Postnatal development of brain alpha 1-adrenergic receptors: in vitro autoradiography with [125I]HEAT in normal rats and rats treated with alpha-difluoromethylornithine, a specific, irreversible inhibitor of ornithine decarboxylase

The postnatal development of brain alpha 1-adrenergic receptors was studied in the rat brain using in vitro autoradiography. In some regions, such as the globus pallidus, receptor-binding sites were present at birth and increased during the first week but then decreased to very low levels by adulthood. In contrast, other regions such as the olfactory bulb and cerebral cortex exhibited little binding at birth, with a subsequent increase in receptors during the second week of life that persisted into the mature stage. Several regions had an intermediate pattern with significant labelling at birth, an increase in the first few weeks and a smaller decrement in binding sites as adulthood was approached. The data suggested that there were two archetypal development patterns, one of which was potentially related to the arrival of noradrenergic nerve projections (olfactory bulb) and the other of which was determined intrinsically by differentiation (globus pallidus). The two patterns could be distinguished by their sensitivity to alpha-difluoromethylornithine, a drug that inhibits ornithine decarboxylase, leading to a slowing of cellular replication, differentiation and migration. Drug treatment dramatically delayed the developmental fall-off of binding in the globus pallidus such that receptor sites remained in high concentration well past the point at which they disappeared in control animals. In the olfactory bulb, however, alpha-difluoromethylornithine had little or no effect on the ontogeny of receptor binding. These studies provide evidence that alpha 1-adrenergic receptors in various brain regions develop at different rates and with at least two characteristic patterns. Autoradiographic techniques provide important insights into receptor development that cannot be garnered from biochemical methods using isolated membrane preparations.     

Biochemical mechanisms of developmental neurotoxicity of methylmercury

Methylmercury has been designated a "behavioral teratogen" because of its ability to evoke abnormalities in the absence of gross morphological damage to the developing brain. Recent work indicates that exposure to doses of methylmercury associated with neurobehavioral actions causes early alterations in brain ornithine decarboxylase, an enzyme whose activity is related to the coordination of cellular maturation. These effects are followed by regionally-targeted perturbation of cell replication and differentiation, indicated by measurements of nucleic acid and protein synthesis and levels. Neurobehavioral disturbances are associated with postnatal alterations in synaptogenesis and synaptic activity, as exemplified by studies in catecholaminergic pathways. Thus, methylmercury alters neurotransmitter uptake and turnover in presynaptic terminals, as well as development of postsynaptic adrenergic receptor binding sites. These changes result in aberrant signal transmission across the synapse, with consequent effects on synaptic function and ultimately on the communication of trophic developmental signals which ordinarily pass from neuron to target tissue. Although the specific linkages among the various biochemical effects of developmental exposure to methylmercury remain to be elucidated, studies of this type can serve as a model with which to understand the subcellular mechanisms underlying behavioral teratogenesis.     

Stomatin‐like protein 2 overexpression in papillary thyroid carcinoma is significantly associated with high‐risk clinicopathological parameters and BRAFV600E mutation

Stomatin‐like protein 2 (SLP‐2), a member of the stomatin protein family, has emerged as a potential molecular hallmark of tumor progression in several human malignancies. The aim of this study was to analyze SLP‐2 expression pattern in benign and malignant thyroid tumors (n = 210) and to examine its relationship with clinicopathological parameters and BRAFV600E mutation in thyroid cancer. SLP‐2 immunohistochemical expression was not detected in benign adenomas and was absent/weak in follicular and anaplastic carcinomas. High expression levels of SLP‐2, found only in papillary thyroid carcinoma (PTC), particularly in the classical variant, were significantly associated with adverse clinicopathological parameters: lymph node metastasis (p = 0.002), extrathyroid invasion (p < 0.001), pT status (p < 0.001), and advanced tumor stage (p = 0.001). Additional genotyping of PTC cases for the BRAFV600E mutation revealed for the first time a close relation between SLP‐2 overexpression and the presence of BRAF mutation (p = 0.02) with high positive rates of lymph node metastasis (70%) and extrathyroid invasion (80%) in these cases. The significant association of SLP‐2 overexpression with unfavorable clinicopathological characteristics and BRAFV600E mutation indicates that SLP‐2 may have a role in aggressiveness of BRAF‐mutated PTC and that SLP‐2 evaluation could be clinically useful in identification of high‐risk PTC patients.     

