Development of a framework to define the functional goals and outcomes of botulinum toxin A spasticity treatment relevant to the child and family living with cerebral palsy using the International Classification of Functioning, Disability and Health for Children and Youth

Objective: To define a sub-set of functional goals and outcomes relevant to children and families living with cerebral palsy following treatment with botulinum toxin type A using the International Classification of Functioning, Disability and Health for Children and Youth. Methods: We identified treatment goals and treatment outcomes from medical case records in 2102 assessments of 239 children with cerebral palsy treated with botulinum toxin between 1994 and 2009. Goals were set through assessment and discussion by experienced clinicians, therapists, parents and children. Results: There were 61 separate goals, mapping to 40 categories, falling mostly within Body Functions: b710 Mobility of joint functions (414 times); b770 Gait pattern functions (374 times); b7351 Tone of muscles of one limb (117 times). A total of 93 separate treatment outcomes were identified, mapping to 51 categories. Two of the 3 most common outcomes correspond to the 2 most common goals (gait pattern and mobility of joint functions). Conclusion: The International Classification of Functioning, Disability and Health for Children and Youth provides a useful framework to categorize the reasons for using botulinum toxin in children and focuses the clinical consultation not only on impairments but also functional outcomes

3-(5-Nitrofuran-2-yl)prop-2-en-1-one Derivatives, with Potent Antituberculosis Activity, Inhibit A Novel Therapeutic Target, Arylamine N-acetyltransferase, in Mycobacteria.

In this study, the inhibitory potential of 3-(5-nitrofuran-2-yl)prop-2-en-1-one derivatives was evaluated against a panel of bacteria, as well as mammalian cell lines to determine their therapeutic index. In addition, we investigated the mechanism of antibiotic action of the derivatives to identify their therapeutic target. We discovered compound 2 to be an extremely potent inhibitor of Mycobacterium tuberculosis H37Rv growth (MIC: 0.031 mg/L) in vitro, performing better than the currently used first-line antituberculosis drugs such as isoniazid, rifampicin, ethambutol, and pretomanid in vitro. Furthermore, compound 3 was equipotent to pretomanid against a multidrug-resistant M. tuberculosis clinical isolate. The derivatives were selective and bactericidal towards slow-growing mycobacteria. They showed low cytotoxicity towards murine RAW 264.7 and human THP-1 cell lines, with high selectivity indices. Compound 1 effectively eliminated the intracellular mycobacteria in a mycobacteria-infected macrophage model. The derivatives were assessed for their potential to inhibit mycobacterial arylamine N-acetyltransferase (NAT) and were identified as good inhibitors of recombinant mycobacterial NAT, a novel target essential for the intracellular survival of M. tuberculosis. This study provided hits for designing new potent and selective antituberculosis leads, having mycobacterial NAT inhibition as their possible endogenous mechanisms of action

A Comparative SEM-EDS Elemental Composition of Mud in Coastal Aquaculture Ponds

The present study was aimed to understand the comparative abundance and source of elemental constituents in mud of four coastal shrimp farming areas, Vunh Tau (VT), Nha Trang (NT), Da Nang (DN) and Hue (HU) in Viet Nam using SEM-EDS analysis. Mud samples were collected from shrimp farming coastal zones and used for SEM-EDS analysis. Obtained results clearly revealed that all muds were predominately constituted with Si (23.39 \u2013 47.42%), Al (4.5 \u2013 15.9%), Fe (0.59 \u20138.29%) and C (6.56 to 12.55%). Despite that K (3.67%), Al (15.9%), Fe (8.29%) and Ti (0.65%) were distributed at highest percentage in the VT than that of the remaining three stations; Na (3.68%) was prevalent in NT; whereas Mg (1.46%) and Si (47.42) were abundant with elevated percentage in DN as well as C (12.55%), P (3.34%) and S (2.72%) pronounced with maximum percentage in HU. Therefore, it may also be concluded that mud of all shrimp ponds are principally composed with Si, Al, Fe and C as major elemental constituents, whereas remaining other elements are present in low percentage in the mud of shrimp ponds in geochemical profile of Viet Nam. Though it is not possible to ascertain the source of all elements from this study but abundance of Al and Fe in the mud of shrimp ponds are largely influenced by the anthropogenic sources. Moreover, from this study it can be suggested that monitoring of elemental composition and their source using SEM-EDS would be a potential tool for understanding the concentration level towards conserving the coastal environment

Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis

The emergence of total drug-resistant tuberculosis (TDRTB) has made the discovery of new therapies for tuberculosis urgent. The cytoplasmic enzymes of peptidoglycan biosynthesis have generated renewed interest as attractive targets for the development of new anti-mycobacterials. One of the cytoplasmic enzymes, uridine diphosphate (UDP)-MurNAc-tripeptide ligase (MurE), catalyses the addition of meso-diaminopimelic acid (m-DAP) into peptidoglycan in Mycobacterium tuberculosis coupled to the hydrolysis of ATP. Mutants of M. tuberculosis MurE were generated by replacing K157, E220, D392, R451 with alanine and N449 with aspartate, and truncating the first 24 amino acid residues at the N-terminus of the enzyme. Analysis of the specific activity of these proteins suggested that apart from the 24 Nterminal residues, the other mutated residues are essential for catalysis. Variations in K m values for one or more substrates were observed for all mutants, except the N-terminal truncation mutant, indicating that these residues are involved in binding substrates and form part of the active site structure. These mutant proteins were also tested for their specificity for a wide range of substrates. Interestingly, the mutations K157A, E220A and D392A showed hydrolysis of ATP uncoupled from catalysis. The ATP hydrolysis rate was enhanced by at least partial occupation of the uridine nucleotide dipeptide binding site. This study provides an insight into the residues essential for the catalytic activity and substrate binding of the ATP-dependent MurE ligase. Since ATP-dependent MurE ligase is a novel drug target, the understanding of its function may lead to development of novel inhibitors against resistant forms of M. tuberculosis

