Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Deficiencies in vitamins or other factors (B6, B12, folic acid, betaine) and genetic disorders for the metabolism of the non-protein amino acid-homocysteine (Hcy) lead to hyperhomocysteinemia (HHcy). HHcy is an integral component of several disorders including cardiovascular disease, neurodegeneration, diabetes and alcoholic liver disease. HHcy unleashes mediators of inflammation such as NFkB, IL-1β, IL-6, and IL-8, increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide (NO), and induces endoplasmic reticulum (ER) stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation, and inflammation. Animal models have played an important role in determining the biological effects of HHcy. ER stress may also be involved in other liver diseases such as a1-antitrypsin (a1-AT) deficiency and hepatitis C and/or B virus infection. Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury, study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans, and examine polymorphism of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease.     

Low-permeability Gore Excluder device versus the original in abdominal aortic aneurysm size regression

We sought to compare the efficacy of a low-permeability version of the Gore Excluder™ device with that of the original device. We used volumetric analysis and maximum transverse diameter measurements to examine abdominal aortic aneurysm size regression after endovascular aneurysm repair.From November 2002 through April 2007, 101 patients (82% men; mean age, 71.5 ± 8.9 yr) underwent endovascular aneurysm repair with the Excluder stent-graft: 34 with the original device, and 67 with the low-permeability device. Only patients without endoleak and with preprocedural and 1- and 2-year follow-up computed tomographic scans were included. Eight patients with type II endoleak and 2 with type I endoleak were excluded. Maximum abdominal aortic aneurysm diameter and volume were measured before endovascular aneurysm repair and annually thereafter. Postprocessing, multiplanar computed tomography, and 3-dimensional reconstructions were compared with baseline measurements. Diameter and volume changes that were greater than 5 mm or that exceeded 10% were considered significant.At 12 months, the mean maximum transverse diameter had decreased by −0.16 ± 12.1 mm in recipients of the original device and by −4.8 ± 5.9 mm in recipients of the low-permeability device (P = NS). In addition, mean reduction in volume had changed by −17 ± 16 mL in original-device recipients and by −36.1 ± 37.9 mL in low-permeability device recipients (P < 0.01).One-year follow-up revealed that the low-permeability stent-graft resulted in a greater decrease in abdominal aortic aneurysm volume than did the original stent-graft.Key words: Aortic aneurysm, abdominal/exclusion/repair; blood vessel prosthesis; endoleak; stent-grafts; stents; tomography, x-ray computed; treatment outcomeEndovascular aortic repair (EVAR) has become an accepted treatment technique for patients with abdominal aortic aneurysm (AAA). Compared with surgery, EVAR is associated with less operative blood loss, shorter hospital and intensive care unit stays, fewer major postoperative complications, and more rapid convalescence.^1–3 In addition, EVAR has proved beneficial in the treatment of high-risk patients who cannot undergo standard surgical AAA repair. Two recent prospective, randomized trials have shown that, compared with surgery, EVAR is associated with a reduction in 30-day perioperative mortality.^4,5 The GORE® EXCLUDER® AAA Endoprosthesis (W.L. Gore & Associates, Inc.; Flagstaff, Ariz) is currently 1 of 5 endografts approved by the U.S. Food and Drug Administration for clinical use in the treatment of infrarenal AAA. The Excluder endograft is a bifurcated endoprosthesis composed of a trunk-ipsilateral endoprosthesis and a contralateral leg endoprosthesis. The graft material consists of expanded polytetrafluoroethylene (ePTFE) and fluorinated ethylene propylene. The material is supported by nitinol (nickel-titanium alloy) wire along its external surface, which is attached to the graft by a bonding film.In the mid-term Excluder Pivotal Trial, the original Excluder device was associated with a higher aneurysm expansion rate than that observed with other commercially available devices.^6,7 Some patients in this trial had aneurysm expansion without an identifiable endoleak, a phenomenon termed endotension. As the trial showed, the causes of aneurysm enlargement are multifactorial and include both endoleaks and endotension due to the material''s high permeability by plasma. As a result, several patients in this trial had to undergo late conversion to open surgical intervention.⁸ In an effort to resolve this issue, in June 2004, W.L. Gore & Associates modified the Excluder graft material to reduce its permeability. The purpose of the present study was to compare the efficacy of the new, low-permeability (LP) Excluder device with that of the original device by using volumetric analysis and measuring maximum transverse diameter to examine regression in AAA size after EVAR.     

