Potential Metabolite Biomarkers of Multiple Sclerosis from Multiple Biofluids.

Multiple sclerosis (MS) is a chronic and progressive neurological disorder without a cure, but early intervention can slow disease progression and improve the quality of life for MS patients. Obtaining an accurate diagnosis for MS is an arduous and error-prone task that requires a combination of a detailed medical history, a comprehensive neurological exam, clinical tests such as magnetic resonance imaging, and the exclusion of other possible diseases. A simple and definitive biofluid test for MS does not exist, but is highly desirable. To address this need, we employed NMR-based metabolomics to identify potentially unique metabolite biomarkers of MS from a cohort of age and sex-matched samples of cerebrospinal fluid (CSF), serum, and urine from 206 progressive MS (PMS) patients, 46 relapsing-remitting MS (RRMS) patients, and 99 healthy volunteers without a MS diagnosis. We identified 32 metabolites in CSF that varied between the control and PMS patients. Utilizing patient-matched serum samples, we were able to further identify 31 serum metabolites that may serve as biomarkers for PMS patients. Lastly, we identified 14 urine metabolites associated with PMS. All potential biomarkers are associated with metabolic processes linked to the pathology of MS, such as demyelination and neuronal damage. Four metabolites with identical profiles across all three biofluids were discovered, which demonstrate their potential value as cross-biofluid markers of PMS. We further present a case for using metabolic profiles from PMS patients to delineate biomarkers of RRMS. Specifically, three metabolites exhibited a variation from healthy volunteers without MS through RRMS and PMS patients. The consistency of metabolite changes across multiple biofluids, combined with the reliability of a receiver operating characteristic classification, may provide a rapid diagnostic test for MS.

Interferons in the Treatment of Multiple Sclerosis: A Clinical Efficacy, Safety, and Tolerability Update.

Interferon beta (IFNß) was the first disease-modifying therapy available to treat multiple sclerosis (MS), providing patients with a treatment that resulted in reduced relapse rates and delays in the onset of disability. Four IFNß drugs are currently approved to treat relapsing forms of MS: subcutaneous (SC) IFNß-1b, SC IFNß-1a, intramuscular IFNß-1a, and, most recently, SC peginterferon beta-1a. Peginterferon beta-1a has an extended half-life and requires less frequent administration than other available treatments (once every 2 weeks vs every other day, 3 times per week, or weekly). Large randomized controlled clinical trials have confirmed the efficacy of interferons for the treatment of relapsing MS. The most frequent adverse events in patients receiving IFNs include injection site reactions and flu-like symptoms. Patient education and mitigation strategies are key to managing these adverse events and supporting therapy adherence. With fewer injections needed, peginterferon beta-1a is associated with less frequent discomfort, which may translate to improved adherence, a major factor in treatment efficacy. Because the available interferon therapies differ in administration route and frequency of injection, switching among these therapies may be a viable option for patients who experience issues with tolerability. Although a variety of disease-modifying therapies are now available to treat relapsing MS, the efficacy and long-term safety profile of interferons make them an important first-line option for treatment.

Distribution of cancer mortality rates by province in South Africa.

INTRODUCTION: Cancer mortality rates are expected to increase in developing countries. Cancer mortality rates by province remain largely unreported in South Africa. This study described the 2014 age standardised cancer mortality rates by province in South Africa, to provide insight for strategic interventions and advocacy. METHODS: 2014 deaths data were retrieved from Statistics South Africa. Deaths from cancer were extracted using 10th International Classification of Diseases (ICD) codes for cancer (C00-C97). Adjusted 2013 mid-year population estimates were used as a standard population. All rates were calculated per 100 000 individuals. RESULTS: Nearly 38 000 (8%) of the total deaths in South Africa in 2014 were attributed to cancer. Western Cape Province had the highest age standardised cancer mortality rate in South Africa (118, 95% CI: 115-121 deaths per 100 000 individuals), followed by the Northern Cape (113, 95% CI: 107-119 per 100 000 individuals), with the lowest rate in Limpopo Province (47, 95% CI: 45-49 per 100 000). The age standardised cancer mortality rate for men (71, 95% CI: 70-72 per 100 000 individuals) was similar to women (69, 95% CI: 68-70 per 100 000). Lung cancer was a major driver of cancer death in men (13, 95% CI: 12.6-13.4 per 100 000). In women, cervical cancer was the leading cause of cancer death (13, 95% CI: 12.6-13.4 per 100 000 individuals). CONCLUSION: There is a need to further investigate the factors related to the differences in cancer mortality by province in South Africa. Raising awareness of risk factors and screening for cancer in the population along with improved access and quality of health care are also important.

