Factors associated with postponed health checkups during the COVID-19 pandemic in Germany.

OBJECTIVES: The COVID-19 pandemic has serious social, economic and health consequences. Particularly in these times, it is important to maintain individual health. Therefore, it is important to take part in routine health checkups. Consequently, our objective was to describe the frequency and to identify the determinants of postponed routine health checkups. STUDY DESIGN: Cross-sectional data from the nationally representative online-survey "COVID-19 Snapshot Monitoring in Germany (COSMO)" was used (wave 17; July 2020). METHODS: In sum, 974 individuals were included in our analytical sample (average age was 45.9 years, SD: 16.5, 18-74 years). Postponed routine health checkups (yes or no) since March 2020 due to the COVID-19 pandemic were assessed. RESULTS: More than 16% of the individuals reported postponed routine health checkups in the past few months due to the COVID-19 pandemic. Particularly, individuals aged 30-49 years had postponed health checkups (21%). The probability of postponed health checkups was positively associated with the presence of chronic diseases (odds ratio [OR]: 1.68, 95% confidence interval [CI]: 1.15-2.47), higher affect regarding COVID-19 (OR: 1.44, 95%-CI: 1.16-1.78), and higher presumed severity of COVID-19 (OR: 1.17, 95%-CI: 1.01-1.35), whereas the outcome measure was not associated with socioeconomic factors. Data showed that a sizeable part (about one of six individuals) of the population reported postponed routine health checkups due to the COVID-19 pandemic between March and July 2020. CONCLUSIONS: Postponed checkups should not be neglected during the COVID-19 pandemic. Individuals at risk for postponed health checkups should be appropriately addressed.

PDGFRß(+) cells in human and experimental neuro-vascular dysplasia and seizures.

INTRODUCTION: Neuro-vascular rearrangement occurs in brain disorders, including epilepsy. Platelet-derived growth factor receptor beta (PDGFRß) is used as a marker of perivascular pericytes. Whether PDGFRß(+) cell reorganization occurs in regions of neuro-vascular dysplasia associated with seizures is unknown. METHODS: We used brain specimens derived from epileptic subjects affected by intractable seizures associated with focal cortical dysplasia (FCD) or temporal lobe epilepsy with hippocampal sclerosis (TLE-HS). Tissues from cryptogenic epilepsy, non-sclerotic hippocampi or peritumoral were used for comparison. An in vivo rat model of neuro-vascular dysplasia was obtained by pre-natal exposure to methyl-axozy methanoic acid (MAM). Status epilepticus (SE) was induced in adult MAM rats by intraperitoneal pilocarpine. MAM tissues were also used to establish organotypic hippocampal cultures (OHC) to further assess pericytes positioning at the dysplastic microvasculature. PDGFRß and its colocalization with RECA-1 or CD34 were used to segregate perivascular pericytes. PDGFRß and NG2 or IBA1 colocalization were performed. Rat cortices and hippocampi were used for PDGFRß western blot analysis. RESULTS: Human FCD displayed the highest perivascular PDGFRß immunoreactivity, indicating pericytes, and presence of ramified PDGFRß(+) cells in the parenchyma and proximal to microvessels. Tissues deriving from human cryptogenic epilepsy displayed a similar pattern of immunoreactivity, although to a lesser extent compared to FCD. In TLE-HS, CD34 vascular proliferation was paralleled by increased perivascular PDGFRß(+) pericytes, as compared to non-HS. Parenchymal PDGFRß immunoreactivity co-localized with NG2 but was distinct from IBA1(+) microglia. In MAM rats, we found pericyte-vascular changes in regions characterized by neuronal heterotopias. PDGFRß immunoreactivity was differentially distributed in the heterotopic and adjacent normal CA1 region. The use of MAM OHC revealed microvascular-pericyte dysplasia at the capillary tree lining the dentate gyrus (DG) molecular layer as compared to control OHC. Severe SE induced PDGFRß(+) immunoreactivity mostly in the CA1 region of MAM rats. CONCLUSION: Our descriptive study points to microvascular-pericyte changes in the epileptic pathology. The possible link between PDGFRß(+) cells, neuro-vascular dysplasia and remodeling during seizures is discussed.

