Search

Background The burden of long-term symptoms (ie, long COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCWs), frequency and risk factors for symptoms compatible with long COVID are assessed. Methods Participants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long COVID (including psychometric scores) were asked and compared between HCWs with positive NPS, seropositive HCWs without positive NPS (presumable asymptomatic/pauci-symptomatic infections), and negative controls. The effect of time since diagnosis and quantitative anti-spike protein antibodies (anti-S) was evaluated. Poisson regression was used to identify risk factors for symptom occurrence. Results Of 3334 HCWs (median, 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCWs with positive NPS more frequently reported ≥1 symptom compared with controls (73% vs 52%, P 6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores. Conclusions Seropositive HCWs without positive NPS are only mildly affected by long COVID. Exhaustion/burnout is common, even in noninfected HCWs. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.

BackgroundThe burden of long-term symptoms (i.e. long-COVID) in patients after mild COVID-19 is debated. Within a cohort of healthcare workers (HCW), frequency and risk factors for symptoms compatible with long-COVID are assessed.MethodsParticipants answered baseline (August/September 2020) and weekly questionnaires on SARS-CoV-2 nasopharyngeal swab (NPS) results and acute disease symptoms. In January 2021, SARS-CoV-2 serology was performed; in March, symptoms compatible with long-COVID (including psychometric scores) were asked and compared between HCW with positive NPS, seropositive HCW without positive NPS (presumable a-/pauci-symptomatic infections), and negative controls. Also, the effect of time since diagnosis and quantitative anti-S was evaluated. Poisson regression was used to identify risk factors for symptom occurrence.ResultsOf 3’334 HCW (median 41 years; 80% female), 556 (17%) had a positive NPS and 228 (7%) were only seropositive. HCW with positive NPS more frequently reported ≥1 symptom compared to controls (73%vs.52%, pvs.6%, pvs.10%, p=0.004) were more common. Exhaustion/burnout was reported by 24% of negative controls. Many symptoms remained elevated in those diagnosed >6 months ago; anti-S titers correlated with high symptom scores. Acute viral symptoms in weekly questionnaires best predicted long-COVID symptoms. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue scores.ConclusionsSeropositive HCW without positive NPS are only mildly affected by long-COVID. Exhaustion/burnout is common, even in non-infected HCW. Physical activity might be protective against neurocognitive impairment/fatigue symptoms after COVID-19.summaryIn this prospective healthcare worker cohort, participants with SARS-CoV-2-positive nasopharyngeal swab were most likely to report long-COVID symptoms, whereas seropositive participants without positive swab were only mildly affected. Physical activity at baseline was negatively associated with neurocognitive impairment and fatigue.

Die psychosomatische Perspektive kommt meist ins Spiel, wenn Schwindel ohne nachweisbares organisches oder funktionelles Korrelat auftritt. Diagnostisch lassen sich die so definierten Beschwerden unter die somatoformen Störungen einordnen (ICD-10 F45). Ätiologisch hilft diese Einordnung nicht weiter, da die Erklärungskonzepte somatoformer Störungen uneinheitlich sind. Diese ätiologische Unsicherheit widerspiegelt sich im Fehlen eindeutig belegter wirksamer Therapieoptionen, die medikamentöse Behandlung mit SSRI und Benzodiazepinen sowie kognitiv behaviorale Psychotherapie umfassen. Im zweiten Teil des Artikels wird an Hand von Fallbeispielen versucht, über das Konzept einer Unterscheidung leiblicher von körperlichen Phänomenen Schwindel in seinen Auswirkungen auf das leibliche Befinden von Patienten zu verstehen und daraus therapeutische Interventionen abzuleiten. Betont wird die Abhängigkeit der Inzidenz von Schwindel als ängstigendes Symptom vom Zeitgeist einer Epoche, der darüber entscheidet, welche Wahrnehmungen Krankheitswert erhalten. Schwindel als leibliche Regung kann Orientierungslosigkeit bedeuten, oder abgeleitet sein aus Zuständen des sich Verlierens in die Weite der Schläfrigkeit; beides wird an Fallbeispielen erläutert.

