Publications

Aluminum salts are widely used as the active antiperspirant in underarm cosmetic. Experimental observations indicate that its long term application may correlate with breast cancer development and progression. This action is proposed to be attributed, among others, to aluminum possible estrogen-like activities. In this study we showed that aluminum, in the form of aluminum chlorohydrate (ACH), caused increase in estrogen receptor alpha (ERα) protein levels, in ERα-positive MCF-7 cells. This effect was accompanied by moderate activation of Estrogen Response Elements (ERE)-driven reporter gene expression and 20%-50% increase in certain estrogen responsive, ERE-independent genes expression. Genes affected were ERα, p53, cyclin D1, and c-fos, crucial regulators of breast cancer development and progression. ACH-induced genes expression was eliminated in the presence of the estrogen antagonist: ICI 182780, in MCF-7 cells, whereas it was not observed in ERα-negative MDA-MB-231 breast cancer cells, indicating aluminum interference with estrogen signaling. Moreover, ACH caused increase in the perinuclear localization of estrogen receptor alpha in MCF-7 breast cancer cells and increase in the mitochondrial Bcl-2 protein, possibly affecting receptors-mediated mitochondrial actions and mitochondrial-dependent apoptosis. ACH-induced perinuclear localization of estrogen receptor beta was also observed in MDA-MB-231. Our findings indicate that aluminum actions on estrogen receptors protein level and subcellular localization possibly affect receptors-mediated actions and thus, aluminum interference with estrogen signaling.

Although insomnia is by far the most common sleep disorder, our understanding of its neurobiology is limited. Insomnia, particularly when associated with objective sleep disturbance, has been associated with activation of the hypothalamic-pituitary-adrenal axis. The objective of this experimental study was to compare the response of the hypothalamic-pituitary-adrenal axis to ovine corticotropin-releasing hormone, a stress test, in men with insomnia versus controls. Circulating adrenocorticotropic hormone and cortisol levels were assayed before (-30 min, -15 min), at (0 min) and after (+5 min, +15 min, +30 min, +60 min, +90 min, +120 min) exogenous ovine corticotropin-releasing hormone administration in 23 men (11 insomnia, 12 controls), who underwent four consecutive nights of in-lab polysomnography. Men with insomnia compared with controls demonstrated markedly and significantly shorter total sleep time (368.4 ± 8.99 min versus 411.61 ± 8.61 min; p < 0.01) and lower sleep efficiency (76.77 ± 1.80% versus 86.04 ± 1.72%; p < 0.01) on polysomnography, and showed decreased adrenocorticotropic hormone and cortisol levels after ovine corticotropin-releasing hormone administration. Adrenocorticotropic hormone levels at 15 min and 30 min were significantly lower in men with insomnia than in controls (p < 0.05). Similarly, the peak levels of cortisol at +60 min, and the total and net area under the curve levels of this hormone were significantly lower in men with insomnia than controls (all p < 0.01). Adrenocorticotropic hormone and cortisol response to ovine corticotropin-releasing hormone administration was attenuated in men with insomnia associated with objective sleep disturbance, suggesting that objectively defined insomnia subtypes have a disrupted hypothalamic-pituitary-adrenal axis function and highlight the need to develop treatments targeting the underlying hypothalamic-pituitary-adrenal axis dysregulation.

