Reduction in ulnar pressure distribution when walking with forearm crutches with a novel cuff design: Cross-sectional intervention study on the biomechanical efficacy of an ulnar recess

Walking with crutches is an effective way of reducing the load on the lower extremity and is often indicated after injury or surgery. However, walking with forearm crutches with conventional cuffs can trigger symptoms including tenosynovitis in the biceps tendon, ulnar neuropraxia at the wrist, pain, or skin hematoma. The purpose of this study was to test the hypothesis that a crutch cuff design with an ulnar recess reduces ulnar pressure during walking with forearm crutches. The pressure distribution between the forearm and crutch cuff was measured in 15 healthy participants for crutch walking with conventional and novel cuffs, respectively. Relative peak pressure in the proximal medial region compared to the overall peak pressure was reduced by 8.6% when walking with crutches with the novel cuff design compared to conventional cuffs (p < 0.001). Relative peak pressure in the distal intermediate and lateral regions were increased by 3.3% and 3.7% for the novel compared with conventional cuffs, respectively (p < 0.001 for both). Hence, the novel crutch cuffs shifted regions of high pressure away from the proximal ulnar region towards more distal regions that are covered by more soft tissue

Anti-Trypanosomal Proteasome Inhibitors Cure Hemolymphatic and Meningoencephalic Murine Infection Models of African Trypanosomiasis

Current anti-trypanosomal therapies suffer from problems of longer treatment duration, toxicity and inadequate efficacy, hence there is a need for safer, more efficacious and 'easy to use' oral drugs. Previously, we reported the discovery of the triazolopyrimidine (TP) class as selective kinetoplastid proteasome inhibitors with in vivo efficacy in mouse models of leishmaniasis, Chagas Disease and African trypanosomiasis (HAT). For the treatment of HAT, development compounds need to have excellent penetration to the brain to cure the meningoencephalic stage of the disease. Here we describe detailed biological and pharmacological characterization of triazolopyrimidine compounds in HAT specific assays. The TP class of compounds showed single digit nanomolar potency against Trypanosoma brucei rhodesiense and Trypanosoma brucei gambiense strains. These compounds are trypanocidal with concentration-time dependent kill and achieved relapse-free cure in vitro. Two compounds, GNF6702 and a new analog NITD689, showed favorable in vivo pharmacokinetics and significant brain penetration, which enabled oral dosing. They also achieved complete cure in both hemolymphatic (blood) and meningoencephalic (brain) infection of human African trypanosomiasis mouse models. Mode of action studies on this series confirmed the 20S proteasome as the target in T. brucei. These proteasome inhibitors have the potential for further development into promising new treatment for human African trypanosomiasis

Study of the Tissue Distribution of TLQP-21 in Mice Using [18F]JMV5763, a Radiolabeled Analog Prepared via [18F]Aluminum Fluoride Chelation Chemistry

TLQP-21 is a neuropeptide that is involved in the control of several physiological functions, including energy homeostasis. Since TLQP-21 could oppose the early phase of diet-induced obesity, it has raised a huge interest, but very little is known about its mechanisms of action on peripheral tissues. Our aim was to investigate TLQP-21 distribution in brain and peripheral tissues after systemic administration using positron emission tomography. We report here the radiolabeling of NODA-methyl phenylacetic acid (MPAA) functionalized JMV5763, a short analog of TLQP-21, with [18F]aluminum fluoride. Labeling of JMV5763 was initially performed manually, on a small scale, and then optimized and implemented on a fully automated radiosynthesis system. In the first experiment, mice were injected in the tail vein with [18F]JMV5763, and central and peripheral tissues were collected 13, 30, and 60 min after injection. Significant uptake of [18F]JMV5763 was found in stomach, intestine, kidney, liver, and adrenal gland. In the CNS, very low uptake values were measured in all tested areas, suggesting that the tracer does not efficiently cross the blood–brain barrier. Pretreatment with non-radioactive JMV5763 caused a significant reduction of tracer uptake only in stomach and intestine. In the second experiment, PET analysis was performed in vivo 10–120 min after i.v. [18F]JMV5763 administration. Results were consistent with those of the ex vivo determinations. PET images showed a progressive increase of [18F]JMV5763 uptake in intestine and stomach reaching a peak at 30 min, and decreasing at 120 min. Our results demonstrate that 18F-labeling of TLQP-21 analogs is a suitable method to study its distribution in the body

Health facility-based data on women receiving sulphadoxine-pyrimethamine during pregnancy in Tanzania : lessons to learn from a cross-sectional survey in Mkuranga and Mufindi districts and other national survey reports

