Publications

Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, is also secreted in peripheral inflammatory sites, where it acts as a local proinflammatory agent. Arthritis-susceptible LEW/N rats have profoundly deficient hypothalamic CRH responses to inflammatory stimuli and other stressors. Arthritis-resistant F344/N rats, on the other hand, have a robust increase in hypothalamic CRH in response to the same stimuli. Contrasting with these hypothalamic CRH responses, we now show that CRH expression is markedly increased in the joints and surrounding tissues of LEW/N rats with streptococcal cell wall- and adjuvant-induced arthritis, whereas it is not increased in similarly treated F344/N rats and is only transiently increased in congenitally athymic nude LEW.rnu/rnu rats. Glucocorticoid treatment suppressed, but did not eliminate, CRH immunoreactivity in the joints of LEW/N rats. CRH mRNA was present in inflamed synovia, as well as in spinal cord, and inflamed synovia also expressed specific CRH-binding sites. We compared CRH expression in inflamed joints with another well-characterized proinflammatory neuropeptide, substance P (SP), and found that SP immunoreactivity paralleled that of CRH. In summary, although LEW/N rats have deficient hypothalamic CRH responses to inflammatory stimuli compared with F344/N rats, they express relatively high levels of CRH at the site of inflammation. Analogous to SP, CRH may be delivered to the inflammatory site by peripheral nerves and/or synthesized at the inflammatory site. These data provide further support for the concept that CRH not only triggers the pituitary-adrenal antiinflammatory cascade, but also functions as an antithetically active local mediator of acute and chronic inflammatory arthritis. These data also illustrate the complex interrelationships of the nervous, endocrine, immune, and inflammatory systems.

<b>Background</b>: Telomere attrition has been implicated in immune function and vulnerability to infectious diseases. However, the relation between telomere length and COVID-19 severity remains unclear. <b>Methods</b>: In this cross-sectional study, patients aged 30-75 years, with confirmed SARS-CoV-2 infection, as well as age- and BMI-matched controls without COVID-19, were recruited over a period of 1 year (2021-2022) from the outpatient clinics and wards of the General Hospitals "Laiko" and "Elpis" in Athens, Greece. Telomere length, expressed as a telomere to single-copy gene (T/S) ratio, was measured in all participants using a quantitative PCR-based method. Participants' clinical, biochemical, demographic, and respiratory parameters were assessed in relation to their telomere length. <b>Results</b>: Study participants included a total of 139 individuals divided into three groups: controls (n = 34), patients with non-severe COVID-19 (n = 50), and patients with severe COVID-19 (n = 55). Patients with severe COVID-19 had significantly shorter telomeres when compared to both the non-severe COVID-19 group and controls (<i>p</i> < 0.001). Logistic regression analysis confirmed that telomere length was independently associated with disease severity (<i>p</i> < 0.001). Females demonstrated longer telomeres than males (<i>p</i> = 0.039), but no significant correlation was found between telomere length and age. When patients with non-severe and severe COVID-19 were analyzed together, no significant difference in telomere length was observed compared to controls (<i>p</i> = 0.727). <b>Conclusions</b>: Shortened telomeres may be linked to more severe forms of COVID-19, suggesting a potential role for telomere biology in disease progression. Results highlight the need for further research into telomere dynamics as a biomarker for disease susceptibility and outcome in viral infections.

OBJECTIVEAdrenocorticotrophin (ACTH) is the main hormone‐regulating steroid secretion from the adrenal cortex. The ACTH receptor (ACTH‐R) has recently been cloned, allowing systematic evaluation of its expression and function in adrenal tumorigenesis. We investigated ACTH‐R and P450 side‐chain cleavage enzyme (P450scc) mRNA expression in a variety of neoplastic adrenocortical tissues by Northern blot and reverse‐transcriptase‐PCR (RT‐PCR). PATIENTS AND MEASUREMENTSWe studied tissue from eight normal adrenals, six diffuse adrenocortical hyperplasias in patients with ACTH‐dependent Cushing's syndrome, 22 adrenal adenomas, six carcinomas and two carcinoma cell lines. Poly A mRNA was electrophoresed, immobilized on a nylon membrane and hybridized using α 32 P‐CTP labelled human ACTH‐R and P450scc cDNAs. RESULTSMean ACTH‐R mRNA expression showed significant differences between groups ( P =0.0001), but appeared to be independent of plasma ACTH concentrations. Compared to normal adrenal =100±12%), expression was low in non‐functional adenomas (23±11%) and carcinomas (19±12%), intermediate in adrenocortical hyperplasias (88±6%) and cortisol‐producing adenomas (81±15%) and high in aldosteronomas (175±29%). In adenomas, ACTH‐R mRNA expression correlated closely with the expression of P450scc mRNA r =0.8, P =0.0001) suggesting regulation by similar factors. However, carcinomas and cancer cell lines did not show a positive correlation between these two parameters r =−0.44, P =0.2). CONCLUSIONSWe have demonstrated that plasma ACTH is not the major factor influencing ACTH‐receptor mRNA expression in neoplastic adrenal tissue. In benign tumours of the adrenal cortex there was a close positive correlation between ACTH‐receptor mRNA and P450scc mRNA which was missing in adrenocortical carcinomas, probably as a result of tumour dedifferentiation.