Background. Analysis of isoniazid (INH) uptake has been based on measurement of plasma concentrations providing a short-term and potentially biased view.Objectives. To establish hair analysis as a tool to measure long-term uptake of INH and to assess whether acetylator phenotype in hair reflects N-acetyltransferase-2 (NAT2) genotype.Design and Methods. INH and acetyl-INH concentrations in hair were determined in patients on INH treatment forM. tuberculosisinfection using high pressure liquid chromatography/mass spectrometry. Acetyl-INH/INH ratios were correlated with NAT-2 genotype.Results. Hair concentrations of INH, determined in 40 patients, were not dependent on ethnic group or body mass index and were significantly higher in male compared to female patients (median (range) 2.37 ng/mg (0.76–4.9) versus 1.11 ng/mg (0.02–7.20) (P=0.02). Acetyl-INH/INH ratios were a median of 15.2% (14.5 to 31.7) in homozygous rapid acetylator NAT-2 genotype and 37.3% (1.73 to 51.2) in the heterozygous rapid acetylator NAT-2 genotype and both significantly higher than in the slow acetylator NAT-2 genotype with 5.8% (0.53 to 14.4) (P<0.05).Conclusions. Results of hair analysis for INH showed lower concentrations in females. Acetyl-INH/INH ratios were significantly lower in patients with slow acetylator versus rapid acetylator genotypes.

ims: Periodic leg movements in sleep (PLMS) are a frequent finding in polysomnography. Most patients with restless legs syndrome (RLS) display PLMS. However, since PLMS are also often recorded in healthy elderly subjects, the clinical significance of PLMS is still discussed controversially. Leg movements are seen concurrently with arousals in obstructive sleep apnoea (OSA) may also appear periodically. Quantitative assessment of the periodicity of LM/PLM as measured by inter movement intervals (IMI) is difficult. This is mainly due to influencing factors like sleep architecture and sleep stage, medication, inter and intra patient variability, the arbitrary amplitude and sequence criteria which tend to broaden the IMI distributions or make them even multi-modal. Methods: Here a statistical method is presented that enables eliminating such effects from the raw data before analysing the statistics of IMI. Rather than studying the absolute size of IMI (measured in seconds) we focus on the shape of their distribution (suitably normalized IMI). To this end we employ methods developed in Random Matrix Theory (RMT). Patients: The periodicity of leg movements (LM) of four patient groups (10 to 15 each) showing LM without PLMS (group 1), OSA without PLMS (group 2), PLMS and OSA (group 3) as well as PLMS without OSA (group 4) are compared. Results: The IMI of patients without PLMS (groups 1 and 2) and with PLMS (groups 3 and 4) are statistically different. In patients without PLMS the distribution of normalized IMI resembles closely the one of random events. In contrary IMI of PLMS patients show features of periodic systems (e.g. a pendulum) when studied in normalized manner. Conclusions: For quantifying PLMS periodicity proper normalization of the IMI is crucial. Without this procedure important features are hidden when grouping LM/PLM over whole nights or across patients. The clinical significance of PLMS might be eluded when properly separating random LM from LM that show features of periodic systems.

STR investigations of telogen hair are invariably difficult due to the small amounts of nuclear DNA and its degradation products. However, in recent years there has been a considerable improvement. This study examined the suitability of a new STR kit with shortened amplicons for the investigation of hair in routine casework. This kit allows the simultaneous amplification of the eight STR-loci D3S1358, VWA, FGA, TH01, SE33, D8S1179, D18S51, and D21S11, and the sex-determining amelogenin system. It was tested against the genRES MPX-SP1 and genRES MPX-SP2 kits. The sensitivity of the new genRES MPX-2SP kit was demonstrated to be inferior to that of the genRES MPX-SP1, but almost equal to that of the genRES MPX-SP2 kit.

Ghrelin, an endogenous ligand of the growth hormone (GH) secretagogue receptor, stimulates sleep, appetite and weight gain as well as the secretion of GH, adrenocorticotropic hormone (ACTH), cortisol in humans and rodents. The interaction between nocturnal ghrelin levels, sleep EEG and the secretion of these hormones was not investigated systematically so far. Furthermore conflicting data exist on gender differences in nocturnal ghrelin secretion. We examined simultaneously sleep EEG and the nocturnal levels of ghrelin, GH, ACTH and cortisol in young and middle-aged normal human subjects (eight males, eight females). A significant interaction between gender and the course of ghrelin concentration was observed to the interval between 20:00 and 23:00 hours. In males a continuous increase of ghrelin levels before sleep onset was found. In females, however, a rise of ghrelin during the night was missed. We found a trend suggesting a lower time spent in stage I sleep in subjects with high nocturnal ghrelin levels. Other systematic interactions between plasma ghrelin, sleep EEG and other hormones were not found. No peak in plasma ghrelin levels resembling the GH surge was observed. We suggest that under naturalistic conditions plasma ghrelin levels show no distinct interaction with sleep.

To test for human population substructure and to investigate human population history we have analysed Y-chromosome diversity using seven microsatellites (Y-STRs) and ten binary markers (Y-SNPs) in samples from eight regionally distributed populations from Poland (n = 913) and 11 from Germany (n = 1,215). Based on data from both Y-chromosome marker systems, which we found to be highly correlated (r = 0.96), and using spatial analysis of the molecular variance (SAMOVA), we revealed statistically significant support for two groups of populations: (1) all Polish populations and (2) all German populations. By means of analysis of the molecular variance (AMOVA) we observed a large and statistically significant proportion of 14% (for Y-SNPs) and 15% (for Y-STRs) of the respective total genetic variation being explained between both countries. The same population differentiation was detected using Monmonier's algorithm, with a resulting genetic border between Poland and Germany that closely resembles the course of the political border between both countries. The observed genetic differentiation was mainly, but not exclusively, due to the frequency distribution of two Y-SNP haplogroups and their associated Y-STR haplotypes: R1a1*, most frequent in Poland, and R1*(xR1a1), most frequent in Germany. We suggest here that the pronounced population differentiation between the two geographically neighbouring countries, Poland and Germany, is the consequence of very recent events in human population history, namely the forced human resettlement of many millions of Germans and Poles during and, especially, shortly after World War II. In addition, our findings have consequences for the forensic application of Y-chromosome markers, strongly supporting the implementation of population substructure into forensic Y chromosome databases, and also for genetic association studies.

A population study on 10 tetrameric STR loci (ACTBP2 (=SE33), D18S51, D8S1132, D12S391, D2S1360, D3S1744, D5S2500, D7S1517, D10S2325, D21S2055) was performed with Germans from Bavaria.

In forensic genetics mitochondrial DNA (mtDNA) is usually analyzed by direct Sanger-type sequencing (STS). This method is known to be laborious and sometimes prone to human error. Alternative methods have been proposed that lead to faster results. Among these are methods that involve mass-spectrometry resulting in base composition profiles that are, by definition, less informative than the full nucleotide sequence. Here, we applied a highly automated electrospray ionization mass spectrometry (ESI-MS) system (PLEX-ID) to an mtDNA population study to compare its performance with respect to throughput and concordance to STS. We found that the loss of information power was relatively low compared to the gain in speed and analytical standardization. The detection of point and length heteroplasmy turned out to be roughly comparable between the technologies with some individual differences related to the processes. We confirm that ESI-MS provides a valuable platform for analyzing mtDNA variation that can also be applied in the forensic context.

