Publications

Abstract Diabetes mellitus is a group of disorders characterized by prolonged high levels of circulating blood glucose. Type 1 diabetes is caused by decreased insulin production in the pancreas whereas type 2 diabetes may develop due to obesity and lack of exercise; it begins with insulin resistance whereby cells fail to respond properly to insulin and it may also progress to decreased insulin levels. The brain is an important target for insulin, and there is great interest in understanding how diabetes affects the brain. In addition to the direct effects of insulin on the brain, diabetes may also impact the brain through modulation of the inflammatory system. Here we investigate how perturbation of circulating insulin levels affects the expression of Hes3 , a transcription factor expressed in neural stem and progenitor cells that is involved in tissue regeneration. Our data show that streptozotocin-induced β-cell damage, high fat diet, as well as metformin, a common type 2 diabetes medication, regulate Hes3 levels in the brain. This work suggests that Hes3 is a valuable biomarker helping to monitor the state of endogenous neural stem and progenitor cells in the context of diabetes mellitus.

The long-term effects on bone and fat mass in children with endogenous CS are unknown. In 14 children followed for 3-7 years into young adulthood after cure of CS, whereas bone mass largely recovered, persisting increases in total body and visceral fat suggests an increase risk of the metabolic syndrome.Endogenous Cushing syndrome (CS) is associated with decreased bone mass and increased central fat mass. Whereas bone mass seems to improve after successful treatment, little is known about whether central fat persists.This was a prospective study of 14 children (10 girls and 4 boys) and adolescents with CS who were successfully treated and remained eucortisolemic. Growth, puberty, bone mass, and body composition were evaluated at baseline and during regular follow-up for 3 years and in seven children for a further 4 years of remission to assess final adult height (FH), BMI, bone mass, and body composition.CS compromised growth, leading to about a -0.8 SD loss of FH and 0.9 SD increase in weight and BMI. BMD apparent density (BMAD) SD Score (SDS) at the lumbar spine (LS) at diagnosis were -1.8 and -1.25, respectively, and after 3 years of follow-up approached the mean with no further increase apparent up to 7 years of follow-up. Whereas hip BMD SDS increased from -1.3 at diagnosis to -0.40 at 3 years and 0 at 7 years of follow-up, femoral neck BMAD remained at or around 0 SDS at diagnosis and during follow-up. BMI was >25 kg/m(2) in five of seven adult subjects, most of whom were women. Total body fat and the ratio of visceral to subcutaneous was abnormally high in the majority of these subjects, whereas LS volumetric BMD was -0.7 SDS.Despite remission of CS, children and adolescents have significant alterations in body composition that result in a small but significant decrease in bone mass and increase in visceral adiposity. Although bone mass largely recovers after endogenous CS, changes in total and visceral fat suggest these subjects are at increased risk of the metabolic syndrome. Therefore, long-term monitoring of body fat and bone mass is mandatory after treatment of CS.

Glucocorticoid (GC)-insensitive asthma is a challenging clinical problem that can be associated with life-threatening disease progression. The molecular basis of GC insensitivity is unknown. Alternative splicing of the GC receptor (GCR) pre-mRNA generates a second GCR, termed GCR β , which does not bind GC but antagonizes the transactivating activity of the classic GCR. Thus increased expression of GCR β could account for glucocorticoid insensitivity. Bronchoalveolar lavage (BAL) cells and peripheral blood mononuclear cells (PBMC) were examined for GCR β immunoreactivity using a GCR β -specific antibody by immunohistochemical staining. Cell localization of GCR β expression was performed using a double immunostaining technique. Patients with GC-insensitive asthma expressed a significantly higher number of GCR β -immunoreactive cells in their BAL and peripheral blood than GC-sensitive asthmatics or normal control subjects. Furthermore, GCR β expression in GC-insensitive asthma was particularly high in airway T cells, which are thought to play a major role in the pathogenesis of asthma. We also examined the expression of GCR β in specimens from the airways of patients with chronic bronchitis. In chronic bronchitis, few cells were GCR β -positive and their numbers did not differ significantly from normal control subjects. We conclude that GC-insensitive asthma is associated with increased expression of GCR β in airway T cells.

Hypercortisolism in depression seems to preferentially reflect activation of hypothalamic CRH secretion. Although it has been postulated that this hypercortisolism is an epiphenomenon of the pain and stress of major depression, our data showing preferential participation of AVP in the hypercortisolism of chronic inflammatory disease suggest specificity for the pathophysiology of hypercortisolism in depression. Our findings that imipramine causes a down-regulation of the HPA axis in experimental animals and healthy controls support an intrinsic role for CRH in the pathophysiology of melancholia and in the mechanism of action of psychotropic agents. Our data suggest that hypercortisolism is not the only form of HPA dysregulation in major depression. In a series of studies, commencing in patients with Cushing's disease, and extending to hyperimmune fatigue states such as chronic fatigue syndrome and examples of atypical depression such as seasonal affective disorder, we have advanced data suggesting hypofunction of hypothalamic CRH neurons. These data raise the question that the hyperphagia, hypersomnia, and fatigue associated with syndromes of atypical depression could reflect a central deficiency of a potent arousal-producing anorexogenic neuropeptide. In the light of data presented elsewhere in this symposium regarding the role of a hypofunctioning hypothalamic CRH neuron in susceptibility to inflammatory disease, these data also raise the question of a common pathophysiological mechanism in syndromes associated both with inflammatory manifestations and atypical depressive symptoms. This concept of hypofunctioning of hypothalamic CRH neurons in these disorders also raises the question of novel forms of neuropharmacological intervention in both inflammatory diseases and atypical depressive syndromes.

