Superoxide dismutase entrapped-liposomes restore the impaired endothelium-dependent relaxation of resistance arteries in experimental diabetes

Diabetes is associated with impaired endothelium-dependent relaxation. We questioned whether administration of superoxide dismutase (superoxide: superoxide oxidoreductase, EC 1.15.1.1) entrapped in long-circulating liposomes improves the vascular reactivity of the resistance arteries. Using the myograph technique, the vasodilation in response to acetylcholine was measured in mesenteric resistance arteries isolated from diabetic or normal hamsters treated for 3 days with superoxide dismutase entrapped in liposomes, with the same concentrations of free superoxide dismutase and plain liposomes, or untreated. Superoxide dismutase activity and nitric oxide (NO) levels were assayed by spectrophotometry, superoxide dismutase levels by Western blot and the role of N(pi)-nitro-L-arginine ethylester (L-NAME) on vasodilation by the myograph technique. Our data revealed that: (i) superoxide dismutase entrapped in liposomes restored to a great extent the endothelium-dependent relaxation of diabetic hamster resistance arteries; (ii) in superoxide dismutase entrapped in liposomes-treated diabetic animals, the activity and the level of superoxide dismutase in arterial homogenates as well as the serum nitrite levels were significantly higher than those in untreated hamsters or hamsters treated with free superoxide dismutase and plain liposomes: (iii) L-NAME inhibited the response of arteries to acetylcholine in superoxide dismutase entrapped in liposomes-treated diabetic hamsters. These results suggest that superoxide dismutase entrapped in liposomes is effective in scavenging superoxide anions, increases nitric oxide bioactivity and improves the vasorelaxation of resistance arteries in diabetic hamsters.     

Prostaglandin E2 inhibits production of the inflammatory chemokines CCL3 and CCL4 in dendritic cells

Dendritic cells bridge innate and adaptive immunity and participate in both responses. Upon capture of pathogens, dendritic cells release inflammatory cytokines and chemokines, attracting other immune cells to the infection site. Anti-inflammatory cytokines, glucocorticoids, anti-inflammatory neuropeptides, and lipid mediators such as prostaglandin E2 (PGE2) limit and control the inflammatory response. In this study we report that exogenous PGE2 inhibits CCL3 (MIP-1alpha) and CCL4 (MIP-1beta) expression and release from dendritic cells stimulated with either lipopolysaccharide (LPS), a TLR4 ligand, or peptidoglycan, a TLR2 ligand. The inhibition is dose-dependent and occurs at both the mRNA and protein levels. The inhibitory effect is mediated through EP2 and EP4 receptors and requires the presence of PGE2 at the time of LPS stimulation. Intraperitoneal administration of PGE2 together with LPS results in a reduction in the levels of CCL3 and CCL4 released in the peritoneal fluid, a reduction in the number of dendritic cells accumulating in the peritoneal cavity, and a reduction in CCL3 amount per cell in the peritoneal cell population. These results suggest that one of the mechanisms by which endogenous PGE2 acts as an anti-inflammatory agent, is the inhibition of inflammatory chemokine release from activated dendritic cells, preventing the excess accumulation of activated immune cells.     

Risk of increase in nosocomial infections incidence in a surgical clinic. A case-control study

