A longitudinal and cross-sectional study of plasma neurofilament light chain concentration in Charcot-Marie-Tooth disease

Advances in genetic technology and small molecule drug development have paved the way for clinical trials in Charcot-Marie-Tooth disease (CMT); however, the current FDA-approved clinical trial outcome measures are insensitive to detect a meaningful clinical response. There is, therefore, a need to identify sensitive outcome measures or clinically relevant biomarkers. The aim of this study was to further evaluate plasma neurofilament light chain (NFL) as a disease biomarker in CMT. Plasma NFL was measured using SIMOA technology in both a cross-sectional study of a US cohort of CMT patients and longitudinally over 6 years in a UK CMT cohort. In addition, plasma NFL was measured longitudinally in two mouse models of CMT2D. Plasma concentrations of NFL were increased in a US cohort of patients with CMT1B, CMT1X and CMT2A but not CMT2E compared with controls. In a separate UK cohort, over a 6-year interval, there was no significant change in plasma NFL concentration in CMT1A or HSN1, but a small but significant reduction in patients with CMT1X. Plasma NFL was increased in wild type compared to GARSC201R mice. There was no significant difference in plasma NFL in GARSP278KY compared to wild type mice. In patients with CMT1A, the small difference in cross-sectional NFL concentration vs healthy controls and the lack of change over time suggests that plasma NFL may lack sufficient sensitivity to detect a clinically meaningful treatment response in adulthood

Risk of venous thromboembolism after total hip and knee replacement in older adults with comorbidity and co-occurring comorbidities in the Nationwide Inpatient Sample (2003-2006)

<p>Abstract</p> <p>Background</p> <p>Venous thromboembolism is a common, fatal, and costly injury which complicates major surgery in older adults. The American College of Chest Physicians recommends high potency prophylaxis regimens for individuals undergoing total hip or knee replacement (THR or TKR), but surgeons are reluctant to prescribe them due to fear of excess bleeding. Identifying a high risk cohort such as older adults with comorbidities and co-occurring comorbidities who might benefit most from high potency prophylaxis would improve how we currently perform preoperative assessment.</p> <p>Methods</p> <p>Using the Nationwide Inpatient Sample, we identified older adults who underwent THR or TKR in the U.S. between 2003 and 2006. Our outcome was VTE, including any pulmonary embolus or deep venous thrombosis. We performed multivariate logistic regression analyses to assess the effects of comorbidities on VTE occurrence. Comorbidities under consideration included coronary artery disease, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), diabetes, and cerebrovascular disease. We also examined the impact of co-occurring comorbidities on VTE rates.</p> <p>Results</p> <p>CHF increased odds of VTE in both the THR cohort (OR = 3.08 95% CI 2.05-4.65) and TKR cohort (OR = 2.47 95% CI 1.95-3.14). COPD led to a 50% increase in odds in the TKR cohort (OR = 1.49 95% CI 1.31-1.70). The data did not support synergistic effect of co-occurring comorbidities with respect to VTE occurrence.</p> <p>Conclusions</p> <p>Older adults with CHF undergoing THR or TKR and with COPD undergoing TKR are at increased risk of VTE. If confirmed in other datasets, these older adults may benefit from higher potency prophylaxis.</p

Larvicidal, antimicrobial and brine shrimp activities of extracts from Cissampelos mucronata and Tephrosia villosa from coast region, Tanzania