This study aims to search for mutations in relevant genes in a woman with primary ovarian insufficiency (POI) and blepharophimosis-ptosis-epicanthus inversus syndrome (BPES).This study reports on the case of a woman with POI, BPES, and autoimmune endocrine disorder. Bidirectional sequencing of the coding regions and intron/exon boundaries of FOXL2 and BMP15 genes and hormonal assays for the measurement of follicle-stimulating hormone, luteinizing hormone, estradiol, testosterone, Δ4-androstenedione, and dehydroepiandrosterone sulfate were employed.A novel de novo heterozygous deletion (p.K150Rfs*121) in the FOXL2 gene was identified to coexist with two BMP15 gene variants located in the same allele (c.-9C>G; p.N103S).The novel, de novo FOXL2 gene mutation (p.K150Rfs*121) expands the spectrum of molecular defects identified in women with BPES. Coexisting gene variants in POI-related genes, such as BMP15, may act synergistically and explain the observed phenotypic variability in women with BPES (ie, BPES with or without POI). The concept of digenic inheritance suggested herein has been previously introduced for other nosologies such as hypogonadotrophic hypogonadism. Endocrine autoimmunity might also contribute to the POI phenotype.

To investigate adipocytokine secretion, at diagnosis and during chemotherapy in children with the acute lymphoblastic leukemia (ALL).Serial measurements (6/patient) of the anti-inflammatory cytokine adiponectin and the proinflammatory adipocytokines leptin and resistin were performed at diagnosis and in nearly the entire period of therapy (up to 21 months), in 9 patients with ALL aged 2 to 7 years (median 4.3 y). Body mass index and leukemic burden were estimated at the same time points and correlated with adipocytokine levels. Nine healthy children matched for age, sex, and body mass index were used as controls.At diagnosis, mean adiponectin levels were low (P<0.001) and mean leptin and resistin levels were high, compared with controls (P<0.001). During maintenance phase, adiponectin increased significantly (P=0.024), whereas leptin and resistin decreased (P=0.018 and P=0.020, respectively), compared with baseline values. However, adiponectin, despite its progressive increase, remained at lower levels toward the end of the maintenance phase, compared with controls, (P<0.001). Delta (final-baseline) mean adiponectin was negatively correlated with leukemic burden (P=0.019), whereas delta mean leptin and resistin were positively correlated with it (P=0.011 and P=0.031, respectively).Low-plasma adiponectin and high leptin and resistin level are present at the ALL diagnosis. Adipocytokines alterations are progressively restored during therapy.

Background/Aim: Tic habit cough (THC) is not easily recognized and requires a high index of suspicion. Since there is evidence for stress-related etiology, the study presents our experience during the eight-year period of the recent Greek financial crisis. Patients and Methods: This is a descriptive prospective cross-sectional clinical study using a consistent approach to diagnosis, possible triggers and treatment options. Results: Fifty-one children (26 girls, age 9.5±3.1y) from a total of 3,793 new referrals for chronic cough fulfilled the criteria of THC (1.34%). Incidence rates per 1,000 person-years were 1.34 (95%CI=0.34-5.40), 3.91 (95%CI=1.86-8.19), 4.03 (95%CI=2.01-8.06) and 14.60 (95%CI=10.43-20.44) for every two years. Poisson analysis showed an increased trend during the four time periods with an incidence rate ratio equal to 2.21 (95%CI=1.58-3.09, p&lt;0.001). THC was mainly attributed to learning difficulties, as well as stress-related impact of peer or family bullying, family financial problems and child anxiety disorders. Conclusion: The incidence of THC is associated with the negative aspects of stressors during a period of financial crisis. The potential underlining psycho-physiological mechanisms are discussed as well as the fact that prompt diagnosis may result in successful interventions.

<ns4:p>Mapping time-structures is a burgeoning scientific field enriching the (P4) medicine models. Local evidence in Mediterranean populations is underinvestigated. The Censed stroke-related death events (D) in the largest East-Mediterranean port (Piraeus), during (1985-1989), when local population had diet and genetic homogeneity-been interrupted by the immigration into Greece in 1990s, and Sunspot numbers indexed by Wolf numbers (Rz) (1944-2004), were evaluated using Fast Fourier Analysis and Singular Spectrum Analysis in MATLAB. D were turned with fluctuations &gt;35% in Rz. A non-anthropogenic 6.8 days cycle was recognized. This study may be taken into consideration in future public health planning and chronotherapy evaluations.</ns4:p>

Exposure of animals/biological samples to human‑made electromagnetic fields (EMFs), especially in the extremely low frequency (ELF) band, and the microwave/radio frequency (RF) band which is always combined with ELF, may lead to DNA damage. DNA damage is connected with cell death, infertility and other pathologies, including cancer. ELF exposure from high‑voltage power lines and complex RF exposure from wireless communication antennas/devices are linked to increased cancer risk. Almost all human‑made RF EMFs include ELF components in the form of modulation, pulsing and random variability. Thus, in addition to polarization and coherence, the existence of ELFs is a common feature of almost all human‑made EMFs. The present study reviews the DNA damage and related effects induced by human‑made EMFs. The ion forced‑oscillation mechanism for irregular gating of voltage‑gated ion channels on cell membranes by polarized/coherent EMFs is extensively described. Dysfunction of ion channels disrupts intracellular ionic concentrations, which determine the cell's electrochemical balance and homeostasis. The present study shows how this can result in DNA damage through reactive oxygen species/free radical overproduction. Thus, a complete picture is provided of how human‑made EMF exposure may indeed lead to DNA damage and related pathologies, including cancer. Moreover, it is suggested that the non‑thermal biological effects attributed to RF EMFs are actually due to their ELF components.