[Caesarean section in german hospitals: validity of hospital quality report data for monitoring C-section rates]. / Kaiserschnitte in deutschen Krankenhäusern: Wie zuverlässig sind Routinedaten aus dem strukturierten Qualitätsbericht für die Bestimmung der Kaiserschnittraten?

OBJECTIVE: It is not known if "hospital quality reports" (HQR) document Caesarean (C-) section rates at the hospital level accurately enough for use as a reliable data source when it comes to explaining regional variations of C-sections in Germany by factors at the hospital level. We aimed to answer this question using HQR from hospitals in Baden-Württemberg as data source. METHOD: Diagnostic and procedure codes from HQR for the year 2008 (HQRdata), were used to calculate numbers of births, numbers of C-sections, and rates of births by C-section (CSR) for 94 of 97 hospitals in Baden-Württemberg. These numbers were compared to internal hospital (IH) data delivered upon request by 80 of 97 hospitals and stemming from vital statistics, birth registry forms, or external quality assurance datasets. RESULTS: There was no difference in the number of births between HQR data and IH data, but the number of C-sections and the CSR differed significantly (p<0.05; Wilcoxon rank sum test). CSR calculated using HQR data was 4.9 ± 17.9% higher than CSR from IH data (absolute difference 1.5 ± 5.8%). The correlation between the 2 data sources was moderate (r=0.73). Only 55% of the variance in IH data-based CSR was explained by HQR data. The proportion between highest and lowest CSR in hospitals in Baden-Württemberg was 4.9 for HQR data and 3.6 for IH data. CONCLUSION: There are significant and relevant differences between C-section rates based on ei-ther HQR or IH data. This questions routine data from HQR for 2008 as a reliable data source for research work.

Effect of status epilepticus and antiepileptic drugs on CYP2E1 brain expression.

P450 metabolic enzymes are expressed in the human and rodent brain. Recent data support their involvement in the pathophysiology of epilepsy. However, the determinants of metabolic enzyme expression in the epileptic brain are unclear. We tested the hypothesis that status epilepticus (SE) or exposure to phenytoin or phenobarbital affects brain expression of the metabolic enzyme CYP2E1. SE was induced in C57BL/6J mice by systemic kainic acid. Brain CYP2E1 expression was evaluated 18-24h after severe SE by immunohistochemistry. Co-localization with neuronal nuclei (NEUN), glial fibrillary acidic protein (GFAP) and CD31 was determined by confocal microscopy. The effect of phenytoin, carbamazepine and phenobarbital on CYP2E1 expression was evaluated in vivo or by using organotypic hippocampal cultures in vitro. CYP2E1 expression was investigated in brain resections from a cohort of drug-resistant epileptic brain resections and human endothelial cultures (EPI-EC). Immunohistochemistry showed an increase of CYP2E1 expression limited to hippocampal CA2/3 and hilar neurons after severe SE in mice. CYP2E1 expression was also observed at the astrocyte-vascular interface. Analysis of human brain specimens revealed CYP2E1 expression in neurons and vascular endothelial cells (EC). CYP2E1 was expressed in cultured human EC and over-expressed by EPI-EC. When analyzing the effect of drug exposure on CYP2E1 expression we found that, in vivo or in vitro, ethanol increased CYP2E1 levels in the brain and liver. Treatment with phenytoin induced localized CYP2E1 expression in the brain whereas no significant effects were exerted by carbamazepine or phenobarbital. Our data indicate that the effect of acute SE on brain CYP2E1 expression is localized and cell specific. Exposure to selected anti-epileptic drugs could play a role in determining CYP2E1 brain expression. Additional investigation is required to fully reproduce the culprits of P450 enzyme expression as observed in the human epileptic brain.

Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry.