<p>Abstract</p> <p>Background</p> <p>The leaves and roots of <it>Cissampelos mucronata </it>A. Rich (Menispermaceae) are widely used in the tropics and subtropics to manage various ailments such as gastro-intestinal complaints, menstrual problems, venereal diseases and malaria. In the Coast region, Tanzania, roots are used to treat wounds due to extraction of jigger. Leaves of <it>Tephrosia villosa </it>(L) Pers (Leguminosae) are reported to be used in the treatment of diabetes mellitus in India. In this study, extracts from the roots and aerial parts of <it>C. mucronata </it>and extracts from leaves, fruits, twigs and roots of <it>T. villosa </it>were evaluated for larvicidal activity, brine shrimps toxicity and antimicrobial activity.</p> <p>Methods</p> <p>Powdered materials from <it>C. mucronata </it>were extracted sequentially by dichloromethane followed by ethanol while materials from <it>T.villosa </it>were extracted by ethanol only. The extracts obtained were evaluated for larvicidal activity using <it>Culex quinquefasciatus </it>Say larvae, cytotoxicity using brine shrimp larvae and antimicrobial activity using bacteria and fungi.</p> <p>Results</p> <p>Extracts from aerial parts of <it>C. Mucronata </it>exhibited antibacterial activity against <it>Staphylococcus aureus</it>, <it>Escherichia coli</it>, <it>Pseudomonas aeruginosa</it>, <it>Salmonella typhi</it>, <it>Vibrio cholera</it>, <it>Bacillus anthracis</it>, <it>Streptococcus faecalis </it>and antifungal activity against <it>Candida albicans </it>and <it>Cryptococcus neoformans</it>. They exhibited very low toxicity to brine shrimps and had no larvicidal activity. The root extracts exhibited good larvicidal activity but weak antimicrobial activity. The root dichloromethane extracts from <it>C. mucronata </it>was found to be more toxic with an LC₅₀value of 59.608 μg/mL while ethanolic extracts from root were not toxic with LC₅₀>100 μg/mL). Ethanol extracts from fruits and roots of <it>T. villosa </it>were found to be very toxic with LC₅₀values of 9.690 μg/mL and 4.511 μg/mL, respectively, while, ethanol extracts from leaves and twigs of <it>T. villosa </it>were found to be non toxic (LC₅₀>100 μg/mL).</p> <p>Conclusion</p> <p>These results support the use of <it>C. mucronata </it>in traditional medicine for treatment of wounds. Extracts of <it>C. mucronata </it>have potential to yield active antimicrobial and larvicidal compounds. The high brine shrimp toxicity of <it>T. villosa </it>corroborates with literature reports that the plant is toxic to both livestock and fish. The results further suggest that <it>T. villosa </it>extracts have potential to yield larvicidal and possibly cytotoxic compounds. Further studies to investigate the bioactive compounds responsible for the observed biological effects are suggested.</p

Hypericin and pseudohypericin concentrations of a valuable medicinal plant Hypericum perforatum L. are enhanced by arbuscular mycorrhizal fungi

Hypericum perforatum L. (St. John’s-wort, Hypericaceae) is a valuable medicinal plant species cultivated for pharmaceutical purposes. Although the chemical composition and pharmacological activities of H. perforatum have been well studied, no data are available concerning the influence of arbuscular mycorrhizal fungi (AMF) on this important herb. A laboratory experiment was therefore conducted in order to test three AMF inocula on H. perforatum with a view to show whether AMF could influence plant vitality (biomass and photosynthetic activity) and the production of the most valuable secondary metabolites, namely anthraquinone derivatives (hypericin and pseudohypericin) as well as the prenylated phloroglucinol—hyperforin. The following treatments were prepared: (1) control—sterile soil without AMF inoculation, (2) Rhizophagus intraradices (syn. Glomus intraradices), (3) Funneliformis mosseae (syn. Glomus mosseae), and (4) an AMF Mix which contained: Funneliformis constrictum (syn. Glomus constrictum), Funneliformis geosporum (syn. Glomus geosporum), F. mosseae, and R. intraradices. The application of R. intraradices inoculum resulted in the highest mycorrhizal colonization, whereas the lowest values of mycorrhizal parameters were detected in the AMF Mix. There were no statistically significant differences in H. perforatum shoot mass in any of the treatments. However, we found AMF species specificity in the stimulation of H. perforatum photosynthetic activity and the production of secondary metabolites. Inoculation with the AMF Mix resulted in higher photosynthetic performance index (PItotal) values in comparison to all the other treatments. The plants inoculated with R. intraradices and the AMF Mix were characterized by a higher concentration of hypericin and pseudohypericin in the shoots. However, no differences in the content of these metabolites were detected after the application of F. mosseae. In the case of hyperforin, no significant differences were found between the control plants and those inoculated with any of the AMF applied. The enhanced content of anthraquinone derivatives and, at the same time, better plant vitality suggest that the improved production of these metabolites was a result of the positive effect of the applied AMF strains on H. perforatum. This could be due to improved mineral nutrition or to AMF-induced changes in the phytohormonal balance. Our results are promising from the biotechnological point of view, i.e. the future inoculation of H. perforatum with AMF in order to improve the quality of medicinal plant raw material obtained from cultivation

Amplification of asynchronous inhibition-mediated synchronization by feedback in recurrent networks

Synchronization of 30-80 Hz oscillatory activity of the principle neurons in the olfactory bulb (mitral cells) is believed to be important for odor discrimination. Previous theoretical studies of these fast rhythms in other brain areas have proposed that principle neuron synchrony can be mediated by short-latency, rapidly decaying inhibition. This phasic inhibition provides a narrow time window for the principle neurons to fire, thus promoting synchrony. However, in the olfactory bulb, the inhibitory granule cells produce long lasting, small amplitude, asynchronous and aperiodic inhibitory input and thus the narrow time window that is required to synchronize spiking does not exist. Instead, it has been suggested that correlated output of the granule cells could serve to synchronize uncoupled mitral cells through a mechanism called "stochastic synchronization", wherein the synchronization arises through correlation of inputs to two neural oscillators. Almost all work on synchrony due to correlations presumes that the correlation is imposed and fixed. Building on theory and experiments that we and others have developed, we show that increased synchrony in the mitral cells could produce an increase in granule cell activity for those granule cells that share a synchronous group of mitral cells. Common granule cell input increases the input correlation to the mitral cells and hence their synchrony by providing a positive feedback loop in correlation. Thus we demonstrate the emergence and temporal evolution of input correlation in recurrent networks with feedback. We explore several theoretical models of this idea, ranging from spiking models to an analytically tractable model. © 2010 Marella, Ermentrout