The complex activities of epidemiological surveillance of nosocomial infections (NI) have, among the main objectives, the identification of the causes and the assessment of risk factors. In 2002, the Clinic Hospital of Pneumology Iasi had 220 beds and was divided into the following units: Pneumophtisiology Unit (PPU), Thoracic Surgery Unit (TSU) and Intensive Care Unit (ICU). The global incidence of NI was of 0.85%. The incidence of cases with NI in the TSU and ICU increased to 5.39% in the interval April-June 2002 so that urgent epidemiological measures were applied to limit the phenomenon. After that, a case-control study was proposed in order to identify and assess the risk levels. The retrospective study met the methodological conditions such as case definitions for NI and post-surgical NI, for extrinsic and intrinsic risk factors, the selection of cases according to inclusion and exclusion criteria, the formation of the representative sample. The study included 16 patients with pleural NI and 55 controls with the pleurotomy performed between April-June in the TCU, as a common feature. The factors that increased the probability of a post-surgical NI development were: the external pleural drainage maintained more than 30 days (OR = 185.5; p < 0.0001 for CI = 95%), tuberculosis as the most important associated disease among the patients' pathological history records (OR = 28.0; p < 0.0001; CI = 95%); the antibiotherapy with multiple associations (OR = 3.30; p < 0.04; CI = 95%). The conclusions underlined that the patients suffered from tuberculosis since the very admission, which need pleurotomy have an increased risk to develop a NI. This fact should require an appropriate epidemiological, clinical and microbiological surveillance and the empirical antibiotic strategy or that conducted by the antibiogram results has to be performed adequately, according to the operative recommendations.     

Abnormal positions of the heart. An analysis on 1039 cases

The aim was to study the impact of the cardiac malpositions into the group of the 1039 congenital heart diseases registered in the Pediatric Outpatient Department of "Sf. Spiridon" hospital. All patients were investigated noninvasively using clinical examination, electrocardiogram, routine Roentgenogram, two-dimensional and Doppler echocardiography, abdominal echography and, only in two cases, cardiac catheterisation. 23 (2.21%) from 1039 congenital heart diseases registered were cardiac malpositions: dextroposition--3 cases (13.04%), dextrocardia--7 cases (30.43%) and situs inversus--13 cases (56.52%). Most of the children were boys (65.21%), 70% from all cases coming from urban area. Only 3 children had structural cardiac anomalies: two cases with dextrocardia (one with atrial septal defect and one with atrioventricular canal) and one with situs inversus and tetralogy of Fallot, two of them suffering surgical correction. Psychological impact was the main problem of these children, especially during the adolescence, except the two cases with structural cardiac abnormalities who needed following and surgical treatment.     

Morphologic and clinical correlations in medullar thymoma

The medullar thymoma is a rare and distinctive epithelial thymoma, a thymic tumor characterized histologically by a mixture of spindle epithelial cells and lymphoid cells. We are presenting this tumor to a 68 years old man, admitted at CCI, for a mediastinal tumor, treated by tumorectomy, for revealing the cytological, histological and immunohistochemical characteristic features. The surgical biopsy was prepared by using usual histological techniques and haematoxilin eosin and Van Gieson stainings. We are discussing the relation between the thymoma clinicopathological and prognostic features, resulting a clear correlation between histological type and clinical study. We also pointed the Muller-Hermelink thymoma histological subtypes and their correspondence with OMS histological types, reflecting realistically the thymoma clinical behavior.     

Limitations in the histopathologic diagnosis and prognosis of neuroblastoma

Neuroblastoma is the most common nonhematopoietic solid tumor of childhood and has been intensively studied for at least 4 decades. Despite this, few predictive histopathologic clues to its behavior exist. Ages, anatomic sites of occurrence, histopathology of the tumor and clinical stage have traditionally been the only reliable prognostic factors in this disease. In the present study we analyzed these prognostic factors in 72 neuroblastic tumors and our histopathological possibilities of diagnosis.     

Epidemiologic and clinical aspects of acute hepatitis B in the past decade

To study the clinical and epidemiological aspects of acute B hepatitis during the last 11 years. We retrospectively studied 1712 patient files, admitted in the Department of Infectious Diseases Ia?i, with acute B hepatitis between 1992-2002. The majority of the patients (69%) had an urban origin. Teenagers and young adults were predominantly affected (59% had between 15 and 34 years). A point of entry of the pathogen was identified only in 20% of the patients. The mean incubation period was 4 month. 24% of the patients had a prolonged form of the disease (over 30 days of jaundice). A fulminant evolution was noted in 1.2% of cases. Extrahepatic involvement was described in 25% of the patients. The global mortality was 1.15%. The number of patients with acute B hepatitis decreased by half during the last 11 years.     

