Myocardial dysfunction with coronary microembolization: signal transduction through a sequence of nitric oxide, tumor necrosis factor-alpha, and sphingosine

Coronary microembolization results in progressive myocardial dysfunction, with causal involvement of tumor necrosis factor-alpha (TNF-alpha). TNF-alpha uses a signal transduction involving nitric oxide (NO) and/or sphingosine. Therefore, we induced coronary microembolization in anesthetized dogs and studied the role and sequence of NO, TNF-alpha, and sphingosine for the evolving contractile dysfunction. Four sham-operated dogs served as controls (group 1). Eleven dogs received placebo (group 2), 6 dogs received the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME, group 3), and 6 dogs received the ceramidase inhibitor N-oleoylethanolamine (NOE, group 4) before microembolization was induced by infusion of 3000 microspheres (42-microm diameter) per milliliter inflow into the left circumflex coronary artery. Posterior systolic wall thickening (PWT) remained unchanged in group 1 but decreased progressively in group 2 from 20.6+/-4.9% (mean+/-SD) at baseline to 4.1+/-3.7% at 8 hours after microembolization. Leukocyte count, TNF-alpha, and sphingosine contents were increased in the microembolized posterior myocardium. In group 3, PWT remained unchanged (20.3+/-2.6% at baseline) with intracoronary administration of L-NAME (20.8+/-3.4%) and 17.7+/-2.3% at 8 hours after microembolization; TNF-alpha and sphingosine contents were not increased. In group 4, PWT also remained unchanged (20.7+/-4.6% at baseline) with intravenous administration of NOE (19.5+/-5.7%) and 16.4+/-6.3% at 8 hours after microembolization; TNF-alpha, but not sphingosine content, was increased. In all groups, systemic hemodynamics, anterior systolic wall thickening, and regional myocardial blood flow remained unchanged throughout the protocols. A signal transduction cascade of NO, TNF-alpha, and sphingosine is causally involved in the coronary microembolization-induced progressive contractile dysfunction.     

Drinking in the Commonwealth of Independent States--evidence from eight countries

AIMS: To describe the frequency of alcohol consumption and beverage preferences in eight countries of the Commonwealth of Independent States (CIS). DESIGN: Cross-sectional. SETTING: Populations of Armenia, Belarus, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Russian Federation and Ukraine. PARTICIPANTS: Representative samples of the adult population of each country (overall sample size 18,428; response rates: 71-88%). MEASUREMENTS: A standardised questionnaire was administered by trained interviewers to examine alcohol consumption frequency and usual intakes of beer, wine and strong spirits. FINDINGS: Between 11 and 34% of males and 26-71% of females reported never drinking alcohol. Abstention was lowest in the Russian Federation and Belarus, two traditional spirits-drinking countries. It was particularly high in Kyrgyzstan and Georgia, two countries with a relatively low frequency of alcohol consumption but large amounts consumed per occasion (particularly Georgia). On the contrary, Moldovan respondents drank frequently, but consumed smaller amounts per occasion. As expected, spirits were consumed in largest amounts in traditional spirits-drinking countries, as well as Armenia and wine in traditional wine-drinking countries. Beer consumption was relatively high in Russia, Belarus, Ukraine and Kazakhstan (males), particularly in young respondents. CONCLUSIONS: Although cross-country comparisons of alcohol intake should be interpreted cautiously, this study suggested that drinking patterns in the countries examined are not entirely typical of usual dry/wet drinking cultures, and confirms that the CIS is very diverse in terms of drinking patterns and beverage preferences. The study provides an important baseline for future comparisons as markets open to new products, as has been the case elsewhere in Europe.     

Hyperglycemia enhances IGF-I-stimulated Src activation via increasing Nox4-derived reactive oxygen species in a PKCζ-dependent manner in vascular smooth muscle cells