A System in the Wild: Deploying a Two Player Arm Rehabilitation System for Children With Cerebral Palsy in a School Environment

This paper outlines a system for arm rehabilitation for children with upper-limb hemiplegia resulting from cerebral palsy. Our research team designed a two-player, interactive (competitive or collaborative) computer play therapy system that provided powered assistance to children while they played specially designed games that promoted arm exercises. We designed the system for a school environment. To assess the feasibility of deploying the system in a school environment, the research team enlisted the help of teachers and staff in nine schools. Once the system was set up, it was used to deliver therapy without supervision from the research team. Ultimately, the system was found to be suitable for use in schools. However, the overriding need for schools to focus on academic activities meant that children could not use the system enough to achieve the amount of use desired for therapeutic benefit. In this paper, we identify the key challenges encountered during this study. For example, there was a marked reluctance to report system issues (which could have been fixed) that prevented children from using the system. We also discuss future implications of deploying similar studies with this type of system

Influence of Physical Raking and Biological Process in the Mud-water Exchange Dynamics of P in Fish Culture Ponds

Experiment was conducted in the laboratory using radioactive 32P for ascertaining the dynamics and quantifying the exchangeable amount of P between sediment and water phase under the influence of physical raking and biological processes. Collected sediment (100 g) was dispensed in a glass beaker and treated with radioactive 32P after reaction with CaCO3. Each beaker filled with 250 ml tap water. Four different treatments: physical raking once (RO), repeated raking (RR), bacteria (Bacillus, 167 X 102 ml-1) inoculum (BI) and bacteria inoculum (Bacillus, 167 X 102 ml-1) plus repeated raking (BI + RR) were used in the study. Water samples were collected and tested for specific activity of radioactive 32P, concentration of orthophosphate and count of heterotrophic bacterial (HB) population. The 32P value of BI+RR treatment was 20, 25, 37 and 56% higher than BI, RR, RO and control, respectively. Therefore, it can be concluded that synergistic effect of bacteria inoculum plus repeated raking (BI + RR) released maximum amount of phosphorus than the rest three treatments. Critical appraisal of data clearly revealed four states of dynamic of 32P between sediment and overlaying water: initial rapid increase of 32P level in water - rapid desorption period (RDP) from day 0 to 12, slow increase of 32P level of water - slow desorption period (SDP) from day >12 to 55, the 32P moves to sediment resulting in decrease 32P level in water - absorption period (AP) from day >55 to 90 and steady period (SP) from day >90 to 124, when 32P concentration of water and sediment supposed to be equal indicating no movement of 32P occurred between the water and sediment phas

Lesinurad in combination with allopurinol: a randomised, double-blind, placebo-controlled study in patients with gout with inadequate response to standard of care (the multinational CLEAR 2 study).

Determine the efficacy and safety of daily lesinurad (200 or 400 mg orally) added to allopurinol in patients with serum uric acid (sUA) above target in a 12-month, randomised, phase III trial. Patients on allopurinol ≥300 mg (≥200 mg in moderate renal impairment) had sUA level of ≥6.5 mg/dL (≥387 µmol/L) at screening and two or more gout flares in the prior year. Primary end point was the proportion of patients achieving sUA level of <6.0 mg/dL (<357 µmol/L) (month 6). Key secondary end points were mean gout flare rate requiring treatment (months 7 through 12) and proportions of patients with complete resolution of one or more target tophi (month 12). Safety assessments included adverse events and laboratory data. Patients (n=610) were predominantly male, with mean (±SD) age 51.2±10.90 years, gout duration 11.5±9.26 years and baseline sUA of 6.9±1.2 mg/dL (410±71 µmol/L). Lesinurad at 200 and 400 mg doses, added to allopurinol, significantly increased proportions of patients achieving sUA target versus allopurinol-alone therapy by month 6 (55.4%, 66.5% and 23.3%, respectively, p<0.0001 both lesinurad+allopurinol groups). In key secondary end points, there were no statistically significant treatment-group differences favouring lesinurad. Lesinurad was generally well tolerated; the 200 mg dose had a safety profile comparable with allopurinol-alone therapy. Renal-related adverse events occurred in 5.9% of lesinurad 200 mg+allopurinol, 15.0% of lesinurad 400 mg+allopurinol and 4.9% of allopurinol-alone groups, with serum creatinine elevation of ≥1.5× baseline in 5.9%, 15.0% and 3.4%, respectively. Serious treatment-emergent adverse events occurred in 4.4% of lesinurad 200 mg+allopurinol, in 9.5% of lesinurad 400 mg+allopurinol and in 3.9% of allopurinol-alone groups, respectively. Lesinurad added to allopurinol demonstrated superior sUA lowering versus allopurinol-alone therapy and lesinurad 200 mg was generally well tolerated in patients with gout warranting additional therapy. NCT01493531