Background: 4-Aminobiphenyl (4-ABP) and o-toluidine are known human bladder carcinogens, but only 4-ABP-releasing DNA adducts are known.Methods: Determination of 4-ABP and o-toluidine-releasing DNA adducts in epithelial and submucosal bladder tissues of sudden death victims (SDV: n = 46), and bladder tumours (n = 12) by gas chromatography/mass spectrometry.Results: Above background, 4 and 11 of 12 tumour samples contained adducts of 4-ABP (0.057 ± 0.125 fmol/µg DNA) and o-toluidine (8.72 ± 4.49 fmol/µg DNA), respectively. Lower adduct levels were present in both epithelial and submucosal bladder tissues of SDV (4-ABP: 0.011 ± 0.022 and 0.019 ± 0.047 fmol/µg DNA; o-toluidine: 0.24 ± 0.63 and 0.27 ± 0.70 fmol/µg DNA).Conclusion: Detection of o-toluidine-releasing DNA adducts support the carcinogenicity of o-toluidine in the human bladder.

The metabolite ratio of amitriptyline (AT), nortriptyline (NT) and its 10-hydroxy metabolites (E10-OHAT, Z10-OHAT, E10-OHNT and Z10-OHNT) was examined by liquid chromatography-mass spectrometry in hair samples of 23 white infants after long-term administration of AT. High inter-individual variation of the metabolite ratios were observed (e.g. NT/AT = 0.8–8.1, E10-OHNT/Z10-OHNT = 1.6–10.3). The significance of these variations was proven by confirmation of the temporary stability of these ratios within a hair fibre. Moreover, an association of the metabolic phenotype with genetic disposition was observed. The genotypes of CYP2C19 (alleles *2, *3 and *4) and of CYP2D6 (*3, *4, and *6) were examined by conventional polymerase chain reaction genotyping experiments. The relative amount of demethylation (NT/AT) is clearly affected by the number of functional alleles of CYP2C19. The demethylation capacity of CYP2C19 poor metabolizers (3 individuals, compared to 15 extensive metabolizers) was 4.3 times depleted. Moreover, the selectivity of hydroxylation (e.g. E10-OHNT/Z10-OHNT) is significantly correlated with CYP2C19.

Since 2005, increasing numbers of seizures of the designer drug of abuse 1-(3-chlorophenyl)piperazine (mCPP) have been reported. This paper describes the unequivocal proof of a mCPP intake. Differentiation from the intake of its precursor drugs trazodone and nefazodone was performed by a systematic toxicological analysis (STA) procedure using full-scan GC-MS after acid hydrolysis, liquid-liquid extraction and microwave-assisted acetylation. The found mCPP/hydroxy-mCPP ratio indicated altered metabolism of this cytochrome (CYP) 2D6 catalyzed reaction compared to published studies using the same procedure. Although this might be ascribed to a poor metabolizer (PM) phenotype, genotyping revealed no PM genotype but indications for an intermediate metabolizer genotype. However, a PM phenotype could also be caused by drug-drug interactions with CYP2D6 inhibitors or substrates such as the co-consumed cocaine and diltiazem and/or diltiazem metabolites, respectively. In conclusion, the presented data indicate a possible relevance of CYP2D6 polymorphism and/or drug interactions to mCPP toxicokinetics, which is important for risk assessment of this new designer drug of abuse, in particular if it is used as adulterant of CYP2D6 substrates such as cocaine.