Candidates in Astroviruses, Seadornaviruses, Cytorhabdoviruses and Coronaviruses for +1 frame overlapping genes accessed by leaky scanning

<p>Abstract</p> <p>Background</p> <p>Overlapping genes are common in RNA viruses where they serve as a mechanism to optimize the coding potential of compact genomes. However, annotation of overlapping genes can be difficult using conventional gene-finding software. Recently we have been using a number of complementary approaches to systematically identify previously undetected overlapping genes in RNA virus genomes. In this article we gather together a number of promising candidate new overlapping genes that may be of interest to the community.</p> <p>Results</p> <p>Overlapping gene predictions are presented for the astroviruses, seadornaviruses, cytorhabdoviruses and coronaviruses (families <it>Astroviridae</it>, <it>Reoviridae</it>, <it>Rhabdoviridae </it>and <it>Coronaviridae</it>, respectively).</p

Tourism Partnerships in Protected Areas: Exploring Contributions to Sustainability

Partnerships between natural-area managers and the tourism industry have been suggested to contribute to sustainability in protected areas. This article explores how important sustainability outcomes of partnerships are to their members, how well they are realised and the features of partnerships leading to their achievement. In 21 case studies in Australia, interviews (n = 97) and surveys (n = 100) showed that of 14 sustainability outcomes, improved understanding of protected areas values and improved biodiversity conservation were the most important. Other highly ranked outcomes were greater respect for culture, heritage, and/or traditions; improved quality of environmental conditions; social benefits to local communities; and improved economic viability of the protected area. Scores for satisfaction with outcomes were, like those for importance, all high but were less than those for importance for the majority, with improvement in quality of environmental conditions showing the largest gap. The satisfaction score exceeded that for importance only for increased competitiveness of the protected area as a tourist destination. “Brown” aspects of sustainability, i.e., decreased waste or energy use, were among the lowest-scoring outcomes for both importance and satisfaction. The most important factor enabling sustainability outcomes was provision of benefits to partnership members. Others were increased financial support, inclusiveness, supportive organisational and administrative arrangements, direct involvement of decision makers, partnership maturity, creation of new relationships, decreased conflict, and stimulation of innovation. Improving sustainability outcomes, therefore, requires maintaining these partnership attributes and also increasing emphasis on reducing waste and resource use

Administration of Thimerosal to Infant Rats Increases Overflow of Glutamate and Aspartate in the Prefrontal Cortex: Protective Role of Dehydroepiandrosterone Sulfate

Thimerosal, a mercury-containing vaccine preservative, is a suspected factor in the etiology of neurodevelopmental disorders. We previously showed that its administration to infant rats causes behavioral, neurochemical and neuropathological abnormalities similar to those present in autism. Here we examined, using microdialysis, the effect of thimerosal on extracellular levels of neuroactive amino acids in the rat prefrontal cortex (PFC). Thimerosal administration (4 injections, i.m., 240 μg Hg/kg on postnatal days 7, 9, 11, 15) induced lasting changes in amino acid overflow: an increase of glutamate and aspartate accompanied by a decrease of glycine and alanine; measured 10–14 weeks after the injections. Four injections of thimerosal at a dose of 12.5 μg Hg/kg did not alter glutamate and aspartate concentrations at microdialysis time (but based on thimerosal pharmacokinetics, could have been effective soon after its injection). Application of thimerosal to the PFC in perfusion fluid evoked a rapid increase of glutamate overflow. Coadministration of the neurosteroid, dehydroepiandrosterone sulfate (DHEAS; 80 mg/kg; i.p.) prevented the thimerosal effect on glutamate and aspartate; the steroid alone had no influence on these amino acids. Coapplication of DHEAS with thimerosal in perfusion fluid also blocked the acute action of thimerosal on glutamate. In contrast, DHEAS alone reduced overflow of glycine and alanine, somewhat potentiating the thimerosal effect on these amino acids. Since excessive accumulation of extracellular glutamate is linked with excitotoxicity, our data imply that neonatal exposure to thimerosal-containing vaccines might induce excitotoxic brain injuries, leading to neurodevelopmental disorders. DHEAS may partially protect against mercurials-induced neurotoxicity