Increased p38 mitogen-activated protein kinase signaling is involved in the oxidative stress associated with oxygen and glucose deprivation in neonatal hippocampal slice cultures

The pathological basis of neonatal hypoxia–ischemia (HI) brain damage is characterized by neuronal cell loss. Oxidative stress is thought to be one of the main causes of HI‐induced neuronal cell death. The p38 mitogen‐activated protein kinase (MAPK) is activated under conditions of cell stress. However, its pathogenic role in regulating the oxidative stress associated with HI injury in the brain is not well understood. Thus, this study was conducted to examine the role of p38 MAPK signaling in neonatal HI brain injury using neonatal rat hippocampal slice cultures exposed to oxygen/glucose deprivation (OGD). Our results indicate that OGD led to a transient increase in p38 MAPK activation that preceded increases in superoxide generation and neuronal death. This increase in neuronal cell death correlated with an increase in the activation of caspase‐3 and the appearance of apoptotic neuronal cells. Pre‐treatment of slice cultures with the p38 MAPK inhibitor, SB203580, or the expression of an antisense p38 MAPK construct only in neuronal cells, through a Synapsin I‐1‐driven adeno‐associated virus vector, inhibited p38 MAPK activity and exerted a neuroprotective effect as demonstrated by decreases in OGD‐mediated oxidative stress, caspase activation and neuronal cell death. Thus, we conclude that the activation of p38 MAPK in neuronal cells plays a key role in the oxidative stress and neuronal cell death associated with OGD.     

"The family is the clinic, the community is the hospital": community mental health in Timor-Leste

OBJECTIVE: This paper describes the history and recent development of mental health services in Timor-Leste, a small developing country recovering from conflict. Challenges to effective service delivery are discussed as well as plans for future development. CONCLUSIONS: Timor-Leste's mental health service began just over a decade ago. Unlike many other low and middle income countries where hospital-based services predominate, the mental health model in Timor-Leste is entirely community based. However, challenges to effective mental health care delivery are similar to most developing countries and include a lack of sufficient financial resources, human resources, and mental health infrastructure. Addressing these issues successfully requires political will, a greater prioritization of mental health services, close coordination between stakeholders, as well as developments in the area of education, training and infrastructure. Greater understanding and education about the links between mental and physical health would benefit the overall health of the population, and integration of these respective policies may prove a successful method of more equitably redistributing finances and resources.     

Uremic toxin indoxyl sulfate inhibits human vascular smooth muscle cell proliferation

Uremic syndrome is attributed to the progressive retention of a large number of compounds, such as indoxyl sulfate, which under physiological conditions are excreted by the kidneys. Previous in vitro studies have demonstrated that uremic indoxyl sulfate concentrations induce a weak increase in the proliferation of both rat and human vascular aortic smooth muscle cells (hVASMC) after short term exposition to the toxin (i.e. 24 h). In the present study, we evaluated indoxyl sulfate effects on the proliferation of hVASMC at three different concentrations after long-term exposure (seven days). In contrast to previously published studies, we observed a dose-dependent and significant inhibitory effect of this toxin on hVASMC proliferation. We also demonstrated that indoxyl sulfate inhibits epidermal growth factor-induced hVASMC proliferation after long-term exposure. Indoxyl sulfate effects were associated with a dose-dependent induction of intracellular reactive oxygen species and up-regulation of p21 and p27 protein expression. Chronic exposure to indoxyl sulfate produces a significant inhibitory effect on hVASMC proliferation. The relevance of these findings must be evaluated by further studies, particularly in an in vivo setting.     

Prognostic relevance of preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 in a multicenter subset analysis of 179 patients with distal cholangiocarcinoma

BackgroundDistal cholangiocarcinoma (DCC) is a rare malignancy and validated prognostic markers remain scarce. We aimed to evaluate the role of serum CA19-9 as a potential biomarker in DCC.MethodsPatients operated for DCC at 6 high-volume surgical centers from 1994 to 2015 were identified from prospectively maintained databases. Patient baseline characteristics, surgical and histopathological parameters, as well as overall survival after resection were assessed for correlation with preoperative bilirubin-adjusted serum carbohydrate antigen 19-9 (CA19-9). Preoperative CA19-9 to bilirubin ratio (CA19-9/BR) was classified as elevated (≥ 25 U/ml/mg/dl) according to the upper serum normal values of CA19-9 (37 U/ml) and bilirubin (1.5 mg/dl) giving a cut-off at ≥ 25 U/ml/mg/dl.ResultsIn total 179 patients underwent resection for DCC during the study period. High preoperative CA19-9/BR was associated with advanced age and regional lymph node metastases. Median overall survival after resection was 27 months. Elevated preoperative serum CA19-9/bilirubin ratio (HR 1.6, p = 0.025), T3/4 stage (HR 1.8, p = 0.022), distant metastasis (HR 2.5, p = 0.007), tumor grade (HR 1.9, p = 0.001) and R status (HR 1.7, p = 0.023) were identified as independent negative prognostic factors following multivariable analysis.ConclusionElevated preoperative bilirubin-adjusted serum CA19-9 correlates with regional lymph node metastases and constitutes a negative independent prognostic factor after resection of DCC.     

Preferred use of polyhexanide in orthopedic surgery

In orthopedic and trauma surgery, the most frequently used antiseptic is polyhexanide. Its favored application is based on prepossessing tissue compatibility in contrast to various antiseptics and a high antimicrobiological effect. Recent studies showed toxic effects of this antiseptic on human chondrocytes. The aim of this study was to further analyze the toxic and apoptotic effects of polyhexanide on primary human chondrocytes. The hypothesis of this study was that polyhexanide induces apoptosis on human chondrocytes. Primary human chondrocytes were isolated and cultured from human donors with osteoarthritis of the knee who underwent total arthroplasty and had no indication of infection. Polyhexanide at a standard concentration of 0.04% was added to the monolayer cultures. Early and late apoptotic cells were analyzed by flow cytometric detection of annexin V, active caspases, and 7AAD, and by fluorescence microscopy using annexin V and propidium iodide staining. Flow cytometric analysis demonstrated an increase of annexin V and active caspases expression of human chondrocytes after incubation with polyhexanide. Fluorescence microscopy demonstrated a high number of annexin V positive and propidium iodide negative early apoptotic cells. The data show that polyhexanide promotes apoptosis on primary human chondrocytes in vitro, which may indicate the use of polyhexanide in septic joint surgery.