The identification of amitriptyline, nortriptyline and its hydroxy-metabolites including a subsequent measurement of concentration profiles in hair samples was carried out to evaluate the administration history of amitriptyline. Analyses were carried out using liquid chromatography—tandem mass spectrometry, which permits simultaneous identification of all relevant substances in hair at low target concentrations (limit of detection better than 0.5 pg/mg). Standard hair sample preparation was applied for the estimation of average substance concentration in a hair bundle, while segmentation of individual hairs was utilised to examine accurate concentration profiles. Replication of analyses demonstrated a good reproducibility of individual hair concentration profiles, which proved to coincide for all relevant compounds. Significant variations of metabolite ratios (e.g. nortriptyline to amitriptyline and E10- to Z10-hydroxynortriptyline) between individuals suggest a correlation between hair concentration and metabolic phenotype. Different concentration ratios of certain metabolites in hair are highly correlated, indicating a systematic association between demethylation and stereo-specificity of hydroxylation. The trans isomers of hydroxy-metabolites become significantly more prevalent with increasing degree of demethylation of amitriptyline or hydroxylation of amitriptyline.

Narcolepsy with cataplexy is thought to be a hypocretin ligand or hypocretin receptor deficiency syndrome caused by genetic and environmental factors. We looked for an abnormality of the hypocretin pathway in HLA-DQB1*0602-positive monozygotic twins who were concordant for narcolepsy-cataplexy. They had normal cerebrospinal fluid concentrations of hypocretin-1, and we found no mutation in the prepro-hypocretin gene or either hypocretin receptor gene. Our finding points to the existence of presumably genetic forms of narcolepsy with cataplexy without any demonstrable defect in the hypocretin pathway.

Recently, ortho-toluidine (o-Tol) has been added to the list of aromatic amines in group 1 of human carcinogens by the International Agency for Research on Cancer. High levels of o-Tol hemoglobin adducts have been found in workers of a chemical factory with high excess of bladder cancer (Ward et al., JNCI 88:1046-52, 1996) as well as in patients treated with the local anesthetic prilocaine (Gaber et al., Toxicology 229:157-64, 2007). In contrast to 4-aminobiphenyl (4-ABP), the presence of DNA adducts of o-Tol has not yet been proven in humans. For the present study we obtained bladder tissue from 46 sudden death victims (SDV) and 12 samples from human bladder tumors. DNA was isolated from the epithelial and a submucosal layer of the SDV tissue samples and from tumor samples. For analysis of DNA adducts releasing o-Tol and 4-ABP, the aromatic amines were hydrolyzed from DNA by addition of 100 μL 4 N HCl. As internal standards d9-o-Tol and d5-4-ABP were added prior to hydrolysis. The acidic DNA solution was washed with dichloromethane and the amines were extracted with hexane after alkalinization. Determination of o-Tol and 4-ABP was achieved after derivatization with heptafluorobutyric anhydride by capillary gas chromatography/mass spectrometry with negative chemical ionization. Water samples were analyzed with each batch of samples to control for background contamination. Values less than 2-fold higher than background values were designated as not detectable and included as zero values in calculation of mean±standard error. Adducts of o-Tol well above background levels could be detected in 11 of 12 tumor samples (8.72±1.30 fmol/µg DNA). In contrast, only 4 of 12 tumor samples were positive for ABP (0.057±0.036 fmol/µg; p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3461.

