Publications

To facilitate profiling mitochondrial transcriptomes, we developed a third-generation human mitochondria-focused cDNA microarray (hMitChip3) and its bioinformatic tools. hMitChip3 consists of the 37 mitochondrial DNA-encoded genes, 1098 nuclear DNA-encoded and mitochondria-related genes, and 225 controls, each in triplicate. The bioinformatic tools included data analysis procedures and customized database for interpretation of results. The database associated 645 molecular functions with 946 hMitChip3 genes, 612 biological processes with 930 genes, 172 cellular components with 869 genes, 107 biological chemistry pathways with 476 genes, 23 reactome events with 227 genes, 320 genetic disorders with 237 genes, and 87 drugs targets with 55 genes. To test these tools, hMitChip3 was used to compare expression profiles between human melanoma cell lines UACC903 (rapidly dividing) and UACC903(+6) (slowly dividing). Our results demonstrated internal gene-set consistency (correlation R > or = 0.980 +/- 0.005) and interexperimental reproducibility (R > or = 0.931 +/- 0.013). Expression patterns of 16 genes, involved in DNA, RNA, or protein biosyntheses in mitochondrial and other organelles, were consistent with the proliferation rates of both cell lines, and the patterns of 6 tested genes were verified by quantitative reverse transcription PCR (RT-PCR). Thus, hMitChip3 and its bioinformatics software provide an integrated tool for profiling mitochondria-focused gene expression.

Our objective was to investigate IL-6 and CRH secretion during the active phase of human labor and to define their potential involvement in myometrial contractility.Twenty-two primigravid women were studied for 90 minutes during the active phase of term labor by serial plasma sampling every 3 minutes for measurement of IL-6 and CRH concentrations. Uterine contractions, measured by cardiotocograph, were evaluated in Montevideo units. Basic, quantitative, pulsatility, and time cross-correlation statistical analyses were performed.By linear regression analysis, a positive correlation was observed between IL-6 and CRH total mean area under the curve above 0 (r = 0.76184, P = .006). Mean number of pulses was 2.00 ± 0.70 and 3.33 ± 1.29 for IL-6 and CRH, respectively. There was a significant positive correlation between IL-6 and CRH over time, peaking at the 12-minute interval, with IL-6 leading CRH. Also, there was a significant positive correlation between myometrial contractility expressed in Montevideo units and IL-6 concentrations over time, starting at +51 minutes and ending at +57 minutes with myometrial contractility leading IL-6. No significant correlation was found between myometrial contractility and CRH concentrations over time.IL-6 and CRH are both secreted in a pulsatile fashion during the active phase of human labor. The time-integrated concentrations of the two hormones are positively correlated, with IL-6 leading CRH secretion. It appears, thus, that proinflammatory mediators may be direct and/or indirect promoters of placental CRH release. Furthermore, the secretion of IL-6, which is a myokine, seems to be associated positively with uterine contractility. Additional studies are needed to elucidate the combined effect of inflammation, placental CRH release, and/or the receptors of the latter in parturition.

Summary Cytosolic dsDNAs are potent immune-stimulatory molecules that trigger inflammation in several human pathologies 1,2 . A major pathway for the detection of cytosolic dsDNA relies on the cyclic GMP-AMP (cGAMP) synthase (cGAS) that produces the 2’3’-cGAMP cyclic dinucleotide (CDN) for activation of the Stimulator of Interferon Genes (STING) adaptor protein that subsequently drives type I Interferon (IFN) responses 3,4 . Here, we investigated the mechanism regulating intracellular 2’3’-cGAMP levels. We show that the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a major player in the repair of double-strand breaks, directly regulates intracellular levels of 2’3’-cGAMP, thereby reducing STING activation. We describe that the binding of 2’3’-cGAMP to DNA-PKcs occurs in its catalytic cleft, impeding its kinase function. Contrary to other CDN regulatory mechanisms that have been shown to primarily regulate extracellular 2’3’-cGAMP, we show that DNA-PKcs also interacts with the 3’3’-cGAMP bacterial CDN, limiting its capacity to activate STING signaling. Furthermore, we found that DNA-PKcs decreases the potency of pharmacological STING activators. As STING is a major target for therapeutic interventions aiming to boost inflammatory responses in immunosuppressed contexts 5 , our data bear important implications for drug development and deepens our understanding of inflammatory regulation in response to CDNs.

