Restenose nach perkutaner transluminaler Koronar Angioplastie und Insertion/Deletion Polymorphismus im Gen für das Angiotensin-I-Konversionsenzym

Derzeit wird die Bedeutung des Insertions/Deletions (I/D) Gen-Polymorphismus (GP) im Intron 16 des Gens für das Angiotensin-I-Konversionsenzym (ACE) für kardiovaskuläre Erkrankungen kontrovers diskutiert. Für das D-Allel und die In-Stent Restenose ist eine positive Assoziation bekannt. Für die Restenose nach einfacher perkutaner transluminaler koronarer Angioplastie (PTCA) besteht keine Assoziation. Bisher nicht untersucht wurde, ob ein Zusammenhang zwischen Insufflationsdruck und -zeit einer PTCA, I/D Genotyp und der Bildung einer Restenose besteht. Retrospektiv wurden 61 Patienten (52 Männer 42-72 Jahre; Mittelwert 56,8 Jahre, 9 Frauen 49-71 Jahre; Mittelwert 58,6 Jahre) untersucht, die nach primär erfolgreicher komplikationsloser Ein-Gefäß PTCA innerhalb eines Jahres reangiographiert wurden. Es bestand kein Unterschied hinsichtlich des Risikofaktorenprofils in den einzelnen Gruppen. Der ACE I/D Genotyp wurde mittels Polymerase Ketten Reaktion bestimmt; es wurde eine DD und eine nonDD-Gruppe gebildet. Das Vorgehen bei der PTCA wurde anhand der häufigsten verwendeten Kombination von Druck und Zeit in zwei Kategorien geteilt: 1. Medium pressure/Long inflation time (MP/LT): bei Erreichen oder Überschreiten der Kombination von 6 bar oder 60 Sekunden in einem Dilatationschritt, andernfalls 2. Low pressure/short inflation time (LP/ST). Bei 39 Patienten wurde eine Restenose dokumentiert. Zwischen ACE I/D Genotyp (p=0,9) sowie MP/LT und LP/ST PTCA (p=0,49) bestand kein Zusammenhang mit einem Rezidiv. Homozygote Merkmalsträger für das D-Allel hingegen zeigten eine deutlich erhöhte Restenose-Rate, wenn sie mit einer MP/LT PTCA behandelt wurden (p = 0,01; Odd’s Ratio: 4,5; 95% Konfidenzintervall: 1,9 – 10,7). In einer post hoc Analyse zeigte sich mittels eines binären logistischen Regressionsmodells in der DD-Gruppe ein statistisch signifikanter Zusammenhang mit der Insufflationszeit (Regressionskoeffizient 0,287; p=0,037, 90,9% richtige Berechnung der Gruppenzugehörigkeit). In einer Receiver-Operating-Characteristics Analyse wurde bei einer Sensitivität von 100% bei einer Insufflationszeit von 57,5 s eine Wahrscheinlichkeit von 25% für ein falsch positives Ergebnis (1-Spezifität) errechnet (Fläche unter der Kurve: 0,87; Standardfehler: 0,095). Angesichts der Ergebnisse sollte der ACE I/D GP bei der Charakterisierung der komplexen Zusammenhänge der Pathogenese der Restenose in zukünftigen Studien weiterhin Berücksichtigung finden

Feigning ADHD and stimulant misuse among Dutch university students

The increasing number of university students seeking diagnosis of attention-deficit/hyperactivity disorder (ADHD), and findings of an increased stimulant misuse among university students, has raised concerns regarding the credibility of the symptoms of those students. However, most of our current knowledge refers to university students in North America and less is known about this issue on European campuses. The present survey aimed to collect opinions on feigning ADHD and to estimate the prevalence of stimulant misuse among 1071 university students in the Netherlands. The majority of students expressed liberal attitudes towards feigning ADHD. Also, a substantial number of respondents considered feigning ADHD themselves or know someone who feigns ADHD. Furthermore, 68% of students assumed benefits of taking stimulants without prescription and 16% have indeed already taken stimulants without prescription. Feigning ADHD and misuse of prescription medication are prevalent issues among Dutch students. The results underline the need for a careful diagnostic evaluation of individuals for ADHD. Furthermore, efforts are required in order to prevent stimulant drug trafficking and misuse among university students

