Publications

Several lines of experimental evidence suggest that acetylcholine and other cholinergic agonists are excitatory to the hypothalamic-pituitary-adrenal (HPA) axis. To examine the site on the HPA axis that is stimulated by cholinergic agents, we evaluated the in vivo and in vitro effects of the muscarinic cholinergic agonist arecoline in intact and pituitary stalk-transected rats as well as on isolated rat hypothalami, dispersed anterior pituicytes, and adrenocortical cells in culture. Arecoline, injected iv to catheterized, freely moving male Sprague-Dawley rats, stimulated plasma ACTH and corticosterone release in a dose-dependent fashion. The muscarinic cholinergic antagonist atropine significantly blunted the ACTH response to arecoline. Pituitary stalk transection led to diminished plasma ACTH and corticosterone responses to arecoline. Similarly, previous administration of anti-CRH serum significantly blunted these responses. These findings suggest that arecoline stimulates the HPA axis centrally, mainly via secretion of CRH. This hypothesis was confirmed by the dose-dependent ability of arecoline to cause hypothalamic CRH secretion in vitro, an effect antagonized by atropine, and its failure to elicit ACTH and corticosterone secretion by dispersed anterior pituicytes and adrenocortical cells in culture, respectively. These data suggest that the muscarinic cholinergic agonist arecoline stimulates the HPA axis in the rat and that this effect is mediated mainly by the release of endogenous CRH. Arecoline, therefore, appears to be a compound suitable to selectively evaluate the responsiveness of the central component of the HPA axis.

Objective.—To examine the role of glia‐derived S100β protein and to evaluate its use as a biochemical marker in childhood acute recurrent headache. Methods.—Twenty‐five patients with acute recurrent headache (according to International Headache Society criteria) from our department's Headache Clinic were studied. Blood samples for measurement of serum S100β were drawn: (1) ≤3‐hour post pain attack from our patients and (2) from 23 healthy controls. Results.—Of the 25 patients evaluated, 15 suffered from migraine and 10 from tension‐type headache (TTH). Statistical analysis of the mean values of S100β levels demonstrated a significant elevation in children with migraine headache, with values higher than those of both children with TTH and controls ( P = .001). Conclusions.—Our data suggest a direct relation between childhood migraine attacks and increased production of glial S100β protein. Serum S100β determination may be a useful biochemical marker for migraine in acute recurrent headache in childhood.

To examine basal and stimulated hypothalamic-pituitary-adrenal (HPA) axis and related hormone levels, including adrenocorticotropin (ACTH), cortisol, arginine vasopressin (AVP), and neuropeptide Y (NPY), in patients with fibromyalgia (FM).Basal and ovine corticotropin-releasing hormone (oCRH)-stimulated HPA axis function were assessed in 12 patients with FM and in age- and sex-matched normal subjects. Basal plasma AVP levels and AVP release after postural change were assessed, and plasma NPY levels were measured in the same samples.Patients with FM had low 24-hour urinary free cortisol, but normal peak and elevated trough plasma cortisol levels, compared with normal subjects. The net integrated ACTH response to oCRH in FM was not significantly different from that in normal subjects, but tended toward an exaggerated response. There was a significant decrease in net integrated cortisol response to oCRH in FM patients, indicating adrenal hyporesponsiveness. AVP levels were not significantly different between FM patients and control subjects, but variability was greater among the FM patients. Plasma NPY levels were significantly lower in FM patients than in normal subjects.These data support the view that HPA axis function is perturbed in patients with FM. Further study is required to ascertain the cause of HPA axis perturbations and their relationship to symptoms in patients with FM.

Gestational weight gain differs according to pre-pregnancy body mass index and is related to the risks of adverse maternal and child health outcomes. Gestational weight gain charts for women in different pre-pregnancy body mass index groups enable identification of women and offspring at risk for adverse health outcomes. We aimed to construct gestational weight gain reference charts for underweight, normal weight, overweight, and grades 1, 2 and 3 obese women and to compare these charts with those obtained in women with uncomplicated term pregnancies. We used individual participant data from 218,216 pregnant women participating in 33 cohorts from Europe, North America, and Oceania. Of these women, 9065 (4.2%), 148,697 (68.1%), 42,678 (19.6%), 13,084 (6.0%), 3597 (1.6%), and 1095 (0.5%) were underweight, normal weight, overweight, and grades 1, 2, and 3 obese women, respectively. A total of 138, 517 women from 26 cohorts had pregnancies with no hypertensive or diabetic disorders and with term deliveries of appropriate for gestational age at birth infants. Gestational weight gain charts for underweight, normal weight, overweight, and grade 1, 2, and 3 obese women were derived by the Box-Cox t method using the generalized additive model for location, scale, and shape. We observed that gestational weight gain strongly differed per maternal pre-pregnancy body mass index group. The median (interquartile range) gestational weight gain at 40 weeks was 14.2 kg (11.4–17.4) for underweight women, 14.5 kg (11.5–17.7) for normal weight women, 13.9 kg (10.1–17.9) for overweight women, and 11.2 kg (7.0–15.7), 8.7 kg (4.3–13.4) and 6.3 kg (1.9–11.1) for grades 1, 2, and 3 obese women, respectively. The rate of weight gain was lower in the first half than in the second half of pregnancy. No differences in the patterns of weight gain were observed between cohorts or countries. Similar weight gain patterns were observed in mothers without pregnancy complications. Gestational weight gain patterns are strongly related to pre-pregnancy body mass index. The derived charts can be used to assess gestational weight gain in etiological research and as a monitoring tool for weight gain during pregnancy in clinical practice.

