Publications

[This corrects the article on p. e60917 in vol. 8.].

A methodology is proposed to enable state‐of‐the‐art record selection using ground motion components in all three principal loading directions. Relying on the well‐established Conditional Spectrum approach, its fundamental concepts are extended to ensure hazard consistency when the vertical ground motion component is considered along with the horizontal ones. To this end, different record selection techniques are employed, spanning sets of ground motion records with and without vertical motions, as well as with and without vertical ground motion hazard consistency. To demonstrate the effect that each record set can potentially have on a structure, an unanchored liquid storage tank is adopted as a case study, because of the vertical uplift motion it can exhibit, even under the application of horizontal loading only. A reduced‐order structural model is employed to generate the numerical output via multi‐stripe analysis, thus enabling the evaluation of the pertinent record selection approaches. Focusing on uplift and compressive meridional stress, response ratios and response hazard curves are extracted. It is shown that although the vertical ground motion component only mildly affects uplift, its effect on compressive meridional stress, on average, amplifies the response by a factor of 1.8 for moderate intensities and 2.8 for higher ones. Accounting for hazard consistency in the vertical component appears to be important for the case at hand, as it reveals notable discrepancies in the mean annual frequency of exceedance for the response parameters examined.

Screening for cardiovascular disease in athletes is crucial to avoid life-threatening complications. Here, we present the case of a fairly asymptomatic young professional soccer player with several cardiovascular risk factors, who proved to have significant coronary artery disease on coronary computed tomography which was ordered based on clinical suspicion and his family history. Informed consent for publication was obtained from the patient.

Melatonin is the main hormone secreted by the pineal gland in the human brain. It has a strong impact on the sleep-wake cycle and is considered a general modulator of the human circadian rhythm. Apart from these well-established properties, melatonin possesses immunomodulatory, antioxidative and antiinflammatory properties. The potential ability of this hormone to act synergistically with several cytokines by enhancing their antitumoral activity and dramatically decreasing their adverse effects has placed melatonin among the new and promising agents in cancer immunotherapy. The use of the neurohormone alone or in combination with cytokines and traditional chemotherapeutic drugs is currently under vigorous investigation. Experimental and clinical trials have already depicted some of the immunomodulatory and antitumor effects of melatonin, delineating the need for further research in this field.

GLUCOCORTICOIDS are steroid hormones that strongly influence intermediary carbohydrate metabolism by increasing the transcription rate of glucose-6-phosphatase (G6Pase), a key enzyme of gluconeogenesis, and suppress the immune system through the glucocorticoid receptor (GR). The liver X receptors (LXRs), on the other hand, bind to cholesterol metabolites, heterodimerize with the retinoid X receptor (RXR), and regulate the cholesterol turnover, the hepatic glucose metabolism by decreasing the expression of G6Pase, and repress a set of inflammatory genes in immune cells. Since the actions of these receptors overlap with each other, we evaluated the crosstalk between the GR- and LXR-mediated signaling systems. Transient transfection-based reporter assays and gene silencing methods using siRNAs for LXRs showed that overexpression/ligand (GW3965) activation of LXRs/RXRs repressed GR-stimulated transactivation of certain glucocorticoid response element (GRE)-driven promoters in a gene-specific fashion. Activation of LXRs by GW3965 attenuated dexamethasone-stimulated elevation of circulating glucose in rats. It also suppressed dexamethasone-induced mRNA expression of hepatic glucose-6-phosphatase (G6Pase) in rats, mice and human hepatoma HepG2 cells, whereas endogenous, unliganded LXRs were required for dexamethasone-induced mRNA expression of phosphoenolpyruvate carboxylase. In microarray transcriptomic analysis of rat liver, GW3965 differentially regulated glucocorticoid-induced transcriptional activity of about 15% of endogenous glucocorticoid-responsive genes. To examine the mechanism through which activated LXRs attenuated GR transcriptional activity, we examined LXRα/RXRα binding to GREs. Endogenous LXRα/RXRα bound GREs and inhibited GR binding to these DNA sequences both in in vitro and in vivo chromatin immunoprecipitation assays, while their recombinant proteins did so on classic or G6Pase GREs in gel mobility shift assays. We propose that administration of LXR agonists may be beneficial in glucocorticoid treatment- or stress-associated dysmetabolic states by directly and gene-specifically attenuating the transcriptional activity of the GR on glucose and/or lipid metabolism.