ADHD 24/7:Circadian clock genes, chronotherapy and sleep/wake cycle insufficiencies in ADHD

Objectives: The current paper addresses the evidence for circadian clock characteristics associated with attention-deficit hyperactivity disorder (ADHD), and possible therapeutic approaches based on chronomodulation through bright light (BL) therapy. Methods: We review the data reported in ADHD on genetic risk factors for phase-delayed circadian rhythms and on the role of photic input in circadian re-alignment. Results: Single nucleotide polymorphisms in circadian genes were recently associated with core ADHD symptoms, increased evening-orientation and frequent sleep problems. Additionally, alterations in exposure and response to photic input may underlie circadian problems in ADHD. BL therapy was shown to be effective for re-alignment of circadian physiology toward morningness, reducing sleep disturbances and bringing overall improvement in ADHD symptoms. The susceptibility of the circadian system to phase shift by timed BL exposure may have broad cost-effective potential implications for the treatment of ADHD. Conclusions: We conclude that further research of circadian function in ADHD should focus on detection of genetic markers (e.g., using human skin fibroblasts) and development of BL-based therapeutic interventions

Highly variable pharmacokinetics of tyramine in humans and polymorphisms in OCT1, CYP2D6, and MAO-A

Tyramine, formed by the decarboxylation of tyrosine, is a natural constituent of numerous food products. As an indirect sympathomimetic, it can have potentially dangerous hypertensive effects. In vitro data indicated that the pharmacokinetics of tyramine possibly depend on the organic cation transporter OCT1 genotype and on the CYP2D6 genotype. Since tyramine is a prototypic substrate of monoamine oxidase A (MAO-A), genetic polymorphisms in MAO-A may also be relevant. The aims of this study were to identify to what extent the interindividual variation in pharmacokinetics and pharmacodynamics of tyramine is determined by genetic polymorphisms in OCT1, CYP2D6, and MAO-A. Beyond that, we wanted to evaluate tyramine as probe drug for the in vivo activity of MAO-A and OCT1. Therefore, the pharmacokinetics, pharmacodynamics, and pharmacogenetics of tyramine were studied in 88 healthy volunteers after oral administration of a 400 mg dose. We observed a strong interindividual variation in systemic tyramine exposure, with a mean AUC of 3.74 min*µg/ml and a high mean CL/F ratio of 107 l/min. On average, as much as 76.8% of the dose was recovered in urine in form of the MAO-catalysed metabolite 4-hydroxyphenylacetic acid (4-HPAA), confirming that oxidative deamination by MAO-A is the quantitatively most relevant metabolic pathway. Systemic exposure of 4-HPAA varied only up to 3-fold, indicating no strong heritable variation in peripheral MAO-A activity. Systolic blood pressure increased by more than 10 mmHg in 71% of the volunteers and correlated strongly with systemic tyramine concentration. In less than 10% of participants, individually variable blood pressure peaks by >40 mmHg above baseline were observed at tyramine concentrations of >60 µg/l. Unexpectedly, the functionally relevant polymorphisms in OCT1 and CYP2D6, including the CYP2D6 poor and ultra-rapid metaboliser genotypes, did not significantly affect tyramine pharmacokinetics or pharmacodynamics. Also, the MOA-A genotypes, which had been associated in several earlier studies with neuropsychiatric phenotypes, had no significant effects on tyramine pharmacokinetics or its metabolism to 4-HPAA. Thus, variation in tyramine pharmacokinetics and pharmacodynamics is not explained by obvious genomic variation, and human tyramine metabolism did not indicate the existence of ultra-low or -high MAO-A activity

Evolutionary conservations, changes of circadian rhythms and their effect on circadian disturbances and therapeutic approaches

