Development of a best practice statement on the use of ankle-foot orthoses following stroke in Scotland

A National Health Service Quality Improvement Scotland (NHS QIS) scoping exercise in 2007 identified the use of ankle-foot orthoses (AFOs) following stroke as a clinical improvement priority, leading to the development of a best practice statement (BPS) on AFO use after stroke. This paper outlines the development process of the BPS which is available from NHS QIS. The authors were involved in the development of the BPS as part of a working group that included practitioners from the fields of orthotics, physiotherapy, stroke nursing and bioengineering, and staff of NHS QIS and a patient representative. In consultation with an NHS QIS health services researcher, the authors undertook a systematic literature review to evidence where possible the recommendations made in the BPS. Where evidence was unavailable, consensus was reached by the expert working group. As the BPS was designed for the non-specialist and non-orthotic practitioner the authors also developed educational resources which were included within the BPS to aid the understanding of the principles underpinning orthotic design and prescription. The BPS has been widely distributed throughout the health service in Scotland and is available electronically at no cost via the NHS QIS website. At part of an ongoing evaluation of the impact of the BPS on the quality of orthotic provision, NHS QIS has invited feedback regarding successes and challenges to implementation

The substrate lends a hand

Duramycin is a small post-translationally modified peptide with antibody-like affinity for phosphatidylethanolamine. As it turns out, the same functionality that is essential for duramycin activity helps to catalyze the formation of its conformationally constrained and compact polycyclic architecture

Methylating mushrooms

Peptide N-methylation is an important strategy used by medicinal chemists to improve cell permeability, oral bioavailability, and target affinity of peptide-based inhibitors. Correspondingly, N-methyl amides appear extensively in bioactive natural products. In the case of the immunosuppressant cyclosporine, for example, specific N-methylation of seven out of ten backbone amide nitrogens in the cyclic decapeptide is thought to allow a conformational ‘shapeshifting’ that hides polar N–H moieties and facilitates passive diffusion across cell membranes. Until now, N-methylation has primarily been the mark of peptide natural products from complex nonribosomal peptide synthetase (NRPS) assembly lines, and has not previously been found among their cousins, the ribosomally synthesized and post-translationally modified peptide (RiPP) natural products. In this issue, van der Velden et al. uncover the biosynthetic origins of the omphalotins, peptide natural products from the bioluminescent fungus O. olearius (Fig. 1a), and bring peptide backbone N-methylation into the realm of peptide post-translational modifications

Conserved Role of unc-79 in Ethanol Responses in Lightweight Mutant Mice

The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans

Community Analysis of Chronic Wound Bacteria Using 16S rRNA Gene-Based Pyrosequencing: Impact of Diabetes and Antibiotics on Chronic Wound Microbiota

Background: Bacterial colonization is hypothesized to play a pathogenic role in the non-healing state of chronic wounds. We characterized wound bacteria from a cohort of chronic wound patients using a 16S rRNA gene-based pyrosequencing approach and assessed the impact of diabetes and antibiotics on chronic wound microbiota. Methodology/Principal Findings: We prospectively enrolled 24 patients at a referral wound center in Baltimore, MD; sampled patients' wounds by curette; cultured samples under aerobic and anaerobic conditions; and pyrosequenced the 16S rRNA V3 hypervariable region. The 16S rRNA gene-based analyses revealed an average of 10 different bacterial families in wounds-approximately 4 times more than estimated by culture-based analyses. Fastidious anaerobic bacteria belonging to the Clostridiales family XI were among the most prevalent bacteria identified exclusively by 16S rRNA gene-based analyses. Community-scale analyses showed that wound microbiota from antibiotic treated patients were significantly different from untreated patients (p = 0.007) and were characterized by increased Pseudomonadaceae abundance. These analyses also revealed that antibiotic use was associated with decreased Streptococcaceae among diabetics and that Streptococcaceae was more abundant among diabetics as compared to non-diabetics. Conclusions/Significance: The 16S rRNA gene-based analyses revealed complex bacterial communities including anaerobic bacteria that may play causative roles in the non-healing state of some chronic wounds. Our data suggest that antimicrobial therapy alters community structure-reducing some bacteria while selecting for others

