Melt-extruded polyethylene oxide (PEO) rods as drug delivery vehicles: Formulation, performance as controlled release devices and the influence of co-extruded excipients on drug release profiles

The utility of controlled release medication formulations lies in their ability to keep drugs at steady levels in the blood plasma of recipients and within the termini of the maximum and minimum effective therapeutic levels. This avoids the “ups” and “downs” of medication levels within the body which would have been the result had conventional immediate release tablets been administered instead. In the veterinary field, controlled release medications are essential¹ because of the logistical difficulties of administering drugs on a regular (e.g., daily) basis to animals. The chief advantages of controlled release veterinary medications lie in the ease with which they can be administered; decrease in stress for animals, owing to less need for rounding up and frequent dosing; and, most importantly for farmers, the reduced cost of treatment relative to that for a multiple dosage regime

Bone health of middle-aged and older surfers

Purpose: Given the lack of research investigating surfing and bone health, we aimed to assess the bone mineral density (BMD) of middle-aged and older surfers. Patients and methods: In a cross-sectional observational design, we compared a group of middle-aged and older surfers to a group of non-surfers, age- and sex-matched controls. Participants were males, aged between 50 and 75 years. Volunteers were assessed for body mass index, bone-specific physical activity questionnaire (BPAQ) scores, daily calcium intake, and alcohol intake. Primary outcomes included BMD at the femur and lumbar spine (LS), and T-score, assessed via dual-energy X-ray absorptiometry. Bone biomarkers were also analyzed. Results: A total of 104 participants (59 surfers and 45 controls) were assessed. Groups were similar with regards to all demographic characteristics except for percentage of lean mass (higher in surfers, mean difference [MD] +2.57%; 95% CI 0.05–5.09; p=0.046) and current BPAQ score (lower in surfers; MD −0.967; 95% CI −0.395 to −1.539; p=0.001). Surfers had a mean surfing experience of 41.2 (SD ±11.8) years and mean surfing exposure of 26.9 (SD ±15.0) hours/month. Controls were divided into two groups, according to their main physical activity: weight-bearing/high intensity (WBHI) and non-weight-bearing/low intensity (NWBLI). When compared to NWBLI controls, surfers had higher LS BMD (MD +0.064; 95% CI 0.002–0.126; p=0.041) and higher T-score (MD +0.40; 95% CI 0.01–0.80; p=0.042); however, surfers had a lower T-score than the WBHI group (MD −0.52; 95% CI −0.02 to −1.0; p=0.039). No other differences were found between groups. Conclusion: The findings of this study support our hypothesis that regular surfing may be an effective physical activity for middle-aged and older men to decrease bone deterioration related to aging, as we identified positive results for surfers in relation to primary outcomes.Full Tex

Vibrational branching ratios in photoionization of CO and N2

We report results of experimental and theoretical studies of the vibrational branching ratios for CO 4sigma(-1) photoionization from 20 to 185 eV. Comparison with results for the 2sigma(u)(-1) channel of the isoelectronic N-2 molecule shows the branching ratios for these two systems to be qualitatively different due to the underlying scattering dynamics: CO has a shape resonance at low energy but lacks a Cooper minimum at higher energies whereas the situation is reversed for N-2

Beyond osteogenesis: an in vitro comparison of the potentials of six bone morphogenetic proteins

Bone morphogenetic proteins (BMPs) other than the clinically available BMP-2 and BMP-7 may be useful for improving fracture healing through both increasing osteogenesis and creating a favorable healing environment by altering cytokine release by endogenous cells. Given the spectrum of potential applications for BMPs, the objective of this study was to evaluate various BMPs under a variety of conditions to provide further insight into their therapeutic capabilities. The alkaline phosphatase (ALP) activity of both C(2)C(12) and human adipose-derived stem cells (hASCs) was measured after exposure of increasing doses of recombinant human BMP-2, -4, -5, -6, -7, or -9 for 3 and 7 days. BMPs-2, -4, -5, -6, -7, and -9 were compared in terms of their ability to affect the release of stromal derived factor-1 (SDF-1), vascular endothelial growth factor (VEGF), and basic fibroblast growth factor (b-FGF) from human bone marrow stromal cells (hBMSCs). Gene expression of ALP, osteocalcin, SDF-1, VEGF, and b-FGF following shRNA-mediated knockdown of BMP-2 and BMP-6 in hBMSCs or human osteoblasts under osteogenic differentiation conditions was also evaluated. Collectively, BMPs-6 and -9 produced the greatest osteogenic differentiation of C(2)C(12) and hASCs as determined by ALP. The hBMSC secretion of SDF-1 was most affected by BMP-5, VEGF by BMP-4, and b-FGF by BMP-2. The knockdown of BMP-2 in BMSCs had no effect on any of the genes measured whereas BMP-6 knockdown in hBMSCs caused a significant increase in VEGF gene expression. BMP-2 and BMP-6 knockdown in human osteoblasts caused significant increases in VEGF gene expression and trends toward decreases in osteocalcin expression. These findings support efforts to study other BMPs as potential bone graft supplements, and to consider combined BMP delivery for promotion of multiple aspects of fracture healing