The circadian rhythm is essential for the interaction of all living organisms with their environments. Several processes, such as thermoregulation, metabolism, cognition and memory, are regulated by the internal clock. Disturbances in the circadian rhythm have been shown to lead to the development of neuropsychiatric disorders, including attention-deficit hyperactivity disorder (ADHD). Interestingly, the mechanism of the circadian rhythms has been conserved in many different species, and misalignment between circadian rhythms and the environment results in evolutionary regression and lifespan reduction. This review summarises the conserved mechanism of the internal clock and its major interspecies differences. In addition, it focuses on effects the circadian rhythm disturbances, especially in cases of ADHD, and describes the possibility of recombinant proteins generated by eukaryotic expression systems as therapeutic agents as well as CRISPR/Cas9 technology as a potential tool for research and therapy. The aim is to give an overview about the evolutionary conserved mechanism as well as the changes of the circadian clock. Furthermore, current knowledge about circadian rhythm disturbances and therapeutic approaches is discussed

Remdesivir shifts circadian rhythmicity to eveningness; similar to the most prevalent chronotype in ADHD

Circadian clocks control immunity and virus replication, as well as pharmacokinetics and efficacy therapeutics. The aim of this study was to investigate the extent of these relationships by measuring circadian gene expression in primary human-derived dermal fibroblast cultures (HDF) after remdesivir exposure. In the current study, we analysed circadian gene expression in a cohort of participants without a neuropsychiatric diagnosis. After ex vivo exposure to remdesivir to human dermal fibroblast (HDF) cultures and dexamethasone synchronization, the rhythmicity of circadian gene expression (Clock, Bmal1, Per1-3, Cry1) was analysed via qRT-PCR. In this study, D-MEQ scores indicated that participants without a neuropsychiatric diagnosis had no evening preference. Remdesivir leads to a slight phase-shift in Clock, Per1 and Per2. Significant different expressions of Bmal1 and Per3 were detected after remdesivir exposure: Bmal1 at ZT8 (t(22)=3.26, p=0.004), ZT24 (t(22)=− 2.66, p=0.015), ZT28 (t(20)=− 2.14, p=0.045) and Per3 at ZT8 (t(22)=− 4.27, p<0.001) and ZT12 (t(22)=− 2.61, p=0.016). A significant difference between chronotype and circadian gene expression for Bmal1, Cry1 and Per3 was observed. The present study shows that remdesivir has an impact on circadian function. It is well known that the circadian rhythm effects sleep and, moreover, sleep quality. The results suggest that remdesivir medication may alter sleep quality in participants without a neuropsychiatric diagnosis and shifts chronotype to evenness; similar as prevalent in ADH

The impact of the COVID-19 outbreak on the medico-legal and human rights of psychiatric patients

The COVID-19 pandemic has raised significant concerns for population mental health and the effective provision of mental health services in the light of increased demands and barriers to service delivery [1]. Particular attention is being directed toward the possible neuropsychiatric sequelae of both COVID-19 and of the stringent societal mitigation steps deployed by national governments, concerns that are informed by historical increases in the incidence of psychotic disorders following influenza pandemics [2]. However, so far there has been scant attention paid to other important areas of psychiatry during COVID-19, including medico-legal aspects and human rights. In this paper, we discuss the legal implications for psychiatry of the COVID-19 pandemic and report a novel situation in which psychiatric patients may experience diminution of their statutory protections. We believe that this represents a paradigm shift in psychiatric care and that the consideration of the fundamental rights of psychiatric patients as “less important” than infection control measures compel mental health professionals to “advocate for … patients and their caregivers” in this time of crisis [1]

Therapeutic Reference Range for Aripiprazole in Schizophrenia Revised: a Systematic Review and Metaanalysis