Acute administration of corticoids: a new and peculiar stimulus of growth hormone secretion in man

It is widely accepted that chronic administration of corticoids in man inhibits the GH response to all of the stimuli tested so far. To study the action of corticoids administered acutely, several dexamethasone challenge tests were performed, after which GH levels were measured for 7 h. In eight volunteers, administration of 4 mg dexamethasone (Dex), iv, induced a clear-cut GH release compared with saline administration. The secretion followed an unusual pattern; basal GH levels (1.5 +/- 0.1 micrograms/L) started rising 2 h after Dex injection, reaching a peak of 17.5 +/- 4.4 micrograms/L after 3 or 3.5 h. Peak levels were maintained until 5 h post-Dex and decreased thereafter. Similar data were obtained when Dex was administered to five volunteers at the dose of 8 mg, orally, with a 30-min delay of the GH peak (19.6 +/- 7.9 micrograms/L). To study whether there was a cholinergic input responsible for the Dex action, another group of eight volunteers underwent three Dex tests (4 mg, iv) on three occasions, followed 90 min later by the administration of placebo (control), atropine (0.5 mg, iv), or pyridostigmine (120 mg, orally). The Dex-induced GH peak (20.8 +/- 5.2 micrograms/L) was not significantly increased by pyridostigmine (cholinergic agonist) treatment (24.2 +/- 4.0 micrograms/L). The blockade of muscarinic receptors by atropine induced a delay in the Dex-induced secretory peak, which appeared at 5 h. However, the Dex-atropine GH peak (14.9 +/- 4.1 micrograms/L) was not different from the Dex-placebo one. In conclusion, Dex alone is able to induce a clear-cut GH secretion in man. The stimulus followed a peculiar time pattern, with peaks levels attained 3 h after either iv or oral administration.     

Depending on the time of administration, dexamethasone potentiates or blocks growth hormone-releasing hormone-induced growth hormone release in man

In humans, corticoids suppress growth hormone (GH) secretion elicited by a variety of stimuli, while in vitro they potentiate GH release. To further study this problem, the effect of two doses of dexamethasone on GH secretion elicited by GH-releasing hormone (GHRH) in 6 normal volunteers was studied. Each subject underwent three tests, on 3 separate days with GHRH 1-29 (1 microgram/kg i.v. at 12.00 h). On the control day, only GHRH was given, on the second day dexamethasone 4 mg i.v. was administered at 09.00 h (3 h before GHRH) and on the third day dexamethasone 8 mg p.o. was given 12 h before GHRH (at 00.00 h). The GHRH-induced GH peak was 9.9 +/- 2.0 ng/ml, while 4 mg dexamethasone significantly (p less than 0.05) potentiated GH secretion elicited by GHRH (29.2 +/- 5.7 ng/ml). When dexamethasone 8 mg was given 12 h before, GHRH-induced GH secretion was completely blocked (3.0 +/- 1.1 ng/ml) (p less than 0.05). These results indicate that corticoids have two different actions: an acute potentiating activity on GHRH, and a delayed blocking action on GHRH-induced GH secretion.     

