susceptibility analyses for nonthymidine nucleoside analogues conferred by K65R or M184V in mixtures with wild-type HIV-1.

Thymidine-sparing triple-nucleoside regimens have exhibited poor virologic response despite apparent phenotypic susceptibility to 2 of 3 regimen components at early time points. Phenotypic resistance masking by wild-type virus may explain this discrepancy.Consistent with this notion were (1) the presence of low level nucleoside reverse-transcriptase inhibitor-resistant human immunodeficiency virus in subjects receiving failing first-line regimens consisting of tenofovir (TDF), abacavir (ABC), and lamivudine (3TC); (2) lower fold resistance associated with mixtures versus mutants in a clinical-isolate database; and (3) dose dependent changes in susceptibility to ABC, 3TC, TDF, and didanosine on titration of K65R and/or M184V with wild-type virus. These findings underscore the limitations of stand-alone phenotypic susceptibility measures and emphasize the importance of complementary and/or more sensitive techniques.

Effect of tenofovir subtraction on HIV plasma viraemia, CD4+ T-cell count and resistance in a patient with baseline K65R and M184V mutations.

In vitro, the reverse transcriptase mutation K65R can simultaneously reduce drug susceptibility, replicative capacity and restrict HIV-1 replication. Here, we assessed the effect of tenofovir discontinuation for a patient receiving antiretroviral therapy whose HIV-1 had a dominant K65R/M184V genotype. Although limited by the single-case nature, the data support a hypothesis that there is no HIV viral RNA or CD4+ T-cell count benefit of taking tenofovir for experienced patients with genotypic evidence of K65R/M184V.

Performance on the Stroop predicts treatment compliance in cocaine-dependent individuals.

Treatment dropout is a problem of great prevalence and stands as an obstacle to recovery in cocaine-dependent (CD) individuals. Treatment attrition in CD individuals may result from impairments in cognitive control, which can be reliably measured by the Stroop color-word interference task. The present analyses contrasted baseline performance on the color-naming, word-reading, and interference subtests of the Stroop task in CD subjects who completed a cocaine treatment trial (completers: N=50) and those who dropped out of the trial before completion (non-completers: N=24). A logistic regression analysis was used to predict trial completion using three models with the following variables: the Stroop task subscale scores (Stroop model); the Hamilton depression rating scale (HDRS) scores (HDRS model); and both the Stroop task subscale scores and HDRS scores (Stroop and HDRS model). Each model was able to significantly predict group membership (completers vs non-completers) better than a model based on a simple constant (HDRS model p=0.02, Stroop model p=0.006, and Stroop and HDRS model p=0.003). Models using the Stroop preformed better than the HDRS model. These findings suggest that the Stroop task can be used to identify cocaine-dependent subjects at risk for treatment dropout. The Stroop task is a widely available, reliable, and valid instrument that can be easily employed to identify and tailor interventions of at risk individuals in the hope of improving treatment compliance.

Reduced Plasma Nitric Oxide End Products in Cocaine-dependent Men.

Chronic cocaine abusers experience brain and peripheral vascular dysfunction, the severity of which tends to be greater in men than women. The mechanisms underlying these effects of cocaine are unknown. Because nitric oxide (NO) abnormalities play key roles in development of vascular dysfunction in several disorders, we determined whether vascular nitric oxide end product (NOx) levels, which can serve as markers of systemic vascular NO production, are reduced in cocaine-dependent (CD) subjects. Plasma samples from 24 CD men, 12 CD women, and matched comparison subjects (19 men, 14 women) were analyzed with a Sievers 280i nitric oxide chemiluminescence detection analysis system. NOx levels in comparison in women and men were 24.9 ± 6.6 and 23.3 ± 5.7 µmol/L, and in CD women and men were 22.5 ± 8.4 and 13.0 ± 9.6 µmol/L, respectively. ANCOVA analysis, adjusted for lifetime smoking, indicated group (P < 0.0005) and sex (P = 0.04) effects, both of which survived posthoc Scheffe tests. Reduced NOx levels in CD men drove the group difference. These data suggest that chronic cocaine abuse is associated with reduced NOx levels in men, although the finding also may be attributable to factors indirectly related to cocaine abuse, including cohort differences in other drug use or lifestyle factors. These findings warrant additional studies to more directly characterize vascular NO turnover in cocaine abusers and to establish whether NO abnormalities contribute to cocaine-associated vascular dysfunction and to sex differences in cocaine's effects.

Antidepressant-like effects of cranial stimulation within a low-energy magnetic field in rats.

BACKGROUND: Evidence suggests that a novel type of magnetic resonance imaging (MRI) scan called echo planar magnetic resonance spectroscopic imaging (EP-MRSI) has mood-elevating actions in humans during the depressive phases of bipolar disorder. We examined whether a low-energy component of EP-MRSI (low-field magnetic stimulation [LFMS]) has antidepressant-like, locomotor-stimulating, or amnestic effects in rats. METHODS: We examined the effects of LFMS on immobility in the forced swim test (FST) and activity within an open field in separate groups of rats. After exposure to forced swimming, rats received LFMS (three 20-min sessions at 1.5 G/cm and .75 V/m) before behavioral testing. We also examined the effects of LFMS on fear conditioning (FC), a learning paradigm that also involves exposure to stressful conditions. RESULTS: Low-field magnetic stimulation reduced immobility in the FST, an antidepressant-like effect qualitatively similar to that of standard antidepressants. Low-field magnetic stimulation did not alter locomotor activity or FC. CONCLUSIONS: Low-field magnetic stimulation has antidepressant-like effects in rats that seem unrelated to locomotor-activating or amnestic effects. These findings raise the possibility that electromagnetic fields can affect the brain biology and might have physiologic consequences that offer novel approaches to therapy for psychiatric disorders. These same consequences might render MRI-based scans more invasive than previously appreciated.

P1' oxadiazole protease inhibitors with excellent activity against native and protease inhibitor-resistant HIV-1.

HIV-1 protease inhibitors (PI's) bearing 1,3,4-oxadiazoles at the P1' position were prepared by a novel method involving the diastereoselective installation of a carboxylic acid and conversion to the P1' heterocycle. The compounds are picomolar inhibitors of native HIV-1 protease, with most of the compounds maintaining excellent antiviral activity against a panel of PI-resistant strains.