Cofactor regeneration by a soluble pyridine nucleotide transhydrogenase for biological production of hydromorphone

We have applied the soluble pyridine nucleotide transhydrogenase of Pseudomonas fluorescens to a cell-free system for the regeneration of the nicotinamide cofactors NAD and NADP in the biological production of the important semisynthetic opiate drug hydromorphone. The original recombinant whole-cell system suffered from cofactor depletion resulting from the action of an NADP(+)-dependent morphine dehydrogenase and an NADH-dependent morphinone reductase. By applying a soluble pyridine nucleotide transhydrogenase, which can transfer reducing equivalents between NAD and NADP, we demonstrate with a cell-free system that efficient cofactor cycling in the presence of catalytic amounts of cofactors occurs, resulting in high yields of hydromorphone. The ratio of morphine dehydrogenase, morphinone reductase, and soluble pyridine nucleotide transhydrogenase is critical for diminishing the production of the unwanted by-product dihydromorphine and for optimum hydromorphone yields. Application of the soluble pyridine nucleotide transhydrogenase to the whole-cell system resulted in an improved biocatalyst with an extended lifetime. These results demonstrate the usefulness of the soluble pyridine nucleotide transhydrogenase and its wider application as a tool in metabolic engineering and biocatalysis

Cannabis and schizophrenia

BACKGROUND Schizophrenia is a mental illness causing disordered beliefs, ideas and sensations. Many people with schizophrenia smoke cannabis, and it is unclear why a large proportion do so and if the effects are harmful or beneficial. It is also unclear what the best method is to allow people with schizophrenia to alter their cannabis intake. OBJECTIVES To assess the effects of specific psychological treatments for cannabis reduction in people with schizophrenia.To assess the effects of antipsychotics for cannabis reduction in people with schizophrenia.To assess the effects of cannabinoids (cannabis related chemical compounds derived from cannabis or manufactured) for symptom reduction in people with schizophrenia. SEARCH METHODS We searched the Cochrane Schizophrenia Group Trials Register, 12 August 2013, which is based on regular searches of BIOSIS, CINAHL, EMBASE, MEDLINE, PUBMED and PsycINFO.We searched all references of articles selected for inclusion for further relevant trials. We contacted the first author of included studies for unpublished trials or data. SELECTION CRITERIA We included all randomised controlled trials involving cannabinoids and schizophrenia/schizophrenia-like illnesses, which assessed:1) treatments to reduce cannabis use in people with schizophrenia;2) the effects of cannabinoids on people with schizophrenia. DATA COLLECTION AND ANALYSIS We independently inspected citations, selected papers and then re-inspected the studies if there were discrepancies, and extracted data. For dichotomous data we calculated risk ratios (RR) and for continuous data, we calculated mean differences (MD), both with 95% confidence intervals (CI) on an intention-to-treat basis, based on a fixed-effect model. We excluded data if loss to follow-up was greater than 50%. We assessed risk of bias for included studies and used GRADE to rate the quality of the evidence. MAIN RESULTS We identified eight randomised trials, involving 530 participants, which met our selection criteria.For the cannabis reduction studies no one treatment showed superiority for reduction in cannabis use. Overall, data were poorly reported for many outcomes of interest. Our main outcomes of interest were medium-term data for cannabis use, global state, mental state, global functioning, adverse events, leaving the study early and satisfaction with treatment. 