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Marine algae produce complex polysaccharides, which can be degraded by marine heterotrophic bacteria utilizing carbohydrate-active enzymes. The red algal polysaccharide porphyran contains the methoxy sugar 6-O-methyl-D-galactose (G6Me). In the degradation of porphyran, oxidative demethylation of this monosaccharide towards D-galactose and formaldehyde occurs, which is catalyzed by a cytochrome P450 monooxygenase and its redox partners. In direct proximity to the genes encoding for the key enzymes of this oxidative demethylation, genes encoding for zinc-dependent alcohol dehydrogenases (ADHs) were identified, which seem to be conserved in porphyran utilizing marine Flavobacteriia. Considering the fact that dehydrogenases could play an auxiliary role in carbohydrate degradation, we aimed to elucidate the physiological role of these marine ADHs. Although our results reveal that the ADHs are not involved in formaldehyde detoxification, a knockout of the ADH gene causes a dramatic growth defect of Zobellia galactanivorans with G6Me as a substrate. This indicates that the ADH is required for G6Me utilization. Complete biochemical characterizations of the ADHs from Formosa agariphila KMM 3901T (FoADH) and Z. galactanivorans DsijT (ZoADH) were performed, and the substrate screening revealed that these enzymes preferentially convert aromatic aldehydes. Additionally, we elucidated the crystal structures of FoADH and ZoADH in complex with NAD+ and showed that the strict substrate specificity of these new auxiliary enzymes is based on a narrow active site.
Formaldehyde is a toxic metabolite that is formed in large quantities during bacterial utilization of the methoxy sugar 6-O-methyl-d-galactose, an abundant monosaccharide in the red algal polysaccharide porphyran. Marine bacteria capable of metabolizing porphyran must therefore possess suitable detoxification systems for formaldehyde. We demonstrate here that detoxification of formaldehyde in the marine Flavobacterium Zobellia galactanivorans proceeds via the ribulose monophosphate pathway. Simultaneously, we show that the genes encoding the key enzymes of this pathway are important for maintaining high formaldehyde resistance. Additionally, these genes are upregulated in the presence of porphyran, allowing us to connect porphyran degradation to the detoxification of formed formaldehyde.
Abstract
Background
Opioid use for chronic non‐cancer pain (CNCP) is under debate. In the absence of pan‐European guidance on this issue, a position paper was commissioned by the European Pain Federation (EFIC).
Methods
The clinical practice recommendations were developed by eight scientific societies and one patient self‐help organization under the coordination of EFIC. A systematic literature search in MEDLINE (up until January 2020) was performed. Two categories of guidance are given: Evidence‐based recommendations (supported by evidence from systematic reviews of randomized controlled trials or of observational studies) and Good Clinical Practice (GCP) statements (supported either by indirect evidence or by case‐series, case–control studies and clinical experience). The GRADE system was applied to move from evidence to recommendations. The recommendations and GCP statements were developed by a multiprofessional task force (including nursing, service users, physicians, physiotherapy and psychology) and formal multistep procedures to reach a set of consensus recommendations. The clinical practice recommendations were reviewed by five external reviewers from North America and Europe and were also posted for public comment.
Results
The European Clinical Practice Recommendations give guidance for combination with other medications, the management of frequent (e.g. nausea, constipation) and rare (e.g. hyperalgesia) side effects, for special clinical populations (e.g. children and adolescents, pregnancy) and for special situations (e.g. liver cirrhosis).
Conclusion
If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively.
Significance
If a trial with opioids for chronic noncancer pain is conducted, detailed knowledge and experience are needed to adapt the opioid treatment to a special patient group and/or clinical situation and to manage side effects effectively. A collaboration of medical specialties and of all health care professionals is needed for some special populations and clinical situations.
Abstract
Purpose
This study aims to assess the implementation of published research, contraindications, and warnings on the prescription of dual renin‐angiotensin‐hormone system (RAS) blockade in ambulatory care in Germany.
Methods
Cohort study based on health claims data of 6.7 million subjects from 2008 to 2015. Yearly prevalence and incidence for dual RAS blockade with (a) angiotensin‐converting enzyme inhibitors and angiotensin‐receptor blockers (ACEI + ARB) and (b) aliskiren and ACEI or ARB (aliskiren + ACEI/ARB) were calculated. We assessed prescriber specialty and associations between discontinuing dual RAS blockade with specialist (internal medicine, cardiology, nephrology) visits and hospital discharge in the previous year.
Results
A total of 2 984 517 patients were included (age 51.4 ± SD 18.4 y, 48.5% male). Prescription rates for ACEI + ARB decreased from 0.6% (n = 17 907) to 0.4% (n = 12 237) and for aliskiren + ACEI/ARB from 0.23% (n = 6634) to 0.03% (n = 818). Incident prescriptions decreased from 0.23% (n = 6705) to 0.19% (n = 5055) (ACE + ARB) and from 0.1% (n = 2796) to 0.005% (n = 142) (aliskiren + ACE/ARB); 59% of ACEI + ARB and 48% of aliskiren + ACE/ARB combinations were prescribed only by one physician. Of those, 73% (ACEI + ARB) and 58% (aliskiren + ACE/ARB) were primary care providers (PCPs). Discontinuing dual RAS blockade was associated with specialist care and hospital discharge in the previous year (specialist care: RR 1.4, 95% CI, 1.3‐1.6; hospital visit: RR 1.5, 95% CI, 1.3‐1.6).
Conclusions
Our results suggest a delayed uptake of treatment recommendation for ACEI + ARB and a higher impact of Dear Doctor letters addressing PCPs directly compared with published research, contraindications, and warnings. Targeted continuous medical education, practice software alerts, and stronger involvement of pharmacists might improve the implementation of medication safety recommendations in ambulatory care.
The Study of Health in Pomerania (SHIP), a population-based study from a rural state in northeastern Germany with a relatively poor life expectancy, supplemented its comprehensive examination program in 2008 with whole-body MR imaging at 1.5 T (SHIP-MR). We reviewed more than 100 publications that used the SHIP-MR data and analyzed which sequences already produced fruitful scientific outputs and which manuscripts have been referenced frequently. Upon reviewing the publications about imaging sequences, those that used T1-weighted structured imaging of the brain and a gradient-echo sequence for R2* mapping obtained the highest scientific output; regarding specific body parts examined, most scientific publications focused on MR sequences involving the brain and the (upper) abdomen. We conclude that population-based MR imaging in cohort studies should define more precise goals when allocating imaging time. In addition, quality control measures might include recording the number and impact of published work, preferably on a bi-annual basis and starting 2 years after initiation of the study. Structured teaching courses may enhance the desired output in areas that appear underrepresented.