Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation

Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew F344) and syngeneic (Lew Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction.

A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart

Intrahepatic cholestasis of pregnancy may be complicated by fetal arrhythmia, fetal hypoxia, preterm labor, and, in severe cases, intrauterine death. The precise etiology of fetal death is not known. However, taurocholate has been demonstrated to cause arrhythmia and abnormal calcium dynamics in cardiomyocytes. To identify the underlying reason for increased susceptibility of fetal cardiomyocytes to arrhythmia, we studied myofibroblasts (MFBs), which appear during structural remodeling of the adult diseased heart. In vitro, they depolarize rat cardiomyocytes via heterocellular gap junctional coupling. Recently, it has been hypothesized that ventricular MFBs might appear in the developing human heart, triggered by physiological fetal hypoxia. However, their presence in the fetal heart (FH) and their proarrhythmogenic effects have not been systematically characterized. Immunohistochemistry demonstrated that ventricular MFBs transiently appear in the human FH during gestation. We established two in vitro models of the maternal heart (MH) and FH, both exposed to increasing doses of taurocholate. The MH model consisted of confluent strands of rat cardiomyocytes, whereas for the FH model, we added cardiac MFBs on top of cardiomyocytes. Taurocholate in the FH model, but not in the MH model, slowed conduction velocity from 19 to 9 cm/s, induced early after depolarizations, and resulted in sustained re-entrant arrhythmias. These arrhythmic events were prevented by ursodeoxycholic acid, which hyperpolarized MFB membrane potential by modulating potassium conductance. CONCLUSION: These results illustrate that the appearance of MFBs in the FH may contribute to arrhythmias. The above-described mechanism represents a new therapeutic approach for cardiac arrhythmias at the level of MFB.

[Seasonal fluctuations and influence of nutrition on macular pigment density]

PURPOSE: We have previously reported on measuring macular pigment density (MPD) with a scanning laser ophthalmoscope (HRA, Heidelberg Engineering, Heidelberg, Germany). This study war undertaken to evaluate the variation of MPD over a period of 1 year in healthy subjects. METHOD: We used autofluorescence images recorded with a HRA to evaluate MPD with a 2 degrees circle centered on the fovea. Healthy subjects were included in the study and MPD measurements were repeated every 2 months over a period of 1 year. RESULTS: We included a total of 30 healthy subjects aged 19-34 years (mean: 23+/-2 years). Mean MPD at time point 1 was 0.215+/-0.056 density units (DU), at time point 2 0.235+/-0.051 DU, at time point 3 0.218+/-0.055 DU, at time point 4 0.228+/-0.057 DU, at time point 5 0.225+/-0.053 DU, and at time point 6 0.203+/-0.050 DU. The statistical analysis revealed no significant variation of MPD over the follow-up period of 1 year. CONCLUSION: This study demonstrates that MPD shows no variation over a period of 1 year in healthy subjects.

Age of cichlids: new dates for ancient lake fish radiations

Timing divergence events allow us to infer the conditions under which biodiversity has evolved and gain important insights into the mechanisms driving evolution. Cichlid fishes are a model system for studying speciation and adaptive radiation, yet, we have lacked reliable timescales for their evolution. Phylogenetic reconstructions are consistent with cichlid origins prior to Gondwanan landmass fragmentation 121-165 MYA, considerably earlier than the first known fossil cichlids (Eocene). We examined the timing of cichlid evolution using a relaxed molecular clock calibrated with geological estimates for the ages of 1) Gondwanan fragmentation and 2) cichlid fossils. Timescales of cichlid evolution derived from fossil-dated phylogenies of other bony fishes most closely matched those suggested by Gondwanan breakup calibrations, suggesting the Eocene origins and marine dispersal implied by the cichlid fossil record may be due to its incompleteness. Using Gondwanan calibrations, we found accumulation of genetic diversity within the radiating lineages of the African Lakes Malawi, Victoria and Barombi Mbo, and Palaeolake Makgadikgadi began around or after the time of lake basin formation. These calibrations also suggest Lake Tanganyika was colonized independently by the major radiating cichlid tribes that then began to accumulate genetic diversity thereafter. These results contrast with the widely accepted theory that diversification into major lineages took place within the Tanganyika basin. Together, this evidence suggests that ancient lake habitats have played a key role in generating and maintaining diversity within radiating lineages and also that lakes may have captured preexisting cichlid diversity from multiple sources from which adaptive radiations have evolved.