1. Reduction in cannabis use: adjunct psychological therapies (specifically about cannabis and psychosis) versus treatment as usualResults from one small study showed people receiving adjunct psychological therapies specifically about cannabis and psychosis were no more likely to reduce their intake than those receiving treatment as usual (n = 54, 1 RCT, MD -0.10, 95% CI -2.44 to 2.24, moderate quality evidence). Results for other main outcomes at medium term were also equivocal. No difference in mental state measured on the PANSS positive were observed between groups (n = 62, 1 RCT, MD -0.30 95% CI -2.55 to 1.95, moderate quality evidence). Nor for the outcome of general functioning measured using the World Health Organization Quality of Life BREF (n = 49, 1 RCT, MD 0.90 95% CI -1.15 to 2.95, moderate quality evidence). No data were reported for the other main outcomes of interest 2. Reduction in cannabis use: adjunct psychological therapy (specifically about cannabis and psychosis) versus adjunct non-specific psychoeducation One study compared specific psychological therapy aimed at cannabis reduction with general psychological therapy. At three-month follow-up, the use of cannabis in the previous four weeks was similar between treatment groups (n = 47, 1 RCT, RR 1.04 95% CI 0.62 to 1.74, moderate quality evidence). Again, at a medium-term follow-up, the average mental state scores from the Brief Pscychiatric Rating Scale-Expanded were similar between groups (n = 47, 1 RCT, MD 3.60 95% CI - 5.61 to 12.81, moderate quality evidence). No data were reported for the other main outcomes of interest: global state, general functioning, adverse events, leaving the study early and satisfaction with treatment. 3. Reduction in cannabis use: antipsychotic versus antipsychotic In a small trial comparing effectiveness of olanzapine versus risperidone for cannabis reduction, there was no difference between groups at medium-term follow-up (n = 16, 1 RCT, RR 1.80 95% CI 0.52 to 6.22, moderate quality evidence). The number of participants leaving the study early at medium term was also similar (n = 28, 1 RCT, RR 0.50 95% CI 0.19 to 1.29, moderate quality evidence). Mental state data were reported, however they were reported within the short term and no difference was observed. No data were reported for global state, general functioning, and satisfaction with treatment.With regards to adverse effects data, no study reported medium-term data. Short-term data were presented but overall, no real differences between treatment groups were observed for adverse effects. 4. Cannabinoid as treatment: cannabidiol versus amisulprideAgain, no data were reported for any of the main outcomes of interest at medium term. There were short-term data reported for mental state using the BPRS and PANSS, no overall differences in mental state were observed between treatment groups. AUTHORS' CONCLUSIONS Results are limited and inconclusive due to the small number and size of randomised controlled trials available and quality of data reporting within these trials. More research is needed to a) explore the effects of adjunct psychological therapy that is specifically about cannabis and psychosis as currently there is no evidence for any novel intervention being better than standard treatment,for those that use cannabis and have schizophrenia b) decide the most effective drug treatment in treating those that use cannabis and have schizophrenia, and c) assess the effectiveness of cannabidiol in treating schizophrenia. Currently evidence is insufficient to show cannabidiol has an antipsychotic effect