Cognitive predictors of shallow-orthography spelling speed and accuracy in 6th grade children

Spelling accuracy and time course was investigated in a sample of 100 Norwegian 6th grade students completing a standardized spelling-to-dictation task. Students responded by keyboard with accurate recordings of response-onset latency (RT) and inter-keypress interval (IKI). We determined effects of a number of child-level cognitive ability factors, and of word-level factors—particularly the location within the word of a spelling challenge (e.g., letter doubling), if present. Spelling accuracy was predicted by word reading (word split) performance, non-word spelling accuracy, keyboard key-finding speed and short-term memory span. Word reading performance predicted accuracy just for words with spelling challenges. For correctly spelled words, RT was predicted by non-word spelling response time and by speed on a key-finding task, and mean IKI by non-verbal cognitive ability, word reading, non-word spelling response time, and key-finding speed. Compared to words with no challenge, mean IKI was shorter for words with an initial challenge and longer for words with a mid-word challenge. These findings suggest that spelling is not fully planned when typing commences, a hypothesis that is confirmed by the fact that IKI immediately before within word challenges were reliably longer than elsewhere within the same word. Taken together our findings imply that routine classroom spelling tests better capture student competence if they focus not only on accuracy but also on production time course

Rapid automatized naming as an index of genetic liability to autism

This study investigated rapid automatized naming (RAN) ability in high functioning individuals with autism and parents of individuals with autism. Findings revealed parallel patterns of performance in parents and individuals with autism, where both groups had longer naming times than controls. Significant parent-child correlations were also detected, along with associations with language and personality features of the broad autism phenotype (retrospective reports of early language delay, socially reticent personality). Together, findings point towards RAN as a potential marker of genetic liability to autism

Combined effects of precipitation and nitrogen deposition on native and invasive winter annual production in California deserts

Primary production in deserts is limited by soil moisture and N availability, and thus is likely to be influenced by both anthropogenic N deposition and precipitation regimes altered as a consequence of climate change. Invasive annual grasses are particularly responsive to increases in N and water availabilities, which may result in competition with native forb communities. Additionally, conditions favoring increased invasive grass production in arid and semi-arid regions can increase fire risk, negatively impacting woody vegetation that is not adapted to fire. We conducted a seeded garden experiment and a 5-year field fertilization experiment to investigate how winter annual production is altered by increasing N supply under a range of water availabilities. The greatest production of invasive grasses and native forbs in the garden experiment occurred under the highest soil N (inorganic N after fertilization = 2.99 g m−2) and highest watering regime, indicating these species are limited by both water and N. A classification and regression tree (CART) analysis on the multi-year field fertilization study showed that winter annual biomass was primarily limited by November–December precipitation. Biomass exceeded the threshold capable of carrying fire when inorganic soil N availability was at least 3.2 g m−2 in piñon-juniper woodland. Due to water limitation in creosote bush scrub, biomass exceeded the fire threshold only under very wet conditions regardless of soil N status. The CART analyses also revealed that percent cover of invasive grasses and native forbs is primarily dependent on the timing and amount of precipitation and secondarily dependent on soil N and site-specific characteristics. In total, our results indicate that areas of high N deposition will be susceptible to grass invasion, particularly in wet years, potentially reducing native species cover and increasing the risk of fire

Thiolutin is a zinc chelator that inhibits the Rpn11 and other JAMM metalloproteases

Thiolutin is a disulfide-containing antibiotic and anti-angiogenic compound produced by Streptomyces. Its biological targets are not known. We show that reduced thiolutin is a zinc chelator that inhibits the JAB1/MPN/Mov34 (JAMM) domain–containing metalloprotease Rpn11, a deubiquitinating enzyme of the 19S proteasome. Thiolutin also inhibits the JAMM metalloproteases Csn5, the deneddylase of the COP9 signalosome; AMSH, which regulates ubiquitin-dependent sorting of cell-surface receptors; and BRCC36, a K63-specific deubiquitinase of the BRCC36-containing isopeptidase complex and the BRCA1–BRCA2-containing complex. We provide evidence that other dithiolopyrrolones also function as inhibitors of JAMM metalloproteases