IGF-I-stimulated sarcoma viral oncogene (Src) activation during hyperglycemia is required for propagating downstream signaling. The aim of the current study was to determine the mechanism by which hyperglycemia enhances IGF-I-stimulated Src activation and the role of NADPH oxidase 4 (Nox4) and protein kinase C ζ (PKCζ) in mediating this response in vascular smooth muscle cells (VSMCs). Nox4 expression was analyzed in VSMCs exposed to hyperglycemia. The role of Nox4-derived reactive oxygen species (ROS) in IGF-I-stimulated Src activation was investigated via knockdown of Nox4. Different isoforms of PKC were screened to investigate their role in hyperglycemia-induced Nox4. The oxidation of Src was shown to be a prerequisite for its activation in response to IGF-I during hyperglycemia. Hyperglycemia induced Nox4, but not Nox1, and p22 phagocyte oxidase (p22phox) expression and IGF-I stimulated Nox4/p22phox complex formation, leading to increased ROS generation. Knockdown of Nox4 prevented ROS generation and impaired the oxidation and activation of Src in response to IGF-I, whereas knockdown of Nox1 had no effect. PKCζ was shown to mediate the hyperglycemia-induced increase in Nox4 expression. The key observations in cultured VSMCs were confirmed in the diabetic mice. Nox4-derived ROS is responsible for the enhancing effect of hyperglycemia on IGF-I-stimulated Src activation, which in turn amplifies IGF-I-linked downstream signaling and biological actions.     

Reproductive Health and Sexual Violence Among Urban American Indian and Alaska Native Young Women: Select Findings from the National Survey of Family Growth (2002)

Existing data on American Indians and Alaska Natives (AI/ANs) has indicated high rates of unintended pregnancy, high-risk sexual behavior, and experiences of sexual violence. This study from the first analysis to examine AI/ANs and the urban AI/AN subgroup in the National Survey of Family Growth (NSFG) reports new findings of reproductive health and sexual violence among urban AI/AN young women. We examined 2002 NSFG data on urban AI/AN women ages 15–24 years for pregnancies/births, unintended pregnancy, sexual initiation and contraceptive use. We also examined non-voluntary first sexual intercourse among urban AI/AN women ages 18–44 years. Prevalence estimates and 95 % confidence intervals were calculated. Findings include prevalence rates of risk factors among urban AI/AN women ages 15–24 years including unprotected first sex (38 %), first sex with much older partners (36 %), three or more pregnancies (13 %) and births (5 %) and unintended pregnancies (26 %). Seventeen percent of urban AI/ANs ages 18–44 years reported experiencing non-voluntary first sex. Sixty-one percent of urban AI/AN women ages 15–24 years were not using any method of contraception. Current contraceptive methods among those using a method included: injections/implants (23 %), contraceptive pills (32 %) and condoms (25 %). Findings describe reproductive health risk factors among young urban AI/AN women and highlight the need for enhanced surveillance on these issues. Those working to improve AI/AN health need these data to guide programming and identify resources for implementing and evaluating strategies that address risk factors for this overlooked population.     

MR elastography in a murine stroke model reveals correlation of macroscopic viscoelastic properties of the brain with neuronal density

The aim of this study was to investigate the influence of neuronal density on viscoelastic parameters of living brain tissue after ischemic infarction in the mouse using MR elastography (MRE). Transient middle cerebral artery occlusion (MCAO) in the left hemisphere was induced in 20 mice. In vivo 7‐T MRE at a vibration frequency of 900 Hz was performed on days 3, 7, 14 and 28 (n = 5 per group) after MCAO, followed by the analysis of histological markers, such as neuron counts (NeuN). MCAO led to a significant reduction in the storage modulus in the left hemisphere relative to contralateral values (p = 0.03) without changes over time. A correlation between storage modulus and NeuN in both hemispheres was observed, with correlation coefficients of R = 0.648 (p = 0.002, left) and R = 0.622 (p = 0.003, right). The loss modulus was less sensitive to MCAO, but correlated with NeuN in the left hemisphere (R = 0.764, p = 0.0001). In agreement with the literature, these results suggest that the shear modulus in the brain is reduced after transient ischemic insult. Furthermore, our study provides evidence that the in vivo shear modulus of brain tissue correlates with neuronal density. In diagnostic applications, MRE may thus have diagnostic potential as a tool for image‐based quantification of neurodegenerative processes. Copyright © 2013 John Wiley & Sons, Ltd.     