Normal cognitive function depends on a continuous and optimally regulated blood supply, and any pathology that further reduces cerebral blood perfusion in addition to that caused by aging could damage or destroy vulnerable neurons of the brain. Furthermore, glucose serves a crucial role as the primary fuel source for the mammalian brain and any disturbance in its circulating concentrations could directly affect brain function. The term cognitive dysfunction (CD), known also as 'brain fog', refers to deficits in attention, verbal and non‑verbal learning, short‑term and working memory, visual and auditory processing, mathematic problem solving, processing speed, focusing on a specific topic, and motor functioning. CD is the end‑point of various cardiovascular, neural, metabolic and immune function impairments. Although CD has a serious impact on patient survival and quality of life, usually it is clinically underestimated. CD is currently assessed using cognitive tests (questionnaires), which have important limitations in their diagnostic capacity, specifically in the preclinical forms of CD. Cognitive tests may not identify subclinical cases of CD but diagnose CD only when symptoms are clinically overt. Furthermore, these tests do not provide information regarding the underlying pathophysiologic background of CD. The aim of the present review is to summarize the existing literature on CD and emphasize the role of combined brain‑heart magnetic resonance imaging (MRI) in its early diagnosis, before CD questionnaires are abnormal. Combined brain/heart MRI has the potential to identify patients with CD at an early stage, facilitating risk stratification and early intervention. Furthermore, in parallel with brain assessment, it provides valuable information regarding the effect of the underlying disease on the myocardium. Equipment availability, physician familiarity and cost/effectiveness should be considered before wide clinical application of combined brain/heart MRI is recommended.

Background: Τhe majority of Multiple Sclerosis (MS) patients manifest cognitive impairment, stress, anxiety and depression. These factors affect the disease course and relapse as well as the adoption of maladaptive coping strategies. The purpose of the study is to evaluate the effect of the Pythagorean self-awareness intervention on MS patients. Methods: This was a parallel randomized controlled trial in MS patients (N = 55) who were randomized to intervention (IG) and control group (CG). The IG (N = 23) underwent, additional to standardized care, PSAI which consisted of 8 weekly sessions of dietary and physical exercise counselling, cognitive training and stress management. Self-reported questionnaires were used for stress, depression, anxiety, healthy lifestyle, ways of coping, fatigue, memory. Data were collected by pre- and post-intervention. Results: Participants were mostly women, married, of tertiary education and with a mean disease duration of ten years. Statistical analyses revealed a significant amelioration of healthy lifestyle, stress, anxiety, depression, memory, an increase in positive approach and social support seeking, as well as, a decrease in physical, mental and cognitive fatigue. Conclusions: Participation in PSAI was strongly associated with enhancement of self-management abilities. We aspire that PSAI can be introduced in healthcare settings as a multifaceted, meta-cognitive process of stress management and self-empowerment.

This study describes the effect of antalarmin on basal and stimulated activity of the hypothalamo-pituitary-adrenal (HPA) axis function in the late gestation ovine fetus. Fetuses received antalarmin (15 mg/h i.v.) or vehicle (cremophor El 50% in ethanol) from day 130 gestational age. Antalarmin infusion did not significantly affect immunoreactive corticotropin (ir-ACTH) concentrations, although there was a tendency for ir-ACTH to be lower and cortisol concentrations were lower in the antalarmin-treated fetuses (p &lt; 0.01). The ir-ACTH response to corticotropin-releasing hormone (CRH) challenge was attenuated (p &lt; 0.05) in the antalarmin-treated fetuses, but neither antalarmin- nor vehicle-treated fetuses had significant cortisol responses to CRH. The ir-ACTH response to hypoxia was diminished (p &lt; 0.05) in the antalarmin-treated fetuses while the cortisol responses of antalarmin- and vehicle-treated fetuses were indistinguishable. Deconvolution analysis revealed no effect of antalarmin treatment on ir-ACTH secretory dynamics. In contrast, antalarmin decreased (p &lt; 0.05) basal, mean and integrated cortisol. The plasma cortisol responses of antalarmin- and vehicle-treated fetuses to exogenous ACTH&lt;sub&gt;1–24&lt;/sub&gt; were indistinguishable. These data indicate that, while antalarmin inhibits CRH- and stress-induced ir-ACTH secretion, basal ir-ACTH secretion may be less affected by antalarmin treatment. Paradoxically, cortisol secretion is impaired by antalarmin infusion, although adrenal responsiveness to ACTH is not impaired. These results confirm a role for CRH in stress-induced ACTH secretion in the ovine fetus, though its role in the regulation of basal ACTH and cortisol secretion is unclear.