In situ dehydration behavior of zeolite-like cavansite: A single-crystal X-ray study

To track dehydration behavior of cavansite, Ca(VO)(Si4O10)·4H2O space group Pnma, a = 9.6329(2), b = 13.6606(2), c = 9.7949(2) Å, V = 1288.92(4) Å3 single-crystal X-ray diffraction data on a crystal from Wagholi quarry, Poona district (India) were collected up to 400 °C in steps of 25 °C up to 250 °C and in steps of 50 °C between 250 and 400 °C. The structure of cavansite is characterized by layers of silicate tetrahedra connected by V4+O5 square pyramids. This way a porous framework structure is formed with Ca and H2O as extraframework occupants. At room temperature, the hydrogen bond system was analyzed. Ca is eightfold coordinated by four bonds to O of the framework structure and four bonds to H2O molecules. H2O linked to Ca is hydrogen bonded to the framework and also to adjacent H2O molecules. The dehydration in cavansite proceeds in four steps.At 75 °C, H2O at O9 was completely expelled leading to 3 H2O pfu with only minor impact on framework distortion and contraction V = 1282.73(3) Å3. The Ca coordination declined from originally eightfold to sevenfold and H2O at O7 displayed positional disorder.At 175 °C, the split O7 sites approached the former O9 position. In addition, the sum of the three split positions O7, O7a, and O7b decreased to 50% occupancy yielding 2 H2O pfu accompanied by a strong decrease in volume V = 1206.89(8) Å3. The Ca coordination was further reduced from sevenfold to sixfold.At 350 °C, H2O at O8 was released leading to a formula with 1 H2O pfu causing additional structural contraction (V = 1156(11) Å3). At this temperature, Ca adopted fivefold coordination and O7 rearranged to disordered positions closer to the original O9 H2O site.At 400 °C, cavansite lost crystallinity but the VO2+ characteristic blue color was preserved. Stepwise removal of water is discussed on the basis of literature data reporting differential thermal analyses, differential thermo-gravimetry experiments and temperature dependent IR spectra in the range of OH stretching vibrations.

Post-mortem whole body computed tomography of opioid (heroin and methadone) fatalities: frequent findings and comparison to autopsy

OBJECTIVE To investigate frequent findings in cases of fatal opioid intoxication in whole-body post-mortem computed tomography (PMCT). METHODS PMCT of 55 cases in which heroin and/or methadone had been found responsible for death were retrospectively evaluated (study group), and were compared with PMCT images of an age- and sex-matched control group. Imaging results were compared with conventional autopsy. RESULTS The most common findings in the study group were: pulmonary oedema (95 %), aspiration (66 %), distended urinary bladder (42 %), cerebral oedema (49 %), pulmonary emphysema (38 %) and fatty liver disease (36 %). These PMCT findings occurred significantly more often in the study group than in the control group (p < 0.05). The combination of lung oedema, brain oedema and distended urinary bladder was seen in 26 % of the cases in the study group but never in the control group (0 %). This triad, as indicator of opioid-related deaths, had a specificity of 100 %, as confirmed by autopsy and toxicological analysis. CONCLUSIONS Frequent findings in cases of fatal opioid intoxication were demonstrated. The triad of brain oedema, lung oedema and a distended urinary bladder on PMCT was highly specific for drug-associated cases of death. KEY POINTS Frequent findings in cases of fatal opioid intoxication were investigated. Lung oedema, brain oedema and full urinary bladder represent a highly specific constellation. This combination of findings in post-mortem CT should raise suspicion of intoxication.

Whole-Brain Susceptibility-Weighted Thrombus Imaging in Stroke: Fragmented Thrombi Predict Worse Outcome.

BACKGROUND AND PURPOSE The prevalence and clinical importance of primarily fragmented thrombi in patients with acute ischemic stroke remains elusive. Whole-brain SWI was used to detect multiple thrombus fragments, and their clinical significance was analyzed. MATERIALS AND METHODS Pretreatment SWI was analyzed for the presence of a single intracranial thrombus or multiple intracranial thrombi. Associations with baseline clinical characteristics, complications, and clinical outcome were studied. RESULTS Single intracranial thrombi were detected in 300 (92.6%), and multiple thrombi, in 24 of 324 patients (7.4%). In 23 patients with multiple thrombi, all thrombus fragments were located in the vascular territory distal to the primary occluding thrombus; in 1 patient, thrombi were found both in the anterior and posterior circulation. Only a minority of thrombus fragments were detected on TOF-MRA, first-pass gadolinium-enhanced MRA, or DSA. Patients with multiple intracranial thrombi presented with more severe symptoms (median NIHSS scores, 15 versus 11; P = .014) and larger ischemic areas (median DWI ASPECTS, 5 versus 7; P = .006); good collaterals, rated on DSA, were fewer than those in patients with a single thrombus (21.1% versus 44.2%, P = .051). The presence of multiple thrombi was a predictor of unfavorable outcome at 3 months (P = .040; OR, 0.251; 95% CI, 0.067-0.939). CONCLUSIONS Patients with multiple intracranial thrombus fragments constitute a small subgroup of patients with stroke with a worse outcome than patients with single thrombi.

[Smoking and digestive tract: a complex relationship. Part 1: Inflammatory bowel disease and cigarette smoking]

Little is known about the effects of smoking on inflammatory bowel diseases (IBD). However the co-occurrence of smoking and IBD often happens in ambulatory care. Smokers have a doubled risk of developing a Crohn's disease with a more active disease course. After quitting, a decrease in risk can be observed after only one year. An inverse relationship is found between smoking and ulcerative colitis. Smoking seems protective for the development of the disease and its course is less active among smokers. Smoking cessation transitorily increases the risk of developing ulcerative colitis. Nevertheless, continuing smoking cannot be justified among those patients given the risks of long-term extra-digestive effects. It is thus important to counsel all smokers with an IBD to quit smoking.