General practitioners (GPs) should regularly review patients' medications and, if necessary, deprescribe, as inappropriate polypharmacy may harm patients' health. However, deprescribing can be ...challenging for physicians. This study investigates GPs' deprescribing decisions in 31 countries.
In this case vignette study, GPs were invited to participate in an online survey containing three clinical cases of oldest-old multimorbid patients with potentially inappropriate polypharmacy. Patients differed in terms of dependency in activities of daily living (ADL) and were presented with and without history of cardiovascular disease (CVD). For each case, we asked GPs if they would deprescribe in their usual practice. We calculated proportions of GPs who reported they would deprescribe and performed a multilevel logistic regression to examine the association between history of CVD and level of dependency on GPs' deprescribing decisions.
Of 3,175 invited GPs, 54% responded (N = 1,706). The mean age was 50 years and 60% of respondents were female. Despite differences across GP characteristics, such as age (with older GPs being more likely to take deprescribing decisions), and across countries, overall more than 80% of GPs reported they would deprescribe the dosage of at least one medication in oldest-old patients (> 80 years) with polypharmacy irrespective of history of CVD. The odds of deprescribing was higher in patients with a higher level of dependency in ADL (OR =1.5, 95%CI 1.25 to 1.80) and absence of CVD (OR =3.04, 95%CI 2.58 to 3.57).
The majority of GPs in this study were willing to deprescribe one or more medications in oldest-old multimorbid patients with polypharmacy. Willingness was higher in patients with increased dependency in ADL and lower in patients with CVD.
Objective:
Based on findings in animal models of autoimmune optic nerve inflammation, we have assessed the safety and efficacy of erythropoietin in patients presenting with a first episode of optic ...neuritis.
Methods:
Patients with optic neuritis who attended the University Hospitals of Homburg/Saar, Göttingen, or Hamburg (Germany) were included in this double‐blind, placebo‐controlled, phase 2 study (ClinicalTrials.gov, NCT00355095). They were randomly assigned to groups receiving either 33,000IU recombinant human erythropoietin intravenously daily for 3 days or placebo as an add‐on therapy to methylprednisolone. The primary outcome parameter was change in retinal nerve fiber layer (RNFL) thickness after 16 weeks. Secondary outcome parameters included optic nerve atrophy as assessed by magnetic resonance imaging, and changes in visual acuity, visual field, and visual evoked potentials (VEPs).
Results:
Forty patients were assigned to the treatment groups (21/19 erythropoietin/placebo). Safety monitoring revealed no relevant issues. Thirty‐seven patients (20/17 erythropoietin/placebo) were analyzed for the primary endpoint according to the intention‐to‐treat protocol. RNFL thinning was less apparent after erythropoietin treatment. Thickness of the RNFL decreased by a median of 7.5μm by week 16 (mean ± standard deviation, 10.55 ± 17.54μm) compared to a median of 16.0μm (22.65 ± 29.18μm) in the placebo group (p = 0.0357). Decrease in retrobulbar diameter of the optic nerve was smaller in the erythropoietin group (p = 0.0112). VEP latencies at week 16 were shorter in erythropoietin‐treated patients than in the placebo group (p = 0.0011). Testing of visual functions revealed trends toward an improved outcome after erythropoietin treatment.
Interpretation:
These results give the first indications that erythropoietin might be neuroprotective in optic neuritis. ANN NEUROL 2012;72:199–210.
Ciguatoxins (CTXs) are marine toxins that cause ciguatera fish poisoning, a debilitating disease dominated by sensory and neurological disturbances that include cold allodynia and various painful ...symptoms as well as long-lasting pruritus. Although CTXs are known as the most potent mammalian sodium channel activator toxins, the etiology of many of its neurosensory symptoms remains unresolved. We recently described that local application of 1 nM Pacific Ciguatoxin-1 (P-CTX-1) into the skin of human subjects induces a long-lasting, painful axon reflex flare and that CTXs are particularly effective in releasing calcitonin-gene related peptide (CGRP) from nerve terminals. In this study, we used mouse and rat skin preparations and enzyme-linked immunosorbent assays (ELISA) to study the molecular mechanism by which P-CTX-1 induces CGRP release. We show that P-CTX-1 induces CGRP release more effectively in mouse as compared to rat skin, exhibiting EC50 concentrations in the low nanomolar range. P-CTX-1-induced CGRP release from skin is dependent on extracellular calcium and sodium, but independent from the activation of various thermosensory transient receptor potential (TRP) ion channels. In contrast, lidocaine and tetrodotoxin (TTX) reduce CGRP release by 53-75%, with the remaining fraction involving L-type and T-type voltage-gated calcium channels (VGCC). Using transgenic mice, we revealed that the TTX-resistant voltage-gated sodium channel (VGSC) NaV1.9, but not NaV1.8 or NaV1.7 alone and the combined activation of the TTX-sensitive VGSC subtypes NaV1.7 and NaV1.1 carry the largest part of the P-CTX-1-caused CGRP release of 42% and 34%, respectively. Given the contribution of CGRP to nociceptive and itch sensing pathways, our findings contribute to a better understanding of sensory symptoms of acute and chronic ciguatera that may help in the identification of potential therapeutics.