The family-specific α4-helix of the kinesin-13, MCAK, is critical to microtubule end recognition

Kinesins that influence the dynamics of microtubule growth and shrinkage require the ability to distinguish between the microtubule end and the microtubule lattice. The microtubule depolymerizing kinesin MCAK has been shown to specifically recognize the microtubule end. This ability is key to the action of MCAK in regulating microtubule dynamics. We show that the a4-helix of the motor domain is crucial to microtubule end recognition. Mutation of the residues K524, E525 and R528, which are located in the C-terminal half of the a4-helix, specifically disrupts the ability of MCAK to recognize the microtubule end. Mutation of these residues, which are conserved in the kinesin-13 family and discriminate members of this family from translocating kinesins, impairs the ability of MCAK to discriminate between the microtubule lattice and the microtubule end

Chlorpromazine for schizophrenia: a Cochrane systematic review of 50 years of randomised controlled trials

BACKGROUND: Chlorpromazine (CPZ) remains one of the most common drugs used for people with schizophrenia worldwide, and a benchmark against which other treatments can be evaluated. Quantitative reviews are rare; this one evaluates the effects of chlorpromazine in the treatment of schizophrenia in comparison with placebo. METHODS: We sought all relevant randomised controlled trials (RCT) comparing chlorpromazine to placebo by electronic and reference searching, and by contacting trial authors and the pharmaceutical industry. Data were extracted from selected trials and, where possible, synthesised and random effects relative risk (RR), the number needed to treat (NNT) and their 95% confidence intervals (CI) calculated. RESULTS: Fifty RCTs from 1955–2000 were included with 5276 people randomised to CPZ or placebo. They constitute 2008 person-years spent in trials. Meta-analysis of these trials showed that chlorpromazine promotes a global improvement (n = 1121, 13 RCTs, RR 0.76 CI 0.7 to 0.9, NNT 7 CI 5 to 10), although a considerable placebo response is also seen. People allocated to chlorpromazine tended not to leave trials early in both the short (n = 945, 16 RCTs, RR 0.74 CI 0.5 to 1.1) and medium term (n = 1861, 25 RCTs, RR 0.79 CI 0.6 to 1.1). There were, however, many adverse effects. Chlorpromazine is sedating (n = 1242, 18 RCTs, RR 2.3 CI 1.7 to 3.1, NNH 6 CI 5 to 8), increases a person's chances of experiencing acute movement disorders, Parkinsonism and causes low blood pressure with dizziness and dry mouth. CONCLUSION: It is understandable why the World Health Organization (WHO) have endorsed and included chlorpromazine in their list of essential drugs for use in schizophrenia. Low- and middle-income countries may have more complete evidence upon which to base their practice compared with richer nations using recent innovations

Comparing Income Tax Liability Across States: Where Does Missouri Rank?

The answer to the question “Is Missouri a low-tax state?” depends on the approach used. This paper addresses the question by comparing income taxes. Specifically, for purposes of comparison we calculate, for each state, the income tax liability for a representative family of four earning the national median income. With this information we then compare the income tax liability across states, ranking them from highest to lowest. Using our approach, we find that Missouri ranks in the top half of states according to income tax liability. In other words, our ranking shows that Missouri is not a low-tax state

Digital PCR analysis of circulating tumor DNA: a biomarker for chondrosarcoma diagnosis, prognostication, and residual disease detection

Conventional chondrosarcoma is the most common primary bone tumor in adults. Prognosis corresponds with tumor grade but remains variable, especially for individuals with grade (G) II disease. There are currently no biomarkers available for monitoring or prognostication of chondrosarcoma. Circulating tumor DNA (ctDNA) has recently emerged as a promising biomarker for a broad range of tumor types. To date, little has been done to study the presence of ctDNA and its potential utility in the management of sarcomas, including chondrosarcoma. In this study, we have assessed ctDNA levels in a cohort of 71 patients, 32 with sarcoma, including 29 individuals with central chondrosarcoma (CS) and 39 with locally aggressive and benign bone and soft tissue tumors, using digital PCR. In patients with CS, ctDNA was detected in pretreatment samples in 14/29 patients, which showed clear correlation with tumor grade as demonstrated by the detection of ctDNA in all patients with GIII and dedifferentiated disease (n = 6) and in 8/17 patients with GII disease, but never associated with GI CS. Notably detection of ctDNA preoperatively in GII disease was associated with a poor outcome. A total of 14 patients with CS had ctDNA levels assessed at multiple time points and in most patients there was a clear reduction following surgical removal. This research lays the foundation for larger studies to assess the utility of ctDNA for chondrosarcoma diagnosis, prognostication, early detection of residual disease and monitoring disease progression