Risk factors for non-haemorrhagic stroke in patients with coronary heart disease and the effect of lipid-modifying therapy with pravastatin

OBJECTIVE: To determine the relative importance of recognised risk factors for non-haemorrhagic stroke, including serum cholesterol and the effect of cholesterol-lowering therapy, on the occurrence of non-haemorrhagic stroke in patients enrolled in the LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease) study. DESIGN: The LIPID study was a placebo-controlled, double-blind trial of the efficacy on coronary heart disease mortality of pravastatin therapy over 6 years in 9014 patients with previous acute coronary syndromes and baseline total cholesterol of 4-7 mmol/l. Following identification of patients who had suffered non-haemorrhagic stroke, a pre-specified secondary end point, multivariate Cox regression was used to determine risk in the total population. Time-to-event analysis was used to determine the effect of pravastatin therapy on the rate of non-haemorrhagic stroke. RESULTS: There were 388 non-haemorrhagic strokes in 350 patients. Factors conferring risk of future non-haemorrhagic stroke were age, atrial fibrillation, prior stroke, diabetes, hypertension, systolic blood pressure, cigarette smoking, body mass index, male sex and creatinine clearance. Baseline lipids did not predict non-haemorrhagic stroke. Treatment with pravastatin reduced non-haemorrhagic stroke by 23% (P = 0.016) when considered alone, and 21% (P = 0.024) after adjustment for other risk factors. CONCLUSIONS: The study confirmed the variety of risk factors for non-haemorrhagic stroke. From the risk predictors, a simple prognostic index was created for non-haemorrhagic stroke to identify a group of patients at high risk. Treatment with pravastatin resulted in significant additional benefit after allowance for risk factors.     

The Therapeutic Alliance and CBASP-Specific Skill Acquisition in the Treatment of Chronic Depression

This study examined the influences of proposed specific and common psychotherapeutic factors in a sample of chronically depressed adult outpatients. Participants (N = 324) were drawn from a multi-site clinical trial that compared the efficacies of the cognitive behavioral analysis system of psychotherapy (CBASP), nefazodone, and their combination. This report is limited to patients receiving CBASP alone or combination treatment. A series of regression analyses were performed to test whether: (1) the ability to utilize the skills taught in CBASP mediated the relationship between the early therapeutic alliance and endpoint depression, and (2) the therapeutic alliance moderated the relationship between skill utilization and endpoint depression. Neither model was supported. Instead, each of these factors contributed independently and additively to alleviation of depressive symptoms.     

Studies in vivo and in vitro on an abnormality in the metabolism of C3 in a patient with increased susceptibility to infection

In a patient with increased susceptibility to infection, lowered serum C3 concentration, and continuously circulating C3b, it was shown that purified (125)I-labeled C3 was converted to labeled C3b shortly after intravenous administration. The fractional catabolic rate of C3 was approximately five times normal at 10% of the plasma pool per hr. The synthesis rate and pool distribution of C3 were normal. Despite this evidence of C3 instability in vivo, no accelerated inactivation of C3 was found in vitro. Similarly, no free proteolytic activity could be detected in the patient's serum, and serum concentrations of known protease inhibitors were normal.Complement-mediated functions, which were markedly deficient in the patient's serum, could be restored partially or completely by the addition of a 5-6S heat-labile beta pseudoglobulin from normal serum. The C3 proinactivator, which has these physicochemical characteristics, was also shown to be either absent or nonfunctional in the patient's serum. An unidentified 6S beta pseudoglobulin to which a monospecific antiserum was available was not detectable in the patient's serum. This last protein appeared not to be a complement component, nor was it the C3 inactivator or proinactivator. Finally, the substance or substances necessary for the conversion of C3b to C3c were missing from the patient's serum.The administration of 500 ml of normal plasma to the patient corrected all of his abnormalities partially or completely for as long as 17 days. The changes in C3 were dramatic; serum concentration rose from 8 to 70 mg/100 ml, and C3b could no longer be detected. A second metabolic study during this normalization period showed a decrease in fractional catabolic rate toward normal.The patient's histamine excretion was constantly elevated but increased further after a warm shower and after receiving normal plasma; at both times he had urticaria. These observations were consistent with the endogenous production of C3a and the resulting histamine release from mast cells. The inactivating mechanism for C3a was apparently intact in the patient's serum.The difference in the electrophoretic mobilities of C3b and C3c was shown as well as the electrophoretic heterogeneity of C3c. Suggestive evidence was also presented that the form of C3 with an activated combining site for red cells, previously postulated by others, is a transient C3 conversion product with an electrophoretic mobility slower than that of C3 on agarose electrophoresis.     

Voxel-based morphometry reveals increased gray matter density in Broca's area in male symphony orchestra musicians

Broca's area is a major neuroanatomical substrate for spoken language and various musically relevant abilities, including visuospatial and audiospatial localization. Sight reading is a musician-specific visuospatial analysis task, and spatial ability is known to be amenable to training effects. Musicians have been reported to perform significantly better than nonmusicians on spatial ability tests, which is supported by our findings with the Benton judgement of line orientation (JOL) test (P < 0.001). We hypothesised that use-dependent adaptation would lead to increased gray matter density in Broca's area in musicians. Voxel-based morphometry (VBM) and stereological analyses were applied to high-resolution 3D MR images in male orchestral musicians (n = 26) and sex, handedness, and IQ-matched nonmusicians (n = 26). The wide age range (26 to 66 years) of volunteers permitted a secondary analysis of age-related effects. VBM with small volume correction (SVC) revealed a significant (P = 0.002) region of increased gray matter in Broca's area in the left inferior frontal gyrus in musicians. We observed significant age-related volume reductions in cerebral hemispheres, dorsolateral prefrontal cortex subfields bilaterally and gray matter density in the left inferior frontal gyrus in controls but not musicians; a positive correlation between JOL test score and age in musicians but not controls; a positive correlation between years of playing and the volume of gray matter in a significant region identified by VBM in under-50-year-old musicians. We suggest that orchestral musical performance promotes use-dependent retention, and possibly expansion, of gray matter involving Broca's area and that this provides further support for shared neural substrates underpinning expressive output in music and language.     