Little is known about the acute psychological stress responses caused by commuting. Evidence for the benefits of active commuting (e.g., walking, cycling) is usually based on studies without ...measurements in free-living environments and without consideration of daily variations in stress. This study investigated the association between commuting mode (active, passive) and perceived commuting stress, assessed on multiple days immediately after commuting.
Adults participating in the cross-sectional ‘Healthy On The way’ (HOTway) study between 2016 and 2017 in Graz, Austria, were included. Participants completed an online survey and responded to statements about perceived stress (demands, tension) on three days before commuting (baseline stress) and after arrival (commuting stress), respectively. Active commuting was defined as cycling and/or walking (passive: car, motorbike, public transport).
Of 188 participants (93 women, mean age: 28.0 ± 10.0 years) included, 124 were active and 64 were passive commuters. Active commuting was associated with less perceived commuting stress compared to passive commuting (bi = −2.95, 95% CI: −4.97 to −0.92, p = .005), even after controlling for subjective well-being, physical activity, commuting time and other confounding variables.
Active commuting is related to a small reduction in perceived commuting stress. The results of this study support the promotion of active commuting for population (mental) health but future studies on the causal mechanisms and the role of active commuting in the recovery from previous stressors are needed.
•Commuting stress and stress levels before commuting were measured on multiple days.•Active commuters perceive less commuting stress than passive commuters.•Active commuting should be promoted for population health.
Bridging the gap: The berberine bridge enzyme (BBE) was employed for the first preparative oxidative biocatalytic CC coupling that leads to a new intramolecular bond. This unique transformation ...requires O2 as sole stoichiometric oxidant and gives access to novel optically pure (S)‐berbine 2 and (R)‐1‐benzyl‐1,2,3,4‐tetrahydroisoquinoline 1 alkaloid derivatives by kinetic resolution.
Lysosomal acid lipase (LAL) hydrolyzes cholesteryl esters (CE) and triglycerides (TG) to generate fatty acids (FA) and cholesterol. LAL deficiency (LAL-D) in both humans and mice leads to ...hepatomegaly, hypercholesterolemia, and shortened life span. Despite its essential role in lysosomal neutral lipid catabolism, the cell type-specific contribution of LAL to disease progression is still elusive. To investigate the role of LAL in the liver in more detail and to exclude the contribution of LAL in macrophages, we generated hepatocyte-specific LAL-deficient mice (Liv-Lipa−/−) and fed them either chow or high fat/high cholesterol diets (HF/HCD). Comparable to systemic LAL-D, Liv-Lipa−/− mice were resistant to diet-induced obesity independent of food intake, movement, and energy expenditure. Reduced body weight gain was mainly due to reduced white adipose tissue depots. Furthermore, Liv-Lipa−/− mice exhibited improved glucose clearance during glucose and insulin tolerance tests compared to control mice. Analysis of hepatic lipid content revealed a massive reduction of TG, whereas CE concentrations were markedly increased, leading to CE crystal formation in the livers of Liv-Lipa−/− mice. Elevated plasma transaminase activities, increased pro-inflammatory cytokines and chemokines as well as hepatic macrophage infiltration indicated liver inflammation. Our data provide evidence that hepatocyte-specific LAL deficiency is sufficient to alter whole-body lipid and energy homeostasis in mice. We conclude that hepatic LAL plays a pivotal role by preventing liver damage and maintaining lipid and energy homeostasis, especially during high lipid availability.
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•Generation of hepatocyte-specific Lipa-deficient mice•Hepatic cholesteryl ester accumulation in Liv-Lipa−/− mice•Improved glucose tolerance and resistance to diet-induced obesity•Hepatic inflammation and liver fibrosis in Liv-Lipa−/− mice•Hepatocyte-specific LAL is critical for maintaining lipid and energy homeostasis.
