Publications

The susceptibility of Lewis (LEW/N) rats to severe inflammatory disease has been causally associated with subnormal responsiveness of their hypothalamic CRH-secreting neurons and, consequently, their hypothalamic-pituitary-adrenal axis to several stimulatory neurotransmitters and inflammatory cytokines. In the present study we investigated in this strain the secretory dynamics of another major activator of pituitary ACTH secretion, arginine vasopressin (AVP). To accomplish this, we evaluated the circadian plasma concentrations and circadian and glucocorticoid-induced changes in hypothalamic content and in vitro release of AVP in 8- to 10-week-old female LEW/N rats and compared these measurements to those obtained in parallel from age- and sex-matched histocompatible, inflammatory disease-resistant Fischer (F344/N) rats. Plasma concentrations and hypothalamic content and in vitro release of AVP were significantly elevated in LEW/N compared to F344/N rats in both the morning and evening. These indices of higher AVP secretion in LEW/N than in F344/N rats were also present after chronic dexamethasone treatment. These findings suggest increased AVP production and release in LEW/N rats, perhaps representing an adaptive compensation for insufficient CRH and glucocorticoid secretion. The high levels of circulating AVP might contribute to the excessive inflammatory responses of these animals.

All living organisms have developed a highly conserved and regulatory system, the stress system, to cope with a broad spectrum of stressful stimuli that threaten, or are perceived as threatening, their dynamic equilibrium or homeostasis. This neuroendocrine system consists of the hypothalamic-pituitary-adrenal (HPA) axis and the locus caeruleus/norepinephrine-autonomic nervous system. In parallel with the evolution of the homeostasis and stress concepts from ancient Greek to modern medicine, significant advances in the field of neuroendocrinology have identified the physiologic biochemical effector molecules of the stress response. Glucocorticoids, the end-products of the HPA axis, play a fundamental role in the maintenance of both resting and stress-related homeostasis and, undoubtedly, influence the physiologic adaptive reaction of the organism against stressors. If the stress response is dysregulated in terms of magnitude and/or duration, homeostasis is turned into cacostasis with adverse effects on many vital physiologic functions, such as growth, development, metabolism, circulation, reproduction, immune response, cognition and behavior. A strong and/or long-lasting stressor may precipitate and/or cause many acute and chronic diseases. Moreover, stressors during pre-natal, post-natal or pubertal life may have a critical impact on our expressed genome. This review describes the central and peripheral components of the stress system, provides a comprehensive overview of the stress response, and discusses the role of glucocorticoids in a broad spectrum of stress-related diseases.

Huntington's disease (HD) is a neurodegenerative disorder characterized by severe motor, cognitive and psychiatric symptoms. Patients of all ages can present with a dysfunction of the nervous system, which leads to the progressive loss of movement control and disabilities in speech, swallowing, communications, etc. The molecular basis of the disease is well-known, as HD is related to a mutated gene, a trinucleotide expansion, which encodes to the huntingtin protein. This protein is linked to neurogenesis and the loss of its function leads to neurodegenerative disorders. Although the genetic cause of the disorder has been known for decades, no effective treatment is yet available to prevent onset or to eliminate the progression of symptoms. Thus, the present review focused on the development of novel methods for the timely and accurate diagnosis of HD in an aim to aid the development of therapies which may reduce the severity of the symptoms and control their progression. The majority of the therapies include gene-silencing mechanisms of the mutated huntingtin gene aiming to suppress its expression, and the use of various substances as drugs with highly promising results. In the present review, the latest approaches on the diagnosis of HD are discussed along with the need for genetic counseling and an up-to-date presentation of the applied treatments.

We report a case of a 13-year-old girl with chronic recurrent multifocal osteomyelitis (CRMO) who developed severe arthritis in four different joints within the first year from the onset of the disease. Her multiple vertebrae lesions showed significant amelioration after a 2-month treatment with prednisolone. In parallel, the initial severe symmetrical arthritis of both knees showing overt synovitis and joint effusion, in the absence of lesions in the metaphyses of the femur or the tibia, responded remarkably well in intra-articular triamcinolone hexacetonide injections. However, upon discontinuation of prednisolone, the patient developed severe arthritis of her right ankle and the proximal interphalangeal joint of her right middle finger. Thus, prednisolone was reinitiated combined with methotrexate, and the patient went into remission, which persists one year after prednisolone tapering. The appearance of arthritis in both knees in the absence of bone lesions and the emergence of severe arthritis of the ankle after remission of spinal bone lesions suggest that CRMO and juvenile idiopathic arthritis may coexist and be causally related.