Comorbidity and outcomes of coronary artery bypass graft surgery at cardiac specialty hospitals versus general hospitals

BACKGROUND: Cardiac specialty hospitals assert better patient outcomes and efficiency, whereas general hospitals contend they attract healthier patients. OBJECTIVES: To ascertain whether increased cardiac specialization of a hospital's services is associated with improved outcomes for coronary artery bypass graft (CABG) surgery and whether patients with and without comorbid disease have equivalent outcomes to their counterparts at general hospitals. METHODS: We conducted a retrospective cohort study of a 5% sample of Medicare beneficiaries undergoing CABG procedures from 2001 to 2003. Using multivariate analyses, we assessed the hospital degree of cardiac specialization on mortality, length of stay, hospital readmissions, and emergency room visits leading to rehospitalization for all patients and those with more comorbidities. RESULTS: Patients at cardiac specialty hospitals had less comorbid disease (29.7% with Charlson scores > or =2) than those at moderately (37.2%) and least specialized hospitals (36.6%, P = 0.001). Overall, CABG outcomes in all 3 groups were similar for inpatient mortality (P = 0.78), 30-day postdischarge mortality (P = 0.69), emergency room visit leading to rehospitalization (P = 0.35), and hospital readmission within 30 days postdischarge (P = 0.70). However, for patients with greater comorbidity, 30-day postdischarge mortality was worse at cardiac specialty hospitals compared with least specialized hospitals from across the United States (adjusted odds ratio, 1.71; 95% confidence interval, 1.26-2.32; P = 0.001). Results were robust when hospitals were compared within metropolitan statistical areas. CONCLUSIONS: Favorable patient selection may occur at cardiac specialty hospitals. Although healthier patients fare comparably across types of hospitals, patients with greater comorbid disease seem to experience worse 30-day postdischarge mortality at specialty hospitals.     

Role of the AcrAB-TolC efflux pump in determining susceptibility of Haemophilus influenzae to the novel peptide deformylase inhibitor LBM415

Haemophilus influenzae isolates vary widely in their susceptibilities to the peptide deformylase inhibitor LBM415 (MIC range, 0.06 to 32 microg/ml); however, on average, they are less susceptible than gram-positive organisms, such as Staphylococcus aureus and Streptococcus pneumoniae. Insertional inactivation of the H. influenzae acrB or tolC gene in strain NB65044 (Rd strain KW20) increased susceptibility to LBM415, confirming a role for the AcrAB-TolC pump in determining resistance. Consistent with this, sequencing of a PCR fragment generated with primers flanking the acrRA region from an LBM415-hypersusceptible H. influenzae clinical isolate revealed a genetic deletion of acrA. Inactivation of acrB or tolC in several clinical isolates with atypically reduced susceptibility to LBM415 (MIC of 16 microg/ml or greater) significantly increased susceptibility, confirming that the pump is also a determinant of decreased susceptibility in these clinical isolates. Examination of acrR, encoding the putative repressor of pump gene expression, from several of these strains revealed mutations introducing frameshifts, stop codons, and amino acid changes relative to the published sequence, suggesting that loss of pump repression leads to decreased susceptibility. Supporting this, NB65044 acrR mutants selected by exposure to LBM415 at 8 microg/ml had susceptibilities to LBM415 and other pump substrates comparable to the least sensitive clinical isolates and showed increased expression of pump genes.     

Use of ethylene glycol to evaluate gradient performance in gradient-intensive diffusion MR sequences

Imaging a phantom of known dimensions is a widely used and simple method for calibrating MRI gradient strength. However, full-range characterization of gradient response is not achievable using this approach. Measurement of the apparent diffusion coefficient of a liquid with known diffusivity allows for calibration of gradient amplitudes across a wider dynamic range. An important caveat is that the temperature dependence of the liquid's diffusion characteristics must be known, and the temperature of the calibration phantom must be recorded. In this report, we demonstrate that the diffusion coefficient of ethylene glycol is well described by Arrhenius-type behavior across the typical range of ambient MRI magnet temperatures. Because of ethylene glycol's utility as an NMR chemical-shift thermometer, the same (1)H MR spectroscopy measurements that are used for gradient calibration also simultaneously "report" the sample temperature. The high viscosity of ethylene glycol makes it well-suited for assessing gradient performance in demanding diffusion-weighted imaging and spectroscopy sequences.