Autoimmune polyendocrinopathy syndrome type 1 (APS-1; MIM# 240300) is a rare autosomal recessively inherited disease characterised by destructive autoimmune diseases of endocrine glands. The gene responsible for APS-1, known as AIRE (for autoimmune regulator), was recently identified and contains motifs suggestive of a transcription regulator. To date, nine APS-1-associated mutations have been identified in the AIRE gene, including two common mutations R257X and 1094-1106del. In addition to these two mutations, we report seven novel mutations in 16 APS-1 patients from North America. We found that 1094-1106del and R257X were the most common mutations in this population of mixed geoethnic origin, accounting for 17/32 and 4/32 alleles, respectively. Haplotype analyses suggest that both are recurrent mutations, occurring on several different haplotypes with closely linked markers. All the novel mutations appear to be rare, occurring in only single APS-1 families. After examining all coding sequences and exon/intron boundaries of the AIRE gene, the other APS-1 allele remained unidentified in three patients. Genotype-phenotype correlations for APS-1 remain difficult, suggesting that other genetic or environmental factors, or both, influence the clinical presentation and disease progression in individual APS-1 patients. Hum Mutat 13:69–74, 1999. © 1999 Wiley-Liss, Inc.

Obstructive sleep apnea (OSA) has been associated with increased frequency of excessive daytime sleepiness (EDS). Increased plasma TNF-α levels may mediate this association in adults, but conflicting results have been reported in children. We hypothesized that: (i) the higher the OSA severity in childhood, the higher the frequency of EDS and morning plasma TNF-α levels; and (ii) high TNF-α levels predict presence of EDS.Children without and with snoring underwent polysomnography. EDS was determined by parental response to specific questions, and plasma TNF-α levels were measured.Children with moderate-to-severe OSA (n = 24; 5.7 ± 2 years; apnea-hypopnea index [AHI] 11.5 ± 5.1/h), but not participants with mild OSA (n = 22; 6 ± 2.5 years; AHI 2.1 ± 1/h) were at significantly higher risk for EDS than controls (n = 22; 6.8 ± 2.1 years; AHI 0.5 ± 0.3/h) (OR [95% CI] adjusted for age, gender, and obesity: 9.2 [1.7-50.2] and 3.8 [0.7-21.8], respectively). The 3 groups did not differ regarding TNF-α concentration (0.63 ± 0.2 vs 0.65 ± 0.18 vs 0.63 ± 0.17 pg/mL; P > 0.05). TNF-α levels were associated significantly with body mass index z-score (P < 0.05) and not with polysomnography indices (P > 0.05). Subjects with high TNF-α levels (> 0.57 pg/mL) were not at higher risk for EDS than participants with low levels (OR [95% CI] adjusted for age, gender, and obesity: 1.7 [0.5-5.7]).Increasing severity of OSA is associated with increasing frequency of EDS, but not with elevated plasma TNF-α concentration. High TNF-α levels cannot be used as predictor for the presence of EDS in children with sleep apnea.

Petrosal sinus sampling was performed 171 times in 157 patients with known or suspected Cushing disease. In all cases, samples for measuring adrenocorticotropic hormone (ACTH) levels were obtained from both inferior petrosal sinuses and a peripheral vein, both before and after intravenous corticotropin-releasing hormone (CRH) administration. In seven examinations in seven patients, a ratio, or gradient, between the ACTH levels in the inferior petrosal sinuses existed in the samples obtained prior to CRH stimulation; however, poststimulation samples demonstrated reversal of the gradient, suggesting lateralization to the contralateral side of the pituitary gland. Data from surgical exploration of the pituitary gland were available for six of these patients, all of whom had adenomas. Prestimulation samples provided correct lateralization in three patients, and in two patients the poststimulation samples provided correct lateralization. One patient had a midline adenoma. When the results of pre- and poststimulation petrosal sinus sampling conflict, neither can be relied on uniformly to provide correct lateralization of ACTH-secreting pituitary adenomas.