Report in the Grand River Eagle

A report in the Grand River Eagle that a committee was organized in Grand Rapids to help the worthy and enterprising pastor, the Rev. A. C. Van Raalte, and his people in their settlement. Some members of the committee were appointed to visit Holland. E. B. Bostwick was chairman and A. D. Rathbone, secretary.https://digitalcommons.hope.edu/vrp_1840s/1138/thumbnail.jp

Hanford External Dosimetry Technical Basis Manual PNL-MA-842

The Hanford External Dosimetry Technical Basis Manual PNL-MA-842 documents the design and implementation of the external dosimetry system used at Hanford. The manual describes the dosimeter design, processing protocols, dose calculation methodology, radiation fields encountered, dosimeter response characteristics, limitations of dosimeter design under field conditions, and makes recommendations for effective use of the dosimeters in the field. The manual describes the technical basis for the dosimetry system in a manner intended to help ensure defensibility of the dose of record at Hanford and to demonstrate compliance with 10 CFR 835, DOELAP, DOE-RL, ORP, PNSO, and Hanford contractor requirements. The dosimetry system is operated by PNNL’s Hanford External Dosimetry Program (HEDP) which provides dosimetry services to all Hanford contractors. The primary users of this manual are DOE and DOE contractors at Hanford using the dosimetry services of PNNL. Development and maintenance of this manual is funded directly by DOE and DOE contractors. Its contents have been reviewed and approved by DOE and DOE contractors at Hanford through the Hanford Personnel Dosimetry Advisory Committee (HPDAC) which is chartered and chaired by DOE-RL and serves as means of coordinating dosimetry practices across contractors at Hanford. This manual was established in 1996. Since inception, it has been revised many times and maintained by PNNL as a controlled document with controlled distribution. Rev. 0 marks the first revision to be released through PNNL’s Electronic Records & Information Capture Architecture (ERICA) database. Revision numbers that are whole numbers reflect major revisions typically involving changes to all chapters in the document. Revision numbers that include a decimal fraction reflect minor revisions, usually restricted to selected chapters or selected pages in the document. Revision Log: Rev. 0 (2/25/2005) Major revision and expansion. Rev. 0.1 (3/12/2007) Minor revision. Updated Chapters 5, 6 and 9 to reflect change in default ring calibration factor used in HEDP dose calculation software. Factor changed from 1.5 to 2.0 beginning January 1, 2007. Pages on which changes were made are as follows: 5.23, 5.69, 5.78, 5.80, 5.82, 6.3, 6.5, 6.29, 9.2

Hanford External Dosimetry Technical Basis Manual PNL-MA-842

The Hanford External Dosimetry Technical Basis Manual PNL-MA-842 documents the design and implementation of the external dosimetry system used at Hanford. The manual describes the dosimeter design, processing protocols, dose calculation methodology, radiation fields encountered, dosimeter response characteristics, limitations of dosimeter design under field conditions, and makes recommendations for effective use of the dosimeters in the field. The manual describes the technical basis for the dosimetry system in a manner intended to help ensure defensibility of the dose of record at Hanford and to demonstrate compliance with 10 CFR 835, DOELAP, DOE-RL, ORP, PNSO, and Hanford contractor requirements. The dosimetry system is operated by PNNL’s Hanford External Dosimetry Program which provides dosimetry services to all Hanford contractors. The primary users of this manual are DOE and DOE contractors at Hanford using the dosimetry services of PNNL. Development and maintenance of this manual is funded directly by DOE and DOE contractors. Its contents have been reviewed and approved by DOE and DOE contractors at Hanford through the Hanford Personnel Dosimetry Advisory Committee which is chartered and chaired by DOE-RL and serves as means of coordinating dosimetry practices across contractors at Hanford. This manual was established in 1996. Since inception, it has been revised many times and maintained by PNNL as a controlled document with controlled distribution. Rev. 0 marks the first revision to be released through PNNL’s Electronic Records & Information Capture Architecture (ERICA) database

A systematic review and thematic synthesis of patients' experience of medicines adherence

Background: Medicines non-adherence continues to be problematic in health care practice. After decades of research, few interventions have a robust evidence-based demonstrating their applicability to improve adherence. Phenomenology has a place within the health care research environment. Objective: To explore patients’ lived experiences of medicines adherence reported in the phenomenonologic literature. Methods: A systematic literature search was conducted to identify peer-reviewed and published phenomenological investigations in adults that aimed to investigate patients’ lived experiences of medicines adherence. Studies were appraised using the Critical Appraisal Skills Programme (CASP) Qualitative Research Tool. Thematic synthesis was conducted using a combination of manual coding and NVivo10 [QSR International, Melbourne] coding to aid data management. Results: Descriptive themes identified included i) dislike for medicines, ii) survival, iii) perceived need, including a) symptoms and side-effects and b) cost, and iv) routine. Analytic themes identified were i) identity and ii) interaction. Conclusions: This work describes adherence as a social interaction between the identity of patients and medicines, mediated by interaction with family, friends, health care professionals, the media and the medicine, itself. Health care professionals and policy makers should seek to re-locate adherence as a social phenomenon, directing the development of interventions to exploit patient interaction with wider society, such that patients ‘get to know’ their medicines, and how they can be taken, throughout the life of the patient and the prescription

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