A study of health facility (HF) data on women receiving sulphadoxine-pyrimethamine (SP) for intermittent preventive treatment of malaria during pregnancy (IPTp) was carried out at antenatal care clinics in Mkuranga and Mufindi districts.; A review of health management information system (HMIS) registers, interviews with health-care workers (HWs) and district and national level malaria control program managers corroborated by inter-temporal assessment through observations at HF levels. Statistical data were analyzed in Excel and interpreted in triangulation with qualitative data from interviews and observations.; Data indicated that IPTp doses administered to women were inadequate and partly inconsistent. HMIS registers lacked space for IPT records, forcing HWs to manipulate their record-keeping. The proportion/number of IPTp recipients in related to the supply of SP for free delivery, to women's attendance behaviours, showed variation by quarter and year of reporting.; It is impossible to achieve rational health service planning when the HMIS is weak. Whilst it is acknowledged that the HMIS is already overloaded, concerted measures are urgently needed to accommodate data on new interventions and other vertical programs if malaria programs are to achieve their goals

JMV5656, A Novel Derivative of TLQP-21, Triggers the Activation of a Calcium-Dependent Potassium Outward Current in Microglial Cells

TLQP-21 (TLQPPASSRRRHFHHALPPAR) is a multifunctional peptide that is involved in the control of physiological functions, including feeding, reproduction, stress responsiveness, and general homeostasis. Despite the huge interest in TLQP-21 biological activity, very little is known about its intracellular mechanisms of action. In microglial cells, TLQP-21 stimulates increases of intracellular Ca(2+) that may activate functions, including proliferation, migration, phagocytosis and production of inflammatory molecules. Our aim was to investigate whether JMV5656 (RRRHFHHALPPAR), a novel short analogue of TLQP-21, stimulates intracellular Ca(2+) in the N9 microglia cells, and whether this Ca(2+) elevation is coupled with the activation Ca(2+)-sensitive K(+) channels. TLQP-21 and JMV5656 induced a sharp, dose-dependent increment in intracellular calcium. In 77% of cells, JMV5656 also caused an increase in the total outward currents, which was blunted by TEA (tetraethyl ammonium chloride), a non-selective blocker of voltage-dependent and Ca(2+)-activated potassium (K(+)) channels. Moreover, the effects of ion channel blockers charybdotoxin and iberiotoxin, suggested that multiple calcium-activated K(+) channel types drove the outward current stimulated by JMV5656. Additionally, inhibition of JMV5656-stimulated outward currents by NS6180 (4-[[3-(trifluoromethyl)phenyl]methyl]-2H-1,4 benzothiazin-3(4H)-one) and TRAM-34 (triarylmethane-34), indicated that KCa3.1 channels are involved in this JMV5656 mechanisms of action. In summary, we demonstrate that, in N9 microglia cells, the interaction of JMV5656 with the TLQP-21 receptors induced an increase in intracellular Ca(2+), and, following extracellular Ca(2+) entry, the opening of KCa3.1 channels

The profile of patients and current practice of treatment of upper limb muscle spasticity with botulinum toxin type A: an international survey

To document the current practice in relation with the treatment of patients with upper limb spasticity with botulinum toxin type A to inform future research in this area. We designed an international, cross-sectional, noninterventional survey of current practice. Nine hundred and seventy-four patients from 122 investigational centres in 31 countries were studied. Most patients were over 40 years old and had a stroke. Improvement of active function was the most frequent treatment goal in the first 3 months after the onset of upper limb spasticity, but was less common than passive function in the chronic stage. Pain relief was a common goal in both the stages. As a rule, clinicians intended to assess the effectiveness of treatment with impairment level scales. Functional outcome measures seem to be rarely used in clinical practice. The use of these measures should be encouraged to assess whether the reduction in muscle tone translates into functional benefit to patients and their caregivers. soignants. International Journal of Rehabilitation Research 33: 199-204 (C) 2010 Wolters Kluwer Health vertical bar Lippincott Williams & Wilkins

Study of the Tissue Distribution of TLQP-21 in Mice Using [18F]JMV5763, a Radiolabeled Analog Prepared via [18F]Aluminum Fluoride Chelation Chemistry

International audienc

Optimization of PDGFR inhibitors for duration of action, as an inhaled therapy for lung remodeling in pulmonary arterial hypertension

: A series of potent dual PDGFR/cKIT inhibitors has been identified. The series was optimized for duration of action in the lung. A novel kinase occupancy assay was used to directly measure target occupancy after it dosing. Compound 25 shows 24 hour occupancy of the PDGFR kinase domain, after a single it dose and has efficacy at 0.03 mg/kg, in the rat moncrotaline model of pulmonary arterial hypertension. Examination of PK/PD data from the optimization effort has revealed in vitro: in vivo correlations which link duration of action in vivo with low permeability and high basicity, and demonstrate that nonspecific binding to lung tissue increases with lipophilicity