SINCE THE FIRST DESCRIPTION OF THE NARCOLEPTIC TETRADE (EXCESSIVE DAYTIME SLEEPINESS [EDS], CATAPLEXY, HYPNAGOGIC HALLUCINATIONS and sleep paralysis) by Yoss and Daly in 1957,1 it has been increasingly recognized that sleep-maintenance insomnia is a major problem in many patients with narcolepsy-cataplexy (NC).2,3 Nocturnal sleep in NC is characterized by short sleep latency, the presence of sleep-onset rapid eye movement periods (SOREMPs) (in up to 50% of patients4), frequent brief awakenings, long periods of intermittent wakefulness, or a combination of these. Despite sleep fragmentation, patients with NC usually feel refreshed after awakening in the morning, but sleepiness will rapidly evolve within hours and becomes irresistible (“sleep attacks”). Although sleep attacks and voluntary daytime sleep are typically short (< 30 min) and refreshing,5 sleepiness returns after a few hours of wakefulness. The mechanisms underlying sleep fragmentation and the highly refreshing character of even short naps in NC are largely unknown. Coexisting primary sleep disorders such as obstructive sleep apnea, periodic limb movements in sleep, and parasomnias may be present in NC, yet their contribution to disturbed nocturnal sleep and EDS appears to be relatively small.6 Thus, sleep fragmentation and EDS usually persist despite successful treatment of these comorbidities. It has been hypothesized that patients with NC are unable to consolidate wakefulness and sleep because of abnormal sleep-wake regulation. The processes underlying wakefulness and sleep are conceptualized in the 2-process model of sleep-wake regulation.7,8 It is widely accepted that sleep homeostasis (Process S) and the endogenous circadian clock (Process C) interact to regulate the timing and stability of both wakefulness and sleep. Although circadian rhythms have been described to be functional in NC,9,10 homeostatic sleep regulation, as estimated from the time course of electroencephalogram (EEG) slow-wave activity (SWA; power within 0.75–4.5 Hz) over consecutive non-rapid eye movement sleep (NREMS) episodes may be altered in NC.10,11 More specifically, a faster dissipation of SWA from the first to the second NREMS episode has been consistently found in patients with NC, when compared with healthy control subjects.10–12 We recently suggested that the steep decline of SWA from the first to the second NREMS episode is due to a disturbed build-up of SWA in the second cycle.12 Sleep in the second cycle is interrupted by an increased number and a longer duration of short wake periods in NC. We proposed the changes in the time course of SWA to reflect threshold-dependent insufficient NREMS intensity. That is, nocturnal sleep fragmentation occurs after dissipation of sleep pressure in the first sleep cycle, i.e., when NREMS intensity has decayed below a certain threshold. Sleep deprivation is a powerful tool to evaluate the integrity of homeostatic sleep regulation. So far, only 1 sleep-deprivation study consisting of 24 hours of prolonged wakefulness has been performed in NC.11 In this study, sleep deprivation increased initial SWA in both NC and control subjects, compared with baseline values, and SWA dissipated in both groups exponentially with a similar time course in NREMS. Nevertheless, similar to baseline nights, SWA enhancement was most prominent in the first sleep cycle and attenuated in the second cycle in NC. This study is limited by the fact that baseline and recovery sleep were scheduled at different circadian times. Circadian factors may have contributed to sleep and sleep EEG changes in the recovery night. In a second study, Nobili and colleagues10 tested the effects of 16 hours of wakefulness (i.e., wakefulness during the daytime, starting in the morning and lasting until the evening of the same day), which was followed by a 32-hour continuous bedrest, with sleep permitted ad libitum. Patients with NC showed increased SWA and an exponential decline of SWA during sleep. In the night following prolonged bedrest, the exponential decline of SWA was no longer present and the time course of SWA showed a 4-hour periodicity. These findings suggest the presence of an intact homeostatic sleep regulation under conditions of high sleep pressure and ultradian periodicity in SWA, which is unmasked under low homeostatic sleep pressure. Although 16 hours of continuous wakefulness may have enhanced sleep pressure in NC, this duration of wakefulness is not sufficient to increase sleep pressure in healthy control subjects. With the aim to further investigate sleep homeostasis in NC, we employed a 40-hour sleep-deprivation protocol, which allowed us to compare baseline sleep and recovery sleep at the same circadian time. We expected that increased NREMS intensity after sleep deprivation would consolidate sleep in the recovery night and provide us with the opportunity to estimate Process S from the time course of undisturbed SWA. We hypothesized that sleep homeostasis in NC is functional. We predicted that patients with NC would show increased SWA at the beginning of recovery sleep, in comparison with baseline sleep, and an exponential decline of SWA over consecutive NREMS episodes in the recovery night. Furthermore, we expected to find a reduced number of SOREMP in patients with NC in recovery sleep, when compared with baseline.