Risk behaviors such as substance use or deviance are often limited to the early stages of the life course. Whereas the onset of risk behavior is well studied, less is currently known about the ...decline and timing of cessation of risk behaviors of different domains during young adulthood. Prevalence and longitudinal developmental patterning of alcohol use, drinking to the point of drunkenness, smoking, cannabis use, deviance, and HIV-related sexual risk behavior were compared in a Swiss community sample (N = 2,843). Using a longitudinal cohort-sequential approach to link multiple assessments with 3 waves of data for each individual, the studied period spanned the ages of 16 to 29 years. Although smoking had a higher prevalence, both smoking and drinking up to the point of drunkenness followed an inverted U-shaped curve. Alcohol consumption was also best described by a quadratic model, though largely stable at a high level through the late 20s. Sexual risk behavior increased slowly from age 16 to age 22 and then remained largely stable. In contrast, cannabis use and deviance linearly declined from age 16 to age 29. Young men were at higher risk for all behaviors than were young women, but apart from deviance, patterning over time was similar for both sexes. Results about the timing of increase and decline as well as differences between risk behaviors may inform tailored prevention programs during the transition from late adolescence to adulthood.
Objectives This study sought to identify risk factors for thrombus formation on the Amplatzer Cardiac Plug (ACP) (St. Jude Medical, St. Paul, Minnesota) after left atrial appendage occlusion. ...Background Left atrial appendage occlusion with the ACP aims to reduce the risk of embolic stroke and bleeding complications associated with vitamin K antagonists in patients with atrial fibrillation. Methods We performed transesophageal echocardiography before discharge and after 3, 6, and 12 months in 34 patients with atrial fibrillation undergoing ACP implantation and receiving dual antiplatelet therapy. Clinical, echocardiographic, and hemostaseological parameters were retrospectively analyzed to identify risk factors for thrombus formation. Results Three patients had thrombi before discharge, 3 more at the 3-month follow-up. No differences were found in left atrial volume, left atrial appendage velocity, spontaneous echo contrast, transmitral gradient, or mitral regurgitation between patients without or with thrombi. CHADS2 (Congestion, Hypertension, Age, Diabetes, and Stroke) score (2.0 ± 1.1 vs. 4.3 ± 1.0), CHA2 DS2 -VASc (CHADS2 plus Vascular Disease and Sex Category) score (5.2 ± 1.3 vs. 6.8 ± 0.8), and pre-interventional platelet count (215.9 ± 63.9/nl vs. 282.5 ± 84.4/nl) were higher and ejection fraction (50.6 ± 11.4% vs. 39.7 ± 10.6%) lower in those with thrombi. Factor 2, factor 5, or methylenetetrahydrofolate reductase mutations and genetic variants associated with reduced clopidogrel activity were not more frequent in patients with thrombi. Conclusions Transesophageal echocardiography identified 17.6% of patients with thrombus formation on the ACP despite dual antiplatelet therapy. CHADS2 and CHA2 DS2 -VASc scores, platelet count, and ejection fraction are risk factors for such thrombus formation.
Atherosclerosis is the primary cause of coronary artery disease (CAD). Several observational studies have examined the association of traditional CAD risk factors with the progression of coronary ...artery calcification (CAC). In our study we investigated the effect of 11 different genetic risk scores associated with CAD and CAD risk factors on the progression of CAC.
We included 3097 participants from the Heinz Nixdorf Recall study who had available CAC measurements at baseline (CACb) and at the 5-year follow-up (CAC5y). A weighted genetic risk score for CAD and each of the CAD-associated risk factors was constructed. Multiple regression analyses were applied to i) the difference between the observed log(CAC5y+1) (log(obs)) and expected log(CAC5y+1) (log(exp)) at the 5-year follow-up following the individual's log(CACb+1) percentile for the time between scans (log(obs)-log(exp)) and ii) the 5-year CAC progression, defined as 5*(log(CAC5y+1)-log(CACb+1))/time between the scans, adjusted for age, sex, and log(CACb+1) as well as for risk factors. The median percent deviation from the expected (CAC5y+1) and the 5-year progression of (CAC+1) in our study were 0 (first quartile: Q1; third quartile: Q3: -0.32; 0.48) and 45.4% (0%; 171.0%) respectively. In the age-, sex- and log(CACb+1)-adjusted model, the per-standard deviation (SD) increase in CAD genetic risk score was associated with the percent deviation from the expected (CAC5y+1) (9.7% (95% confidence interval: 5.2%; 14.5%), p = 1.6x10-5) and the 5-year progression of CAC (7.1% (3.0%; 11.4%), p = 0.0005). The CAD genetic risk score explains an additional 0.6% of the observed phenotypic variance for "log(obs)-log(exp)" and 0.4% for 5-year progression of CAC. Additionally, the per-SD increase in the CAC genetic risk score was associated with the percent deviation from the expected (CAC5y+1) (6.2% (1.9%; 10.8%, p = 0.005)) explaining an additional 0.2% of the observed phenotypic variance. However, the per-SD increase in the CAC genetic risk score was not associated with the 5-year progression of CAC (4.4% (0.4%; 8.5%), p = 0.03) after multiple testing. Adjusting for risk factors did not change the results. None of the other genetic risk scores showed an association with the percent deviation from the expected (CAC5y+1) or with the 5-year progression of CAC.