Development of new artificial models for splint rigidity evaluation

Abstract – Aim: We developed two versions of an artificial model and assessed their suitability for splint rigidity evaluation. These models allowed the simulation of traumatically loosened teeth and the use of the acid‐etch technique for splint application. Materials and methods: A straight and half‐round arch bar model with bovine tooth facets were manufactured. Using the Periotest method, tooth mobility was evaluated before (PTVpre) and after (PTVpost) splinting. Two types of previously investigated wire‐composite splints, WCS1 (Dentaflex 0.45 mm; Dentaurum) and WCS2 (Strengthens 0.8 × 1.8 mm; Dentaurum), were applied (n = 10) to each model. The relative splint effect (SpErel = ΔPTV/PTVpre) was calculated, and the working times for the models and splints were evaluated. Student’s t‐test and the Mann–Whitney U‐test were employed with Bonferroni correction for multiple hypotheses. Results: When comparing the relative splint effect of the ‘injured’ central incisors between the models within one splint type, differences were only found for tooth 21 (WCS2; P < 0.008); for comparisons of splints within one model type, differences were detected for both incisors and model types (P < 0.008). With the straight model, significantly less working time was necessary (P < 0.05). Conclusion: Using these models for in vitro splint rigidity evaluation, the splints can be applied with the acid‐etch technique and tooth mobility can be individually adjusted. WCS1 is considered flexible compared to the more rigid WCS2. The results from the straight and the round model were predominantly closely related to each other. In terms of working time, the straight model is superior to the round model.     

Towards computerized diagnosis of neurological stance disorders: data mining and machine learning of posturography and sway

We perform classification, ranking and mapping of body sway parameters from static posturography data of patients using recent machine-learning and data-mining techniques. Body sway is measured in 293 individuals with the clinical diagnoses of acute unilateral vestibulopathy (AVS, n = 49), distal sensory polyneuropathy (PNP, n = 12), anterior lobe cerebellar atrophy (CA, n = 48), downbeat nystagmus syndrome (DN, n = 16), primary orthostatic tremor (OT, n = 25), Parkinson’s disease (PD, n = 27), phobic postural vertigo (PPV n = 59) and healthy controls (HC, n = 57). We classify disorders and rank sway features using supervised machine learning. We compute a continuous, human-interpretable 2D map of stance disorders using t-stochastic neighborhood embedding (t-SNE). Classification of eight diagnoses yielded 82.7% accuracy [95% CI (80.9%, 84.5%)]. Five (CA, PPV, AVS, HC, OT) were classified with a mean sensitivity and specificity of 88.4% and 97.1%, while three (PD, PNP, and DN) achieved a mean sensitivity of 53.7%. The most discriminative stance condition was ranked as “standing on foam-rubber, eyes closed”. Mapping of sway path features into 2D space revealed clear clusters among CA, PPV, AVS, HC and OT subjects. We confirm previous claims that machine learning can aid in classification of clinical sway patterns measured with static posturography. Given a standardized, long-term acquisition of quantitative patient databases, modern machine learning and data analysis techniques help in visualizing, understanding and utilizing high-dimensional sensor data from clinical routine.

     

Ventriculostomy-related intracranial hemorrhage following surgical and endovascular treatment of ruptured aneurysms

Endovascular therapy of ruptured aneurysms is regularly accompanied by periprocedural heparinization and requires the use of periprocedural antiplatelets in more complex cases. This raises concerns regarding increased bleeding risks in the case of frequently required ventriculostomy. The aim of this study was to analyze risk factors for ventriculostomy-related intracranial hemorrhages (VS-ICH) in endovascular or surgical treatment of ruptured aneurysms with a focus on antithrombotic therapy. In this retrospective analysis, we included patients admitted to our institution over a 12-year period who had received at least one ventriculostomy due to subarachnoid hemorrhage-related hydrocephalus. Patients were dichotomized into an endovascular and surgical group and rates of VS-ICH were compared. Risk factors for VS-ICH were assessed in uni- and multivariate analyses. A total of 606 ventriculostomies were performed in 328 patients. Within the endovascular group, antiplatelet therapy was used in 44.8% of cases. The overall rate of ventriculostomy-related intracranial hemorrhage was 13.1%. Endovascular treatment was associated with a higher rate of VS-ICH compared to surgical treatment (p?=?0.011), but not in cases without antiplatelet therapy (p?=?0.166). Application of any antiplatelet therapy (odds ratio, 2.647 [95% confidence interval, 1.141–6.143]) and number of ventriculostomies (odds ratio, 2.513 [95% confidence interval, 1.859–3.395]) were independent predictors of ventriculostomy-related hemorrhages. Our findings indicate an increased risk of VS-ICH in the endovascular group if administration of antiplatelets was required. While this aspect has to be included into treatment decision-making, it must be weighed against the benefits of endovascular techniques.