Although corticotropin-releasing hormone (CRH) and Fas ligand (FasL) have been documented in ovarian carcinoma, a clear association with tumour progression and immuno-escape has not been established. FasL plays an important role in promoting tumour cells' ability to counterattack immune cells. Here, we examined immunohistochemically the expression of CRH, CRHR1, CRHR2 and FasL in 47 human ovarian cancer cases. The ovarian cancer cell lines OvCa3 and A2780 were further used to test the hypothesis that CRH might contribute to the immune privilege of ovarian tumours, by modulating FasL expression on the cancer cells. We found that CRH, CRHR1, CRHR2 and FasL were expressed in 68.1, 70.2, 63.8 and 63.8% of the cases respectively. Positivity for CRH or FasL expression was associated with higher tumour stage. Finally, CRH increased the expression of FasL in OvCa3 and A2780 cells through CRHR1 thereby potentiated their ability to induce apoptosis of activated peripheral blood lymphocytes. Corticotropin-releasing hormone produced by human ovarian cancer might favour survival and progression of the tumour by promoting its immune privilege. These findings support the hypothesis that CRHR1 antagonists could potentially be used against ovarian cancer.

Chaperone switching at the kinase CDK5 mediates epigenetic effects of antidepressants.

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.

Prematurity is associated with increased cardiometabolic risk later in life. The adipomyokine irisin has been acknowledged as a modulator of energy metabolism and insulin sensitivity. The aim of this study was to investigate circulating levels of irisin and their relation to anthropometric measurements and cardiometabolic phenotype in a population of preterm-born children versus full-term-born peers.A total of 160 children (87 born preterm aged 8.1-14.8 years and 73 born full-term of similar age and gender distribution) were studied. Arterial blood pressure, anthropometry, body composition assessments with dual energy X-ray absorptiometry, and skinfold measurements were performed. Blood biochemistry and circulating levels of irisin, insulin, cortisol, leptin, and adiponectin were also determined.The preterm group had higher diastolic blood pressure, triceps skinfold, subscapular skinfold (SSSF), and abdominal skinfold measurements and more central adiposity than the full-term group. Irisin was significantly lower (p = 0.002), whereas leptin was higher (p = 0.03) in the preterm than the full-term group. Irisin correlated positively with gestational age (r = 0.19, p = 0.01), birth weight (r = 0.23, p = 0.003), and high-density lipoprotein cholesterol (r = 0.20, p = 0.01) and negatively with SSSF (r = -0.25, p = 0.003) and chronological age (r = -0.21, p = 0.008).Lower levels of irisin and a slightly unhealthy adiposity and cardiometabolic pattern were detected in preterm-born children in comparison to their full-term-born peers. Whether low irisin levels in preadolescents and adolescents born prematurely could be of prognostic value for the development of cardiometabolic sequelae later in life remains to be further studied.

Healthy men exhibit a differential hypothalamic-pituitary-adrenal axis (HPA) response to exercise stress and fall into two groups: high responders (HR) and low responders (LR). The present study examined whether HR to physical stress also exhibit higher HPA reactivity to psychological stress than LR. We examined 14 HR and 13 LR classified based on their ACTH responses to high intensity exercise after pretreatment with dexamethasone. Both groups were of similar age, height, weight, and fitness level. Trait anxiety scores on the Spielberger Trait Anxiety Scale were not different. Subjects underwent a psychological stress test consisting of an interview and mental arithmetic. This test raised heart rate, blood pressure, and plasma ACTH and cortisol levels in both HR and LR. HR tended to have higher heart rates and blood pressures in anticipation of the psychological stress test than LR. ACTH responses of HR were higher, although not significantly, throughout the psychological stress test than LR. HR had a significantly (P &amp;lt; 0.05) greater net integrated cortisol response to the psychological stress than LR. This suggests that the adrenal cortexes of the HR are hypertropic and/or hypersensitive to ACTH. We conclude that men who are highly responsive to exercise stress are also highly responsive to psychological stress.