The association of the CAC genetic risk score and the CAD genetic risk score provides evidence that genetic determinants for CAC and CAD influence the progression of CAC.
Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in ...their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a KFormula: see text' of 8.65 ± 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.
•A new approach to quantifying genetic diversity enables high-resolution analyses of the variation of genotypic patterns in genes and the correlations between genes.•Significant deviations from ...“normal” diversity values were found for major depression; Alzheimer's disease; and schizoaffective disorders.•The central finding of this study was the discovery of “singular genes” characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls.•Neural Net analyses yielded nonlinear classifiers that correctly identified up to 90 % of patients.•Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities.
This study analyzed the extent to which irregularities in genetic diversity separate psychiatric patients from healthy controls.
Genetic diversity was quantified through multidimensional “gene vectors” assembled from 4 to 8 polymorphic SNPs located within each of 100 candidate genes. The number of different genotypic patterns observed per gene was called the gene's “diversity index”.
The diversity indices were found to be only weakly correlated with their constituent number of SNPs (20.5 % explained variance), thus suggesting that genetic diversity is an intrinsic gene property that has evolved over the course of evolution. Significant deviations from “normal” diversity values were found for (1) major depression; (2) Alzheimer's disease; and (3) schizoaffective disorders. Almost one third of the genes were correlated with each other, with correlations ranging from 0.0303 to 0.7245.
The central finding of this study was the discovery of “singular genes” characterized by distinctive genotypic patterns that appeared exclusively in patients but not in healthy controls. Neural Nets yielded nonlinear classifiers that correctly identified up to 90 % of patients. Overlaps between diagnostic subgroups on the genotype level suggested that (1) diagnoses-crossing vulnerabilities are likely involved in the pathogenesis of major psychiatric disorders; (2) clinically defined diagnoses may not constitute etiological entities.
Detailed analyses of the variation of genotypic patterns in genes along with the correlation between genes lead to nonlinear classifiers that enable very robust separation between psychiatric patients and healthy controls on the genotype level.
During the first lockdown of the COVID-19 pandemic, several medical students volunteered as assistants in hospitals, public health departments, and other healthcare services to support and substitute ...permanent staff. The underlying motivations to help are unclear. Therefore, we aimed to assess medical students' motivations and influencing variables such as perceived stress and burden, compassion, and indicators of spirituality.
Cross-sectional survey (convenience sample) from May to June 2020, directly after the first lockdown, among medical students with standardized instruments. One of them is the 12-item Motivations to Help Scale (MtHS) which was designed to fit to the population of medical students.
Among the 731 completers, 52% were working as volunteers during the pandemic in different medical areas, most in hospitals and only a few in other areas (9% in public health departments, 6% in outpatient services), 37% would have liked to work but did not get an appropriate employment, and 21% did not intend to voluntarily support the hospital staff. Their mental burden during work was rather low, while they were somewhat affected by the personal fate of the patients. With respect to their motivations to volunteer as measured with the MtHS,
(Cronbach's alpha = 0.898) scored highest, followed by
(Cronbach's alpha = 0.808), while
(Cronbach's alpha = 0.702) scored lowest. Those who volunteered had significantly higher scores for
and
, while the different phases of medical study (preclinical phase, clinical phase, and higher semester) had no influence on the extent of the students' motivation. The motivations to help were not at all or only marginally (inversely) related to indicators of stress and burden, while
was weakly related to affections by patients' fate.
Medical students' intention to support healthcare professionals as supplementary assistants were both prosocial and proself motivated. With this opportunity to practically apply their current knowledge and to improve their skills and competences, volunteering students might be more motivated for their further studies and their future career as compassionate medical doctors.