The role of PERK and GCN2 in basal and hydrogen peroxide-regulated translation from the hepatitis C virus internal ribosome entry site.

We have previously shown that translation from the HCV IRES is up-regulated by patho/physiological doses of H(2)O(2) but is still sensitive to the inhibitory effect of phospho-eIF2α in hepatocytes. In this study using wild type and 'knockout' mouse embryonic fibroblasts (MEFs), we showed that two of the eIF2α kinases, PERK and GCN2, were not responsible for translational regulation under physiological and a higher apoptotic doses of H(2)O(2) (100 µM). However, a differential translational response was observed at a lower apoptotic dose of H(2)O(2) (50 µM) between Perk+/+ and Perk-/- MEFs but not that between Gcn2+/+ and Gcn2-/- MEFs, suggesting that PERK may play a role in translational up-regulation under oxidative stress. Our results also suggest that PERK mediates such an effect via an eIF2-independent pathway. This is in contrast to the canonical role of PERK on translational inhibition under stress conditions via phosphorylation of eIF2α. When tested for the role of PERK and GCN2 on basal translation from the HCV IRES under non-stressed condition, we found that basal translation from the HCV IRES was also favoured in the presence of PERK or GCN2 in MEFs over that of cap-dependent translation and was favoured in the presence of GCN2 but not PERK in Huh-7 cells. These results suggest that PERK and GCN2 also have a functional role on regulating translation under non-stressed conditions, apart from their long established roles as stress kinases.

Cap-dependent and hepatitis C virus internal ribosome entry site-mediated translation are modulated by phosphorylation of eIF2alpha under oxidative stress.

Chronic hepatitis C is often associated with oxidative stress. Hepatitis C virus (HCV) utilizes an internal ribosome entry site (IRES) element for translation, in contrast to cap-dependent translation of the majority of cellular proteins. To understand how virus translation is modulated under oxidative stress, HCV IRES-mediated translation was compared with cap-dependent translation using a bicistronic reporter construct and hydrogen peroxide (H2O2) as a stress inducer. In H2O2-sensitive HeLa cells, H2O2 repressed translation in a time- and dose-dependent manner, concomitant with the kinetics of eIF2alpha phosphorylation. A phosphomimetic of eIF2alpha, which mimics the structure of the phosphorylated eIF2alpha, was sufficient to repress translation in the absence of H2O2. In H2O2-resistant HepG2 cells, H2O2 activated both HCV IRES-mediated and cap-dependent translation, associated with an increased level of phospho-eIF2alpha. It was postulated that H2O2 might stimulate translation in HepG2 cells via an eIF2alpha-independent mechanism, whereas the simultaneous phosphorylation of eIF2alpha repressed part of the translational activities. Indeed, the translational repression was released in the presence of a non-phosphorylatable mutant, eIF2alpha-SA, resulting in further enhancement of both translational activities after exposure to H2O2. In HuH7 cells, which exhibited an intermediate level of sensitivity towards H2O2, both HCV IRES-mediated and cap-dependent translational activities were upregulated after treatment with various doses of H2O2, but the highest level of induction was achieved with a low level of H2O2, which may represent the physiological level of H2O2. At this level, the HCV IRES-mediated translation was preferentially upregulated compared with cap-dependent translation.

Synthesis and pharmacology of willardiine derivatives acting as antagonists of kainate receptors.

The natural product willardiine (8) is an AMPA receptor agonist while 5-iodowillardiine (10) is a selective kainate receptor agonist. In an attempt to produce antagonists of kainate and AMPA receptors analogues of willardiine with substituents at the N3 position of the uracil ring were synthesized. The N3-4-carboxybenzyl substituted analogue (38c) was found to be equipotent at AMPA and GLUK5-containing kainate receptors in the neonatal rat spinal cord. The N3-2-carboxybenzyl substituted analogue (38a) proved to be a potent and selective GLUK5 subunit containing kainate receptor antagonist when tested on native rat and human recombinant AMPA and kainate receptor subtypes. The GLUK5 kainate receptor antagonist activity was found to reside in the S enantiomer (44a) whereas the R enantiomer (44b) was almost inactive. 5-Iodo substitution of the uracil ring of 44a gave 45, which was found to have enhanced potency and selectivity for GLUK5.