Peroxynitrite Inhibits Glutamate Transporter Subtypes

The reuptake of glutamate in neurons and astrocytes terminates excitatory signals and prevents the persistence of excitotoxic levels of glutamate in the synaptic cleft. This process is inhibited by oxygen radicals and hydrogen peroxide (H2O2). Here we show that another biological oxidant, peroxynitrite (ONOO-), formed by combination of superoxide (O2-) and nitric oxide (NO), potently inhibits glutamate uptake by purified or recombinant high affinity glutamate transporters reconstituted in liposomes. ONOO- reduces selectively the Vmax of transport; its action is fast (reachingor = 90% within 20 s), dose-dependent (50% inhibition at 50 microM), persistent upon ONOO- (or by product) removal, and insensitive to the presence of the lipid antioxidant vitamin E in the liposomal membranes. Therefore, it likely depends on direct interaction of ONOO- with the glutamate transporters. Three distinct recombinant glutamate transporters from the rat brain, GLT1, GLAST, and EAAC1, exhibit identical sensitivity to ONOO . H2O2 also inhibits reconstituted transport, and its action matches that of ONOO- on all respects; however, this is observed only with 5-10 mM H202 and after prolonged exposure (10 min) in highly oxygenated buffer. NO, released from NO donors (up to 10 mM), does not modify reconstituted glutamate uptake, although in parallel conditions it promotes cGMP formation in synaptosomal cytosolic fraction. Overall, our results suggest that the glutamate transporters contain conserved sites in their structures conferring vulnerability to ONOO- and other oxidants

Facing erythrocytosis: Results of an international physician survey.

We observed a good agreement among hematologists regarding the diagnostic procedures and a widespread awareness regarding the importance of the new 2016 WHO criteria and bone marrow his-tology. On the other side, we observed a marked heterogeneity in treatment practice, regarding both the Hct threshold and the use of anti-platelet agents

The politics of impunity: a study of journalists’ experiential accounts of impunity in Bulgaria, Democratic Republic of Congo, India, Mexico and Pakistan

Definitions of impunity regarding crimes against journalists have thus far been too narrow. Therefore we propose a new approach to understanding impunity as also being grounded in journalists’ lived reality and perceptions to better understand the complexity and breadth of impunity. It is based on the findings obtained through a set of semi-structured interviews with 40 editors and senior journalists in five countries and expressed in a new typology of impunity. We argue that what we call the ‘Politics of Impunity’ is a policy of governance whereby impunity is used as a political tool by the state and state-sponsored actors to achieve journalistic self-censorship. This is done through the deliberate deprivation of private autonomy brought about by the enforced exile of journalists into a ‘space of exception’ where they are both within and beyond the law. The exercise of the ‘Politics of Impunity’ in an increasing number of states creates an environment that only allows for politically compliant journalism

Save the children program : an analysis of client reaction

Prison programs to deter juveniles from crime received national attention during 1980 with the release of Scared Straight, a documentary film portraying Rahway State Prison's Juvenile Awareness Project Help. "Save the Children," an inmate-administered project operating at Central Correctional Institution, has survived the scared straight controversy and continues to function, serving primarily clients of the South Carolina Department of Youth Services. The Department of Youth Services developed the "Save the Children" questionnaire. This report which is an analysis of responses to all questionnaires

A study of revocations to the Department of Youth Services, March 16, 1978 - March 15, 1979

This study resulted from a request by the agency’s director that the Research and Evaluation Unit investigate certain factors associated with revocations to the Department of Youth Services. Administrative concern focused on the seemingly large proportion of revocations deriving from status/placement-type problems rather than criminal violations and their effect on the size of the institutional population. A study proposal was developed which designated for analysis the pertinent variables of reason for revocation, complete history of offenses/violations resulting in commitment, and length of revocation stay. In order to document with detail recent instances of children being returned to the Agency because of inadequate placement, a section presenting four case studies was appended to the statistical analysis. A full discussion of the methodology employed in the study followed

Health-related quality of life and late morbidity in concurrent chemoradiation and radiotherapy alone in patients with locally advanced cervical carcinoma

Objective: Concurrent chemoradiation has improved survival of patients with cervical carcinoma. However, follow-up of randomized studies is relatively short and data on long term toxicity are scarce, as is information on their health-related quality of life. This study assesses and compares incidences of late side-effects among patients treated with radiotherapy or chemoradiation using two toxicity scoring systems, and investigates impact on health-related quality of life. Methods: Between 1985 and 1993, 114 patients underwent radiotherapy (n=39) or chemoradiation (n=75) for stage IIA-IVB cervical carcinoma. Late side-effects were scored retrospectively by reviewing medical charts using standardised checklists, focusing on bladder- and intestinal side effects. Health-related quality of life was assessed once using the EORTC QLQ-C30. Results: No significant differences in late treatment-related side-effects between radiotherapy and chemoradiation groups were found. Grade >= 2 toxicity was found in 33% (bladder), and in 6% (bowel). Only 1.8% had both grade 3-4 toxicity. Bladder syndrome with high urinary frequency, urine incontinence and small bowel toxicity had a significant impact on health-related quality of life. Conclusion: Grade 2 are relatively frequent late side effects in curatively treated patients, but are not enhanced by the addition of chemotherapy. Their negative impact on health-related quality of life stresses the importance of new radiation techniques, aiming at reduction of these side effects

Definition of Healthy Ranges for Alanine Aminotransferase Levels: A 2021 Update

The changing epidemiology of liver disease, and modifications in the recommended analytical methodology call for a re-evaluation of the upper reference limits (URLs) of alanine aminotransferase (ALT) levels. Using the same ap- proach consolidated 20 years ago to define the healthy population, we defined the URL for the newly recommended International Federation of Clinical Chemistry (IFCC) standardized test. In a cross-sectional study, we examined 21,296 apparently healthy blood donors (age 18-65 years) and calculated the sex-specific URL by the 95th percentile in indi- viduals without risk factors for liver disease. These were tested for the ability to predict liver damage in a subset of 745 participants with dysmetabolism, in an independent cohort of 977 unselected donors, and in 899 patients with chronic liver disease. ALT levels were measured by the IFCC test. Male sex, body mass index, glucose, lipids, ferritin, hyper- tension, and younger age were independent ALT predictors (P < 0.001). Updated URLs were identified at 42/30 U/L in males/females, approximately 30% lower than those currently recommended by the IFCC. Due to improved sensitiv- ity, they conferred the ability to detect steatosis and significant fibrosis in individuals with dysmetabolism (odds ratio [OR] = 2.31, range 1.40-3.80, P = 0.001; and OR = 3.35, range 1.19-9.42, P = 0.021; respectively), although with a limited accuracy, and significant fibrosis in unselected donors (OR = 2.32, 1.02-5.31, P = 0.045). Updated URLs had a moderate to high accuracy to discriminate liver conditions (area under the receiver operating characteristic curve = 0.81, range 0.78-0.91). Conclusion: Updated URLs by the IFCC method were lower than those calculated in initial studies, but higher than those in use with the recommended old, nonstandardized method, and were able to better predict liver disease. The limited awareness that different techniques are still in use should be regarded as a possible source of medical errors