C-reactive protein levels and survival in patients with moderate to very severe COPD

BACKGROUND: Serum levels of C-reactive protein (CRP) are increased in patients with COPD and correlate modestly with variables predictive of outcomes. In epidemiologic studies, CRP level is associated with all-cause mortality in patients with mild-to-moderate disease. OBJECTIVE: To determine if CRP levels are associated with survival in patients with moderate to very severe COPD in comparison with other well-known prognostic parameters of the disease. METHODS: In 218 stable patients with COPD, we measured baseline serum CRP level, BODE (body mass index, obstruction, dyspnea, and exercise capacity) index and its components, arterial oxygenation (Pao(2)), inspiratory capacity (IC) to total lung capacity (TLC) ratio, and Charlson comorbidity score. We followed up the patients over time and evaluated the strength of the association between the variables and all-cause mortality. RESULTS: During the follow-up time (median, 36 months; 25th to 75th percentiles, 24 to 50 months), 54 patients (25%) died. CRP levels were similar between survivors and the deceased (median, 3.8 mg/L; 95% confidence interval, 1.9 to 8.1; vs median, 4.5 mg/L; 95% confidence interval, 2.1 to 11.5; p = 0.22) and was not significantly associated with survival. CONCLUSIONS: In this population of patients with clinically moderate to very severe COPD, the level of CRP level was not associated with survival compared with other prognostic clinical tools such as the BODE index, modified Medical Research Council scale, 6-min walk distance, percentage of predicted FEV(1), IC/TLC ratio < 0.25, and Pao(2). Other long-term studies of well-characterized patients with COPD could help determine the exact role of CRP levels as a biomarker in patients with clinical COPD.     

Chronic obstructive pulmonary disease and lung cancer: common pathogenesis, shared clinical challenges

Environmental inhaled noxious particles have been known to play a role in several lung diseases, including chronic obstructive pulmonary disease (COPD) and lung cancer, the deadliest malignancy in the world in both sexes. Of the known noxious agents, tobacco smoking is the leading preventable cause of death worldwide and is a recognized risk for the development of both diseases. The association between COPD and lung cancer has been demonstrated in population-based studies, lung cancer screening programs, epidemiological surveys, and case control and biological mechanistic studies. There is evidence that cumulative smoking history is associated with the risk of developing lung cancer and COPD; however, the majority of smokers do not develop clinical COPD or lung cancer. This suggests the presence of one or several factors that modulate the responses to the offending agents and define the final risk for disease development. The 54th Aspen Lung Conference was convened to provide a forum for a systematic dissection of the potential mechanisms by which persons exposed to the causative agents are able to handle and control the process or, in the case of dysfunctional response, the mechanisms that take off in different directions and result in injury and disease. This summary reviews the themes presented and attempts to integrate them for those clinicians and researchers interested in these topics. The challenges and future directions emanating from the discussions may help frame future conferences and hopefully inspire the interest of young researchers.     

Weight-Related Quality of Life in Spanish Obese Subjects Suitable for Bariatric Surgery is Lower Than in Their North American Counterparts: a Case–Control Study

Background

Obesity impairs quality of life, but the perception of the impairment could be different from one country to another. The purpose was to compare weight-related quality of life (QOL) between cohorts from Spain and North America.

Methods

A cross-sectional case–control study was performed between two populations. Four hundred Spanish and 400 North American obese subjects suitable for bariatric surgery closely matched for race, gender, age, and body mass index (BMI) were included. Two non-obese control groups matched for gender, age, and BMI from each population were also evaluated (n?=?400 in each group). The participants completed the Impact of Weight on Quality of Life—Lite (IWQOL—Lite) questionnaire, a measure of weight-related QOL.

Results

Spanish morbidly obese patients showed poorer QOL than their North American counterparts in physical function, sexual life, work, and total score. By contrast, Spanish non-obese control subjects reported better QOL in all domains than their North American counterparts. Women, both in Spain and North America, reported reduced QOL compared to men on the domain of self-esteem. In addition, North American women reported reduced QOL on the sexual life domain compared to men. BMI correlated negatively with all domains of QOL except for self-esteem in both national groups.

Conclusions

Spanish obese subjects suitable for bariatric surgery report poorer weight-related quality of life than their North American counterparts, and obese women, regardless of nationality, perceive a reduced quality of life compared to men.