Scope
Xanthohumol (XN), a prenylated antioxidative and anti‐inflammatory chalcone from hops, exhibits positive effects on lipid and glucose metabolism. Based on its favorable biological properties, ...we investigated whether XN attenuates atherosclerosis in western‐type diet‐fed apolipoprotein‐E‐deficient (ApoE−/−) mice.
Methods and results
XN supplementation markedly reduced plasma cholesterol concentrations, decreased atherosclerotic lesion area, and attenuated plasma concentrations of the proinflammatory cytokine monocyte chemoattractant protein 1. Decreased hepatic triglyceride and cholesterol content, activation of AMP‐activated protein kinase, phosphorylation and inactivation of acetyl‐CoA carboxylase, and reduced expression levels of mature sterol regulatory element‐binding protein (SREBP)‐2 and SREBP‐1c mRNA indicate reduced lipogenesis in the liver of XN‐fed ApoE−/− mice. Concomitant induction of hepatic mRNA expression of carnitine palmitoyltransferase‐1a in ApoE−/− mice‐administered XN suggests increased fatty acid beta‐oxidation. Fecal cholesterol concentrations were also markedly increased in XN‐fed ApoE−/− mice compared with mice fed western‐type diet alone.
Conclusion
The atheroprotective effects of XN might be attributed to combined beneficial effects on plasma cholesterol and monocyte chemoattractant protein 1 concentrations and hepatic lipid metabolism via activation of AMP‐activated protein kinase.
Ciguatoxins are sodium channel activator toxins that cause ciguatera, the most common form of ichthyosarcotoxism, which presents with peripheral sensory disturbances, including the pathognomonic ...symptom of cold allodynia which is characterized by intense stabbing and burning pain in response to mild cooling. We show that intraplantar injection of P‐CTX‐1 elicits cold allodynia in mice by targeting specific unmyelinated and myelinated primary sensory neurons. These include both tetrodotoxin‐resistant, TRPA1‐expressing peptidergic C‐fibres and tetrodotoxin‐sensitive A‐fibres. P‐CTX‐1 does not directly open heterologously expressed TRPA1, but when co‐expressed with Nav channels, sodium channel activation by P‐CTX‐1 is sufficient to drive TRPA1‐dependent calcium influx that is responsible for the development of cold allodynia, as evidenced by a large reduction of excitatory effect of P‐CTX‐1 on TRPA1‐deficient nociceptive C‐fibres and of ciguatoxin‐induced cold allodynia in TRPA1‐null mutant mice. Functional MRI studies revealed that ciguatoxin‐induced cold allodynia enhanced the BOLD (Blood Oxygenation Level Dependent) signal, an effect that was blunted in TRPA1‐deficient mice, confirming an important role for TRPA1 in the pathogenesis of cold allodynia.
Ciguatoxins derived from fish lead to cold allodynia in humans, the perception of intense burning pain in response to mild cooling. A novel mouse model of ciguatoxin‐induced cold allodynia reveals that ciguatoxin activates the TRPA1 thermosensitive ion channel to mediate pain perception.
We aimed to assess whether whole blood expression quantitative trait loci (eQTLs) with effects in cis and trans are robust and can be used to identify regulatory pathways affecting disease ...susceptibility.
We performed whole-genome eQTL analyses in 890 participants of the KORA F4 study and in two independent replication samples (SHIP-TREND, N = 976 and EGCUT, N = 842) using linear regression models and Bonferroni correction.
In the KORA F4 study, 4,116 cis-eQTLs (defined as SNP-probe pairs where the SNP is located within a 500 kb window around the transcription unit) and 94 trans-eQTLs reached genome-wide significance and overall 91% (92% of cis-, 84% of trans-eQTLs) were confirmed in at least one of the two replication studies. Different study designs including distinct laboratory reagents (PAXgene™ vs. Tempus™ tubes) did not affect reproducibility (separate overall replication overlap: 78% and 82%). Immune response pathways were enriched in cis- and trans-eQTLs and significant cis-eQTLs were partly coexistent in other tissues (cross-tissue similarity 40-70%). Furthermore, four chromosomal regions displayed simultaneous impact on multiple gene expression levels in trans, and 746 eQTL-SNPs have been previously reported to have clinical relevance. We demonstrated cross-associations between eQTL-SNPs, gene expression levels in trans, and clinical phenotypes as well as a link between eQTLs and human metabolic traits via modification of gene regulation in cis.
Our data suggest that whole blood is a robust tissue for eQTL analysis and may be used both for biomarker studies and to enhance our understanding of molecular mechanisms underlying gene-disease associations.
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