Over the past 2 decades, polypharmacy has become the de-facto standard of acute treatment in psychiatry where patients with psychiatric disorders receive a multiple medication regimen. There is ...growing evidence for a potential link between major psychiatric disorders and inflammatory processes. Combining these two aspects aims at avoiding polypharmacy attempts among patients with inflammatory activation through alternative treatment strategies. In this study, we addressed the following questions: (1) to what extent can polypharmacy be explained through the factors “diagnosis”, “previous history”, “severity at baseline”, “age”, “gender”, and “psychiatrist in charge”; (2) what are the differences between polypharmacy and monotherapy regarding efficacy and side effect profiles; and (3) what amount of between-patient variance is explainable by the natural antibody immunoglobulin M (IgM) within each diagnostic group. This naturalistic longitudinal study was comprised of 279 patients under therapy with a clinical diagnosis of depressive (ICD-10: “F3x.x”;
n
= 195) or schizophrenic disorders (ICD-10: “F2x.x”;
n
= 84). The study protocol included (1) assessment of previous history by the SADS Syndrome Check List SSCL-16 (lifetime version); (2) repeated measurements over 5 weeks assessing the time course of improvement by the Hamilton Depression Scale HAM-D and the Positive and Negative Syndrome Scale PANSS, along with medication and unwanted side effects through the Medication and Side Effects Inventory MEDIS; and (3) the collection of blood samples from which DNA and serum were extracted. The association between inflammatory response system and psychiatric disorders was detailed by fitting multi-layer Neural Net (NN) models to the observed data (“supervised learning”). The same approach was used to set up prediction models of side effects. Our data showed that polypharmacy was omnipresent. Yet the various polypharmacy regimens had no advantage over monotherapy: we even found slightly larger baseline score reductions under monotherapy, independent of primary diagnoses and for comparable baseline severities. Most patients experienced unwanted side effects. The close link between side effects and treatment regimen was revealed by a linear model in which the mere number of drugs explained a significant (
p
< 0.001) proportion of the observed variance. As to the inflammatory response system: For the F2 patients, our NN model identified a 22.5% subgroup exhibiting a significant correlation of
r
= 0.746 (
p
= 0.0004) between global schizophrenia scores and IgM levels, along with a correct prediction of response of 94.4%, thus explaining 55.7% of the observed between-patient variance. For the F3 patients, our NN model identified a 19.6% subgroup exhibiting a significant correlation of
r
= 0.644 (
p
= 0.00003) between global depression scores and IgM levels, along a correct prediction of response of 89.6%, thus explaining 41.4% of the observed between-patient variance. Polypharmacy is omnipresent in today’s acute treatment of psychiatric disorders. Given the large proportion of patients with unwanted side effects and the strong correlation between side effects and the number of drugs, polypharmacy approaches are not equally suited for every patient. In terms of efficacy, there are no advantages of polypharmacy over monotherapy. Most notably, our study appears to have cleared the way for the reliable identification of a subgroup of patients for whom the inflammatory response system is a promising target of therapeutic intervention.
Ornithine decarboxylase (ODC) is the sentinel enzyme in polyamine biosynthesis. Both ODC and polyamines regulate cell division, proliferation, and apoptosis. Sepiapterin reductase (SPR) catalyzes the ...last step in the biosynthesis of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, and has been implicated in neurological diseases but not yet in cancer. In this study, we present compelling evidence that native ODC and SPR physically interact, and we defined the individual amino acid residues involved in both enzymes using in silico protein–protein docking simulations. The resulting heterocomplex is a surprisingly compact structure, featuring two energetically and structurally equivalent binding modes both in monomer and in dimer conformations. The novel interaction between ODC and SPR proteins was confirmed under physiological conditions by co-immunoprecipitation and co-localization in neuroblastoma (NB) cells. Importantly, we showed that siRNA (small interfering RNA)-mediated knockdown of SPR expression significantly reduced endogenous ODC enzyme activity in NB cells, thus demonstrating the biological relevance of the ODC–SPR interaction. Finally, in a cohort of 88 human NB tumors, we found that high SPR mRNA expression correlated significantly with poor survival prognosis using a Kaplan–Meier analysis (log-rank test, P=5×10−4), suggesting an oncogenic role for SPR in NB tumorigenesis. In conclusion, we showed that ODC binds SPR and thus propose a new concept in which two well-characterized biochemical pathways converge via the interaction of two enzymes. We identified SPR as a novel regulator of ODC enzyme activity and, based on clinical evidence, present a model in which SPR drives ODC-mediated malignant progression in NB.
Discovery of a new protein–protein interaction between sentinel polyamine and nitric oxide pathway enzymes, ODC and SPR, at physiological levels. Suppression of SPR expression in cells strongly reduces ODC enzyme activity and NB cell proliferation. Display omitted
•New paradigm for pathway interaction by protein–protein binding of sentinel pathway enzymes ODC and SPR is discovered.•Molecular modeling predicts both monomer and dimer interactions between ODC and SPR, in silico.•Native enzymes ODC and SPR interact at physiological levels, in vivo.•SPR suppression reduces ODC enzyme activity and suppresses NB cell proliferation.
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