Rationale: While one of the basic axioms of pharmacology postulates that there is a relationship between the concentration and effects of a drug, the value of measuring blood levels is questioned by many clinicians. This is due to the often-missing validation of therapeutic reference ranges. Objectives: Here, we present a prototypical meta-analysis of the relationships between blood levels of aripiprazole, its target engagement in the human brain, and clinical effects and side effects in patients with schizophrenia and related disorders. Methods: The relevant literature was systematically searched and reviewed for aripiprazole oral and injectable formulations. Population-based concentration ranges were computed (N = 3,373) and pharmacokinetic influences investigated. Results: Fifty-three study cohorts met the eligibility criteria. Twenty-nine studies report blood level after oral, 15 after injectable formulations, and nine were positron emission tomography studies. Conflicting evidence for a relationship between concentration, efficacy, and side effects exists (assigned level of evidence low, C; and absent, D). Population-based reference ranges are well in-line with findings from neuroimaging data and individual efficacy studies. We suggest a therapeutic reference range of 120-270 ng/ml and 180-380 ng/ml, respectively, for aripiprazole and its active moiety for the treatment of schizophrenia and related disorders. Conclusions: High interindividual variability and the influence of CYP2D6 genotypes gives a special indication for Therapeutic Drug Monitoring of oral and long-acting aripiprazole. A starting dose of 10 mg will in most patients result in effective concentrations in blood and brain. 5 mg will be sufficient for known poor metabolizers

Transient Receptor Potential Channel Polymorphisms Are Associated with the Somatosensory Function in Neuropathic Pain Patients

Transient receptor potential channels are important mediators of thermal and mechanical stimuli and play an important role in neuropathic pain. The contribution of hereditary variants in the genes of transient receptor potential channels to neuropathic pain is unknown. We investigated the frequency of transient receptor potential ankyrin 1, transient receptor potential melastin 8 and transient receptor potential vanilloid 1 single nucleotide polymorphisms and their impact on somatosensory abnormalities in neuropathic pain patients. Within the German Research Network on Neuropathic Pain (Deutscher Forscbungsverbund Neuropathischer Schmerz) 371 neuropathic pain patients were phenotypically characterized using standardized quantitative sensory testing. Pyrosequencing was employed to determine a total of eleven single nucleotide polymorphisms in transient receptor potential channel genes of the neuropathic pain patients and a cohort of 253 German healthy volunteers. Associations of quantitative sensory testing parameters and single nucleotide polymorphisms between and within groups and subgroups, based on sensory phenotypes, were analyzed. Single nucleotide polymorphisms frequencies did not differ between both the cohorts. However, in neuropathic pain patients transient receptor potential ankyrin 1 710G>A (rs920829, E179K) was associated with the presence of paradoxical heat sensation (p = 0.03), and transient receptor potential vanilloid 1 1911A>G (rs8065080, I585V) with cold hypoalgesia (p = 0.0035). Two main subgroups characterized by preserved (1) and impaired (2) sensory function were identified. In subgroup 1 transient receptor potential vanilloid 1 1911A>G led to significantly less heat hyperalgesia, pinprick hyperalgesia and mechanical hypaesthesia (p = 0.006, p = 0.005 and p<0.001) and transient receptor potential vanilloid 1 1103C>G (rs222747, M315I) to cold hypaesthesia (p = 0.002), but there was absence of associations in subgroup 2. In this study we found no evidence that genetic variants of transient receptor potential channels are involved in the expression of neuropathic pain, but transient receptor potential channel polymorphisms contributed significantly to the somatosensory abnormalities of neuropathic pain patients

COVID-19 paranoia in a patient suffering from schizophrenic psychosis – a case report

The COVID-19 pandemic affects mental health, both in healthcare settings and broader society. Fear responses in both the uninfected and infected may reach psychopathological levels that require psychiatric interventions (Duan and Zhu, 2020), and physicians and mental health professionals may have particularly high need for psychological support in the case of development of stress-related disorders (Chen et al., 2020). An area of key concern is the potential of the psychological context of the pandemic to exacerbate existing psychiatric conditions and influence the manifestation of their symptomatology. Here we report the case of a patient with schizophrenia presenting with COVD-19- related delusions and hallucinations, illustrating the potential of COVID-19 to precipitate entry into a psychotic phase and impact symptom manifestation