OBJECTIVE: Etanercept monotherapy has been studied and approved for treatment of polyarticular juvenile idiopathic arthritis (JIA). The following study evaluates the safety and efficacy of combination therapy of etanercept and methotrexate compared to etanercept monotherapy in JIA. METHODS: We perfomed an open, non-randomised study on patients who had previously failed to respond to at least one disease-modifying antirheumatic drug (DMARD). A total of 722 patients with JIA in whom at least 1 item of follow-up data was recorded were identified; of these, 118 patients treated with further slow acting drugs were excluded. In all, 504 patients were treated with a combination of etanercept and methotrexate. A total of 100 patients treated with etanercept only were in the control group. Efficacy was calculated using the American College of Rheumatology paediatric scores for 30, 50 and 70% improvement (PedACR30/50/70). Adverse events (AEs) and serious adverse events (SAEs) were reported. RESULTS: After 12 months 55 patients in the monotherapy group and 376 patients in the etanercept and methotrexate group were available for comparison. For the intention to treat analysis, 65 patients discontinuing treatment prematurely were included. All activity parameters decreased significantly in both treatment groups. After 12 months 81%/74%/62% of patients of the etanercept and methotrexate group and 70%/63%/45% of patients of the etanercept monotherapy group achieved PedACR30/50/70 scores, respectively (p<0.05 for PedACR30, p<0.01 for PedACR70). The likelihood of achieving a PedACR70 increased with combination therapy with an odds ratio of 2.1 (95% CI 1.2 to 3.5). In total, 25 infectious and 23 non-infectious SAEs including 3 malignancies occurred in the etanercept and methotrexate group, and 1 infectious and 3 non-infectious SAEs occurred in the single etanercept group. CONCLUSIONS: The patients' disease activity improved during etanercept monotherapy and etanercept and methotrexate combination therapy. Tolerability in both treatment groups was comparable.

Hippocampal alterations of apolipoprotein E and D mRNA levels in vivo and in vitro following kainate excitotoxicity.

Alteration in the expression of apolipoprotein E (ApoE) and apolipoprotein D (ApoD) genes was evaluated in rat, 7 days following status epilepticus (SE) induced by intra-amygdala injection of kainate (KA), and in organotypic hippocampal cultures, 2 days after a single 1 h exposure to KA. Global polyadenylated RNA (poly A+) steady state, assessing global regulation of mRNA transcription was first measured in cortices and hippocampi from each animal and in the organotypic cultures. No alteration due to KA treatment was observed and individual concentrations of ApoE and ApoD mRNA species were therefore measured and comparative analysis performed. In the cortices of KA-treated animals, ApoE and ApoD mRNA levels did not show statistically significant changes. In contrast, in hippocampi, 7 days after SE, ApoE and ApoD mRNA levels were significantly increased, respectively, by 123 and 138%. This in vivo effect was confirmed in vitro on organotypic cultures, where KA treatment increased ApoE and ApoD mRNA expressions, respectively, by 72 and 61%. These observations indicate that lipidic metabolism is modified in the lesioned structure and suggest an increased traffic of lipids and a need for more ApoE and D in the hippocampus during the period of recovery and restructuration that follows severe seizures.

The neuronal death induced by endotoxic shock but not that induced by excitatory amino acids requires TNF-alpha.

We studied, using organotypic hippocampal slices in culture, the role of pro-inflammatory cytokines, oxygen radicals and nitric oxide in neuronal death induced either by endotoxic insult [interferon (IFN) gamma, 24 h followed by lipopolysaccharide, 24 h] or by glutamate receptor-mediated excitotoxic insult. We demonstrated that neuronal death induced by endotoxic insult was absolutely dependent on the synthesis of tumour necrosis factor alpha (TNF-alpha). Indeed, TNF-alpha antibodies and SB203580, an inhibitor of p38 stress kinase known to block TNF-alpha and other cytokine synthesis, completely protected neurons from the endotoxic insult. Inhibiting oxygen radical and nitric oxide productions also reduced the endotoxic shock. We also showed that after priming the cultures with IFN-gamma, TNF-alpha was unable to induce neuronal death unless oxygen-free radicals were exogenously provided. In contrast, although glutamate receptor-induced excitotoxicity was associated with a low TNF-alpha synthesis and a modest activation of p38 stress kinase, neither TNF-alpha antibodies nor SB203580 were able to decrease excitotoxic neuronal insult. We did not reduce glutamate receptor-induced neuronal death with superoxide dismutase plus catalase. In conclusion, although inflammation follows glutamate receptor-mediated neurotoxicity, the mechanisms by which an endotoxic insult triggers neuronal death are different from those involved in excitotoxicity.