Determinants of Outbreak Detection Performance

Objective

To predict the performance of outbreak detection algorithms under different circumstances which will guide the method selection and algorithm configuration in surveillance systems, to characterize the dependence of the performance of detection algorithms on the type and severity of outbreak, to develop quantitative evidence about determinants of detection performance.

Introduction

The choice of outbreak detection algorithm and its configuration can result in important variations in the performance of public health surveillance systems. Our work aims to characterize the performance of detectors based on outbreak types. We are using Bayesian networks (BN) to model the relationships between determinants of outbreak detection and the detection performance based on a significant study on simulated data.

Methods

The simulated surveillance data that we used was generated by Surveillance Lab of McGill University using Simulation Analysis Platform [1] considering surveillance in an urban area to detect waterborne outbreaks due to the failure of a water treatment plant. We focus on predicting the performance of the C-family of algorithms, because they are widely used, state-of-art outbreak detection algorithms [2]. We investigate the influence of algorithm characteristics and outbreak characteristics in determining outbreak detection performance. The C1, C2, and C3 are distinguished by the configuration of 2 parameters,the guardband and memory. Generally, gradually increasing outbreaks can bias the test statistic upward, so the detection algorithm will fail to flag the outbreak. To avoid this situation, the C2 and C3 use a 2-day gap, guardband, between the baseline interval and the test interval. The C3 includes 2 recent observations, called memory, in the computation of the test statistic. The W2 algorithm is a modified version of the C2 which takes weekly patterns of surveillance time series into account [3]. In the W2, the baseline data is stratified to 2 distinct baselines: one for weekdays, the other for weekends. The W3 includes 2 recent observations of each baseline while calculating the test statistic in the corresponding baseline.We ran the C1, C2, C3, W2, and W3 on 18k simulated time series and measured the sensitivity and specificity of detection. Then we created the training data set of 5400000 instances. Each instance was the result of performance evaluation of an outbreak detection algorithm with a specific setting of parameters. In order to investigate the determinants of detection performance and reveal their effects quantitatively, we used BN to predict the performance based on algorithm characteristics and outbreak characteristics.

Results

We developed 2 BN models in the Weka machine learning software [4] using 5-fold cross-validation. The first BN determines the effect of the guardband, memory, alerting threshold, and the weekly pattern indicator (0 for C-algorithms, 1 for W-algorithms) and outbreak characteristics (contamination level and duration) on the sensitivity of detection. The value of sensitivity was mapped to 4 classes: (0, 0.3], (0.3, 0.6], (0.6, 0.9], (0.9, 1]. The developed BN correctly classified 67.74% of instances. The misclassification error was 0.9407. The second BN for predicting the specificity of detection correctly classified 95.895% of instances in 10 classes and the misclassification error was 0.2975.

Conclusions

The contamination level and duration of outbreaks, alerting threshold, memory, guardband, and whether the weekly pattern was considered or not influence the sensitivity and specificity of outbreak detection and given the C-algorithm parameter settings, we can predict outbreak detection performance quantitatively. In future work, we plan to investigate other predictors of performance and study how these predictions can be used in algorithm and policy choices.     

Identification of ginkgolide targets in brain by photoaffinity labeling

Ginkgolides are terpene trilactones in Ginkgo biloba, a popular medicinal herb for memory disorders. Although ginkgolides are known for various neurobiological effects, their macromolecular target in brain is unknown. In this work, we employed benzophenone derivatives of ginkgolides to identify their binding target in brain. Photolabeling of bovine hippocampus homogenates identified a series of α‐tubulin isotypes. Selective photolabeling of α‐tubulin over β‐tubulin, which is equally abundant in brain, suggested that ginkgolides might modulate microtubule biology differently than typical microtubule‐binding agents, such as taxol. In fact, ginkgolide A did not affect microtubule polymerization or cell proliferation; instead, it inhibited detyrosination of α‐tubulin and reorientation of microtubule‐organizing centers. Taken together, the current findings indicate that ginkgolides constitute a new class of microtubule‐binding agents with distinct effects on α‐tubulin biology.