Patients with primary affective disorders, such as melancholic depression and anorexia nervosa, frequently have a hyperactive hypothalamic-pituitary-adrenal (HPA) axis, characterized by hypersecretion of CRH and a blunted ACTH response to exogenous CRH. Premenstrual syndrome (PMS) is a luteal phase dysphoric disorder characterized by primarily affective and behavioral disturbances. HPA axis function was compared in PMS patients and control women, respectively, diagnosed by DSM3-R criteria or found to have no current psychiatric disorders, determined by the Schedule for Affective Disorders and Schizophrenia—Lifetime Interview. Urinary free cortisol excretion was the same in PMS and normal women, and no differences in urinary free cortisol excretion between the follicular and luteal phases occurred in either group. Two HPA axis abnormalities, however, were noted when PMS patients were compared to normal women. First, basal evening cortisol concentrations in plasma were significantly decreased, while the time-integrated response of plasma cortisol to ovine (o) CRH was significantly increased. Second, the negative correlation between time-integrated plasma ACTH and cortisol responses to oCRH and basal luteal progesterone concentrations present in normal control women was not seen in the PMS patients. These changes in basal and oCRH-stimulated plasma cortisol levels in association with normal urinary free cortisol excretion suggest that women with PMS might have transient or episodic disturbances of their HPA axis, which appear adequately corrected by this system's servomechanisms. This probably explains the maintenance of regular menstrual cycles in PMS patients, which contrasts with the irregular menses observed in patients with depression, anorexia nervosa, or women who participate in chronic strenuous exercise.

The prevalence of vitamin D deficiency in the kingdom of Saudi Arabia is rising unexpectedly in every age group. Apart from several risk factors, the lack of awareness is posing a serious threat for low vitamin D levels in children as well. The aim of our study was to compare the knowledge and status of vitamin D in Saudi school children.

In October 2002, a workshop was held in Ancona, Italy, to reach a Consensus on the management of Cushing's syndrome. The workshop was organized by the University of Ancona and sponsored by the Pituitary Society, the European Neuroendocrine Association, and the Italian Society of Endocrinology. Invited international participants included almost 50 leading endocrinologists with specific expertise in the management of Cushing's syndrome. The consensus statement on diagnostic criteria and the diagnosis and treatment of complications of this syndrome reached at the workshop is hereby summarized.

Several months after the onset of the epidemic, COVID-19 remains a global health issue. Scientific data on pregnancy, perinatal outcomes and vertical transmission of SARS-CoV-2 are constantly emerging but are still limited and unclear. The purpose of this systematic review was to summarize current evidence on vertical transmission rates, maternal, perinatal and neonatal outcomes and mode of delivery in pregnancies affected by COVID-19. An extensive search was conducted in PubMed, Google Scholar, Embase, and Scopus databases up to June 20, 2020. A total of 133 articles (51 case reports, 31 case series, 40 cohort studies and 2 case-control studies) reporting data from 8,092 subjects (6,046 pregnant women and 2,046 neonates) were considered eligible for inclusion in the systematic review. A substantial proportion of pregnant women with COVID-19 underwent caesarean section (case reports 82.2%, case series 74.2% and cohort studies 66.0%). Regarding vertical transmission, most neonates were tested negative (case reports 92.7%, case series studies 84.2%, cohort studies 97.1% and case control studies 100%). Maternal mortality rates ranged from 1% in cohort studies to 5.7% in case reports; neonatal mortality ranged from 2% in case reports to 3.3% in case series. Vertical transmission of SARS-CoV-2 from mother to child is rare. Careful screening of pregnant women seems important and specific guidelines with evidence-based decision algorithms for the mode of delivery in the context of a pregnancy affected by COVID-19 should be established.

The Greek ASQ-14 emerges as a psychometrically sound tool for screening stress among Greek adolescents.