Alterations of metallothionein II and apolipoprotein J mRNA levels in kainate-treated rats.

Although different mechanisms have been proposed, it has been suggested that apolipoprotein J (ApoJ) and metallothionein II (MTII), expressed by astrocytes, are protective proteins. Alterations in their expression may contribute to the involvement of astrocytes in epileptogenesis. We studied the expression of MTII and ApoJ genes 7 days following status epilepticus induced in rats by intra-amygdala injection of kainate (KA). ApoJ mRNA levels were increased in both cortex (77%, p < 0.01) and hippocampus (64%, p < 0.02), whereas, in contrast to previous findings 3 days after KA injection, DNA fragmentation was not detected on agarose gel electrophoresis. These results show that ApoJ is induced along with early genes during massive apoptosis, and remains induced after the acute phase. MTII mRNA levels were altered only in hippocampus (62%, p < 0.05), whereas KA-treated rats had no seizure for 7 days. The sustained induction of MTII mRNA shows that zinc homeostasis is not returned to normal or alternatively that astrocytes maintain an altered phenotype in spite of normal zinc release. Polyadenylated RNA and beta-actin mRNA levels were in contrast unaltered in cortex or hippocampus at this time point. These specific variations in ApoJ and MTII mRNA expression during the latent period suggest that they are part of long term biochemical and/or phenotypic alterations in astrocytes, following a single episode of severe seizures.

Release of TNF alpha in the rat hippocampus following epileptic seizures and excitotoxic neuronal damage.

We studied the production of tumor necrosis factor alpha (TNF alpha) and interleukin-6 (IL-6) 2 and 7 days following status epilepticus (SE), induced in rats by intra-amygdala injection of kainate. At day 2 the release of both cytokines by hippocampal slices prepared from epileptic animals was increased compared to controls, whereas at day 7 only TNF alpha secretion was enhanced. Since SE-induced neuronal damage is probably due to excitotoxicity, we investigated the effects of agonists of glutamate receptors on TNF alpha release in organotypic hippocampal cultures. A correlation was found between the damage intensity and the release of TNF alpha, suggesting production of this cytokine by macrophagic microglia. We propose a role for TNF alpha and IL-6 in the adaptive phenomena which follow severe limbic seizures.

NADPH diaphorase-positive cells in the brain after status epilepticus.

Using NADPH-diaphorase (NADPH-d) histochemistry, the expression of nitric oxide synthase (NOS) was studied in the rat brain 1 week after kainate-induced status epilepticus. Major changes were observed in the hippocampi of epileptic animals, especially a loss of NADPH-d positive fibres in the periphery of degenerative pyramidal cells, the survival of NOS-containing interneurones in the dentate hilus, a different pattern of NADPH-d staining in lesioned areas, probably corresponding to the expression of inducible NOS by glial cells and an increased staining of the vasculature. These different sources of NO may exert different functions in the epileptic focus.

Chronic NO synthase inhibition fails to protect hippocampal neurones against NMDA toxicity.

Since nitric oxide (NO) is supposed to mediate excitotoxicity in various brain structures, the effects of two NO synthase inhibitors were studied on rat hippocampal lesions induced by the focal injection of N-methyl-D-aspartate (NMDA). Although both drugs (NG-nitro-L-arginine methyl ester: L-NAME and L-NG-nitroarginine: L-NOARG) were given twice daily for 4 days before NMDA injection, at doses which are known to profoundly inhibit NO synthase activity, no significant decrease of NMDA-induced damage could be observed. These results do not confirm the current hypothesis of a NO involvement in NMDA toxicity at least on hippocampal neurons, in vivo.