Obesity is a growing global concern with strong associations with cardiovascular disease, cancer and type-2 diabetes. Although various genome-wide association studies have identified more than 40 genes associated with obesity, these genes cannot fully explain the heritability of obesity, suggesting there may be other contributing factors, including epigenetic effects. We performed genome wide DNA methylation profiling comparing normal-weight and obese 9–13 year old children to investigate possible epigenetic changes correlated with obesity. Of note, obese children had significantly lower methylation levels at a CpG site located near coronin 7 (CORO7), which encodes a tryptophan-aspartic acid dipeptide (WD)-repeat containing protein most likely involved in Golgi complex morphology and function. Anatomical profiling of coronin 7 (Coro7) mRNA expression in mice revealed that it is highly expressed in appetite and energy balance regulating regions, including the hypothalamus, striatum and locus coeruleus, the main noradrenergic brain site. Interestingly, we found that food deprivation in mice downregulates hypothalamic Coro7 mRNA levels, and injecting ethanol, an appetite stimulant, increased the number of Coro7 expressing cells in the locus coeruleus. Finally, by employing the genetically-tractable Drosophila melanogaster model we were able to demonstrate an evolutionarily conserved metabolic function for the CORO7 homologue pod1. Knocking down the pod1 in the Drosophila adult nervous system increased their resistance to starvation. Furthermore, feeding flies a high-calorie diet significantly increased pod1 expression. We conclude that coronin 7 is involved in the regulation of energy homeostasis and this role stems, to some degree, from the effect on feeding for calories and reward.

<b><i>Background/Aims:</i></b> Kisspeptin (KISS1)/GPR54 (KISSR) signaling complex and neurokinin B (NKB)/NKB receptor (TACR3) signaling have been proposed as an integral part of the network coordinating GnRH release. GPR54 (KISS1R) and TACR3 gene mutations have been described in cases of idiopathic hypogonadotrophic hypogonadism, while limited data exist on gain-of-function mutation in GPR54 (KISS1R) gene causing idiopathic central precocious puberty (ICPP). No data on TACR3 mutations in ICPP have been described so far. The aim of this study was to elucidate the possible impact of GPR54 (KISS1R) and TACR3 mutations in ICPP. <b><i>Methods:</i></b> PCR-amplified genomic DNA of 38 girls with ICPP was analyzed for GPR54 and TACR3 gene mutations. <b><i>Results:</i></b> No GPR54 or TACR3 mutations were found. The A/G coding sequence single nucleotide polymorphism (SNP) on the GPR54 gene (dbSNP ID: rs10407968) was found in 2 patients with ICPP. <b><i>Conclusion:</i></b> Our data indicate that GPR54 and TACR3 gene mutations are not a frequent cause of ICPP. The identified A/G synonymous SNP (dbSNP ID: rs10407968) located in exon 1 of the gene is not likely to have a pathogenic role in exon splicing and therefore in the premature initiation of puberty.

Viral infections constitute a fundamental and continuous challenge for the global scientific and medical community, as highlighted by the ongoing COVID‑19 pandemic. In combination with prophylactic vaccines, the development of safe and effective antiviral drugs remains a pressing need for the effective management of rare and common pathogenic viruses. The design of potent antivirals can be informed by the study of the three‑dimensional structure of viral protein targets. Structure‑based design of antivirals <em>in silico</em> provides a solution to the arduous and costly process of conventional drug development pipelines. Furthermore, rapid advances in high‑throughput computing, along with the growth of available biomolecular and biochemical data, enable the development of novel computational pipelines in the hunt of antivirals. The incorporation of modern methods, such as deep‑learning and artificial intelligence, has the potential to revolutionize the structure‑based design and repurposing of antiviral compounds, with minimal side effects and high efficacy. The present review aims to provide an outline of both traditional computational drug design and emerging, high‑level computing strategies.

Acoustic startle reflex (ASR) constitutes a reliable, cross-species indicator of sensorimotor and inhibitory mechanisms, showing distinct signature in cognitive aging, sex, and psychopathological characterization. ASR can be modulated by the prepulse inhibition (PPI) paradigm, which comprises the suppression of reactivity to a startling stimulus (pulse) following a weak prepulse (30- to 500-ms time difference), being widely linked to inhibitory capabilities of the sensorimotor system. If the prepulse-pulse tones are more clearly separated (500-2,000 ms), ASR amplitude is enhanced, termed as prepulse facilitation (PPF), reflecting sustained or selective attention. Our study aimed to investigate early-life sensorimotor sex/age differences using Electroencephalographic recordings to measure muscular and neural ASR in a healthy young population. Sixty-three children and adolescents aged 6.2-16.7 years (31 females) took part in the experiment. Neural ASR was assessed by two different analyses, namely, event-related potentials (ERPs) and first-derivative potentials (FDPs). As expected, PPF showed enhanced responses compared with PPI, as indicated by eyeblink, ERP and FDP measures, confirming the gating effect hypothesis. Sex-related differences were reflected in FDPs, with females showing higher ASR than males, suggesting increased levels of poststartle excitability. Intragroup age effects were evaluated via multipredictor regression models, noticing positive correlation between age versus eyeblink and ERP responses. Attention-related ERPs (N100 and P200) showed distinct patterns in PPI versus PPF, potentially indicative for alternative attentional allocation and block-out of sensory overload. Screening measures of participants' neurodevelopmental (assessed by Wechsler Intelligence Scale for Children) and behavioral (assessed by Child Behavior Checklist) markers were also associated with increased N100/P200 responses, presumably indexing synergy between perceptual consistency, personality profiling, and inhibitory performance. Conclusively, modulation of ASR by PPI and PPF is associated with biological sex and internal/external personality traits in childhood and adolescence, potentially useful to guide symptomatology and prevention of psychopathology.