Background Autonomic responses participate in the pathophysiology of acute myocardial infarction, but their precise time course remains unclear. Here, we investigated the autonomic activity and ventricular tachyarrhythmias in conscious, unrestrained rats post-infarction. Methods The left coronary artery was ligated in 12 Wistar rats, and six rats were sham operated, followed by 24-h electrocardiographic recording via implanted telemetry transmitters. Sympathetic activity was assessed by detrended fluctuation analysis and vagal activity by time- and frequency-domain analysis of heart rate variability. The duration of the ventricular tachyarrhythmias was measured, and voluntary motion served as a marker of heart failure. Results In sham-operated rats, heart rate and sympathetic activity remained low, whereas vagal activity rose progressively after the fourth hour. Post-ligation, medium-sized antero-septal necrosis was observed, reaching ~20% of the left ventricular volume; tachyarrhythmias were frequent, displaying a bimodal curve, and motion counts were low. Vagal activity decreased early post-ligation, coinciding with a high incidence of tachyarrhythmias, but tended to rise subsequently in rats with higher motion counts. Sympathetic activity increased after the third hour, along with a second tachyarrhythmia peak, and remained elevated throughout the 24-h period. Conclusions Vagal withdrawal, followed by gradual sympathetic activation, may participate in arrhythmogenesis during acute myocardial infarction.

Abstract Background Since the introduction of Assisted Reproduction Technologies (ART) in clinical practice several studies have addressed concerns regarding the long-term health of the offspring and have revealed indications of an adverse cardiovascular/cardiometabolic outcome. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and lipoprotein (a) (Lp[a]) levels have been associated with cardiovascular risk. Purpose To investigate PCSK9 and Lp(a) levels of children born after ART compared with naturally conceived (NC) controls. Methods In this case-control study, 73 sex- and age-matched children (mean age 98±35 months) of ART (intracytoplasmic sperm injection [ICSI]: n=33, classic in vitro fertilization [IVF]: n=40) and 73 NC children were assessed. Blood lipid profile, including PCSK9 and Lp(a) levels, was measured. Children were grouped according to age (&lt;8 years, 8–10 years, ≥10 years). Results In the univariate model of the overall population, circulating PCSK9 levels were related to total cholesterol (r=0.186, P=0.025), LDL-C (r=0.180, P=0.029) and SBP (r=0.199, P=0.021). Similarly, circulating Lp(a) levels were related to age (r=0.269, P=0.001), apoB (r=0.214, P=0.01), birth weight (r=−0.183, P=0.037), height (r=0.263, P=0.001), waist-to-hip ratio (r=−0.350, P&lt;0.001), HOMA-IR (r=0.319, P&lt;0.001), insulin (r=0.316, P&lt;0.001), and hsCRP (ρ=0.241, P=0.018). No significant differences were observed regarding lipid biomarkers between ART and NC children. (p=0.515 for PCSK9 and p=0.277 for Lp(a) values). It is noteworthy that a significant interaction was found between age groups and conception method (P&lt;0.001) showing that PCSK9 levels increase with age in ART children, while they decline with age in NC offspring (Figure 1). IVF children showed higher levels of adjusted mean Lp(a) than ICSI (13.5 vs. 6.8 mg/dl, P=0.010) and NC children (12.3 vs. 8.3 mg/dl, P=0.048). Mean LogPCSK9 concentrations with the st Conclusions PCSK9 and Lp(a) levels did not differ between ART and NC children. Nonetheless, PCSK9 levels increase with age in ART children indicating a gradual deterioration of lipidemic profile that could lead to increased cardiovascular risk. Moreover, our results imply that ART method may be of importance given that classic IVF is associated with higher levels of Lp(a). The impact of the method of conception on PCSK9 and Lp(a) values should be validated in larger patient series.