Abstract We demonstrate 2 novel mutations of the LHCGR, each homozygous, in a 46,XY patient with severe Leydig cell hypoplasia. One is a mutation in the signal peptide (p.Gln18_Leu19ins9; referred to here as SP) that results in an alteration of the coding sequence of the N terminus of the mature mutant receptor. The other mutation (p.G71R) is also within the ectodomain. Similar to many other inactivating mutations, the cell surface expression of recombinant human LHR(SP,G71R) is greatly reduced due to intracellular retention. However, we made the unusual discovery that the intrinsic efficacy for agonist-stimulated cAMP in the reduced numbers of receptors on the cell surface was greatly increased relative to the same low number of cell surface wild-type receptor. Remarkably, this appears to be a general attribute of misfolding mutations in the ectodomains, but not serpentine domains, of the gonadotropin receptors. These findings suggest that there must be a common, shared mechanism by which disparate mutations in the ectodomain that cause misfolding and therefore reduced cell surface expression concomitantly confer increased agonist efficacy to those receptor mutants on the cell surface. Our data further suggest that, due to their increased agonist efficacy, extremely small changes in cell surface expression of misfolded ectodomain mutants cause larger than expected alterations in the cellular response to agonist. Therefore, for inactivating LHCGR mutations causing ectodomain misfolding, the numbers of cell surface mutant receptors on fetal Leydig cells of 46,XY individuals exert a more exquisite effect on the relative severity of the clinical phenotypes than already appreciated.

We report the dietary intake of selected nutrients in apparently healthy adults and children and its correlation with circulating levels of serum leptin and resistin. In this observational study, 47 Saudi children (mean age 13.1 ± 2.8 year) and 47 adults (mean age 45.7 ± 10.5 year) were recruited. Anthropometric data and lipid profile were obtained. Food intake was assessed by a food questionnaire and a 24-hour diet recall method. The dietary intake of selected nutrients was compared with the estimated average requirement (EAR) or adequate intake (AI) for establishing nutritional status. Results demonstrated that the levels of choline and calcium intake were significantly lower than the EAR in adults (p= 0.01 and 0.04, respectively) and relatively low in children. The level of manganese in adults was significantly higher (p= 0.02) than their AI level. The increasing levels of dietary vitamin B6 and B12 were associated with a significant increase in serum concentrations of leptin in adults and children (p=0.02). Overall, the dietary intakes of selected nutrients in Saudi adults and children were not adequate with most of them below cut-off EAR values except for essential amino acids.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system. It is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Uterine CRH participates in local immune early pregnancy phenomena, such as decidualization of endometrial strom a and protection of the fetus from maternal immune system. This is maintained through induction of the expression of apoptotic FasL on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases apoptosis of activated T lymphocytes through FasL induction participating in the process of implantation and early pregnancy. Female rats treated with the non-peptidic CRH receptor 1 (CRHR1) specific antagonist antalarmin, in the first 6 days of gestation, have undergone a decrease of endometrial implantation sites and live embryos and markedly diminished endometrial FasL expression.

The psychological consequences on the caregivers taking care of mentally ill patients are well known; however, little evidence exists as to whether taking care of a mentally ill patient affects the physical health of the caregiver. To examine the effect of caregiving on emotional and physical health. To study the association between caregiving for mentally ill and physical illness. One hundred twenty-eight caregivers, relatives of patients suffering from schizophrenia or bipolar disorder, who were hospitalized consecutively during the past three years (2011–2013), and 117 controls completed over telephone a structured questionnaire. Eligible patients were all those with duration of illness more than 5 yrs. Data included demographics and detailed information about past or present mental and/or physical illness. Data were analyzed using the Pearson's chi-square test and multivariate binary regression controlling for BMI, age, sex, and smoking. Significant correlation was found between caregiving and anxiety (OR=4,1, p<0,0001), depression (OR=3,5 p=0,03), sleep disturbances (OR=2,6, p=0,05), arthritis (OR=2,5, p=0,03), rheumatopathy (OR=2,8, p=0.09) and allergies (OR=2,5, p=0,09). The association of caregiving with allergies/ arthritis was independent of anxiety and depression. No correlation was found with diabetes, hypertension and cardiovascular disease. The stress of taking care of a mentally ill patient appears to affect physical health, specifically increasing the risk for autoimmune disorders (allergy, arthritis), independently of anxiety, depression and sleep disturbances.

Sleep is an important component of mammalian homeostasis, vital for our survival. Sleep disorders are common in the general population and are associated with significant adverse behavioral and health consequences. Sleep, in particular deep sleep, has an inhibitory influence on the hypothalamic-pituitary- adrenal (HPA) axis, whereas activation of the HPA axis or administration of glucocorticoids can lead to arousal and sleeplessness. Insomnia, the most common sleep disorder, is associated with a 24hour increase of ACTH and cortisol secretion, consistent with a disorder of central nervous system hyperarousal. On the other hand, sleepiness and fatigue are very prevalent in the general population, and studies have demonstrated that the pro inflammatory cytokines IL6 and/or TNF-alpha are elevated in disorders associated with excessive daytime sleepiness, such as sleep apnea, narcolepsy and idiopathic hypersomnia. Sleep deprivation leads to sleepiness and daytime hypersecretion of IL6, whereas daytime napping following a night of total sleep loss appears to be beneficial both for the suppression of IL6 secretion and for the improvement of alertness. These findings suggest that the HPA axis stimulates arousal, while IL6 and TNF-alpha are possible mediators of excessive daytime sleepiness in humans. It appears that the interactions of and disturbances between the HPA axis and inflammatory cytokines determine whether a human being will experience deep sleep/sleepiness or poor sleep/fatigue. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .