Influence of the frequency of ovine corticotropin-releasing factor administration on adrenocorticotropin and corticosterone secretion in the rat

We have examined the pattern of ACTH secretion in rats receiving two or more injections of synthetic ovine corticotropin-releasing factor (CRF). A first exposure of cannulated intact rats to CRF caused a blunting of the ACTH response when CRF was again injected 0.5-6 h later. Since plasma corticosterone levels stayed elevated for only 2 h after the first injection of CRF, the diminished pituitary responsiveness persisted at a time when plasma corticosterone levels had returned to control values. When cannulated adrenalectomized animals were subjected to a similar treatment, the blunting of the ACTH release due to the second injection of CRF, though present, was of significantly shorter duration. Duplication of the corticosterone levels that follow one CRF injection by exogenous administration of the steroid inhibited the subsequent ACTH response to CRF for a maximum of 2 h. Finally, CRF infused into intact rats for 14 days consistently caused elevation of both ACTH and corticosterone secretion. We conclude that CRF administered in a repeated or continuous manner to intact rats, while causing some pituitary desensitization, still elicits a significant degree of ACTH secretion despite the presence of elevated corticosterone release. This observation as well as the fact that CRF-injected adrenalectomized animals exhibit some blunting of their ACTH responses suggest that steroid feedback, while participating in the diminished ability of CRF to repeatedly stimulate ACTH release, does not represent the sole modulator of pituitary responsiveness.     

Interaction between Ethanol and Stress on ACTH and β-Endorphin Secretion

The intraperitoneal infusion of ethanol (EtoH) (1 g/hr/kg body weight for 3 hr) to intact rats blunted the secretion of adrenocorticotropic hormone (ACTH) and β-endorphin induced by a subsequent 10-min exposure to mild, inescapable electroshocks (1.5 mA; 2 sec; four shocks/min) or by corticotropin-releasing factor (CRF). Conversely, administration of the shocks for 3 hr diminished the pituitary response to an acute i.p. injection of EtoH. While we have previously shown (Rivier C, Vale W Endocrinology 121:1320–1328, 1987) that prolonged stress induces a loss of pituitary responsiveness due to the depletion of pituitary ACTH stores, the infusion of EtoH did not cause statistically significant changes in pituitary ACTH content. In adrenalectomized rats, the infusion of EtoH caused an elevation of ACTH plasma levels that was significantly ( p ≤ 0.01) larger than intact animals. These rats also showed a blunted pituitary response to the acute injection of CRF, possibly because they were already secreting ACTH at a maximal rate. These results support the hypothesis that CRF, stress, and alcohol do not potentiate each other on pituitary ACTH and β-endorphin secretion.     

Increased pituitary sensitivity to glucocorticoid feedback during the stress nonresponsive period in the neonatal rat

Neonatal rats show a diminished response to stress [the stress-nonresponsive period (SNRP)] from day 2-3 until day 14 of age; the physiological bases for the SNRP are unknown. We examined whether enhanced sensitivity of the brain or pituitary to the inhibitory feedback effects of circulating glucocorticoids (GC) contributes to the SNRP. Age-related changes in the ability of corticosterone (CORT) and dexamethasone (DEX) to inhibit the ACTH secretion induced by urethane or CRF were studied. We also examined the ACTH response to ether stress or CRF in intact or 24 h-adrenalectomized 5-day-old rats. Plasma ACTH did not increase in intact rats after ether stress (basal: 64.6 +/- 9.1 pg/ml vs. stressed: 66.8 +/- 8.9 pg/ml; P greater than 0.05), whereas small elevations occurred after CRF challenge (184.6 +/- 40 pg/ml; P less than or equal to 0.01). Five-day-old adrenalectomized rats, which had elevated basal ACTH concentrations, increased ACTH secretion after exposure to ether or CRF. Thus, negative feedback appears to mediate critically the SNRP. Furthermore, sensitivity to such feedback was enhanced during the SNRP since the capacity of CORT to inhibit urethane-induced ACTH secretion in vivo declined with age; 1 mg/kg BW was the minimal dose that inhibited ACTH secretion at day 10, whereas at day 18, the threshold for a similar inhibition was 5 mg/kg BW. In contrast, at both ages, a dose of 10 micrograms/kg BW DEX inhibited ACTH release. In vitro dose response studies in whole pituitaries further demonstrated the enhanced pituitary sensitivity to GC feedback during the SNRP since the IC50 for CORT inhibition of CRF-induced ACTH release increased from days 3-5 to days 22-23. A similar, although not statistically significant trend was observed for DEX inhibition. Thus, neonatal rats exhibit an enhanced pituitary sensitivity to GC during the SNRP and removal of this inhibition allows ACTH secretion in response to ether stress.     

Interval between neoadjuvant treatment and definitive surgery in locally advanced rectal cancer: impact on response and oncologic outcomes

Purpose

The optimal waiting period between neoadjuvant treatment completion and surgery in locally advanced rectal cancer (LARC) is controversial. The specific purpose of this study was to evaluate the effect of prolonging this interval on the pathologic response, postoperative morbidity, and long-term oncologic outcomes.

Methods

Retrospective data analysis is reported from LARC patients who had been treated with chemoradiation followed by surgery and intra-operative radiotherapy, between February 1995 and December 2012. In total, two groups were studied, according to the time elapsed between neoadjuvant treatment and surgery: conventional interval (CI; <6 weeks) and delayed interval (DI; ≥6 weeks). Clinicopathological data related to tumor response, postoperative morbidity, and oncologic outcomes were compared.

Results

This study included 335 consecutive LARC patients. There was a higher proportion of patients with clinical staging nodal involvement (cN+) in the DI group (76.6 vs. 64.1 %; p = 0.01). The pathologic complete response (pCR) was not significantly different among groups (8.8 vs. 12.1 %; p = 0.34). Longer intervals did not affect complication incidence or severity or hospital admission length. Certain postneoadjuvant tumor effect parameters were significantly increased in the DI group, including N-downstaging and T-downsizing. After a median follow-up of 71 months, patients in the DI group presented with superior 5-year overall survival (OS) (55.9 vs. 70.4 %, p = 0.014); however, no statistically significant differences were observed in 5-year disease-free survival (DFS) or 5-year local control (LC) (69.9 vs. 74.9 %, p = 0.223; 90.4 vs. 94.5 %, p = 0.123, respectively).

Conclusions

A modest surgical interval delay (≥6 weeks) did not increase postoperative complications and was identified as a favorable prognostic factor for OS, although no differences were observed in pCR, LC, or DFS. Innovative multidisciplinary strategies incorporating further time extension of the surgical interval can be safely explored.     

Cardiorespiratory fitness,pulmonary function and C-reactive protein levels in nonsmoking individuals with diabetes

The objective of this study was to evaluate cardiorespiratory fitness and pulmonary function and the relationship with metabolic variables and C-reactive protein (CRP) plasma levels in individuals with diabetes mellitus (DM). Nineteen men with diabetes and 19 age- and gender-matched control subjects were studied. All individuals were given incremental cardiopulmonary exercise and pulmonary function tests. In the exercise test, maximal workload (158.3±22.3 vs 135.1±25.2, P=0.005), peak heart rate (HR_peak: 149±12 vs 139±10, P=0.009), peak oxygen uptake (VO_2peak: 24.2±3.2 vs 18.9±2.8, P<0.001), and anaerobic threshold (VO_2VT: 14.1±3.4 vs 12.2±2.2, P=0.04) were significantly lower in individuals with diabetes than in control subjects. Pulmonary function test parameters, blood pressure, lipid profile (triglycerides, HDL, LDL, and total cholesterol), and CRP plasma levels were not different in control subjects and individuals with DM. No correlations were observed between hemoglobin A1C (HbA1c), CRP and pulmonary function test and cardiopulmonary exercise test performance. In conclusion, the results demonstrate that nonsmoking individuals with DM have decreased cardiorespiratory fitness that is not correlated with resting pulmonary function parameters, HbA1c, and CRP plasma levels.     

Rheumatoid Arthritis Bone Fragility Is Associated With Upregulation of IL17 and DKK1 Gene Expression

Our aim was to compare bone gene expression in rheumatoid arthritis (RA) and primary osteoporosis (OP) patients. Secondary aims were to determine the association of gene expression of the Wnt/β-catenin signaling pathway with inflammatory cytokines in the bone microenvironment and to assess the serum levels of Wnt/β-catenin proteins in both groups. RA patients referred for hip replacement surgery were recruited. Primary OP patients were used as controls. Gene expression of Wnt pathway mediators, matrix proteins, and pro-inflammatory cytokines were analyzed in bone samples. Bone turnover markers, inflammatory cytokines, and Wnt mediators were measured in serum. Twenty-two patients were included: 10 with RA and 12 with primary OP. The expressions of Wnt10b (p?=?0.034), its co-receptor LRP6 (p?=?0.041), and its negative regulator DKK1 (p?=?0.008) were upregulated in RA bone. IL17 gene expression in bone was upregulated in RA patients (p?=?0.031) and correlated positively with Wnt10b (r?=?0.810, p?=?0.015), DKK2 (r?=?0.800, p?=?0.010), and RANKL/OPG ratio (r?=?0.762, p?=?0.028). DKK2 (p?=?0.04) was significantly decreased in RA serum compared with primary OP. In conclusion, bone fragility in RA patients is induced by an unbalanced bone microenvironment and is associated with a specific gene expression pattern, namely, the upregulation of IL17 and DKK1, suggesting that the modulation of these two pathways might prevent RA systemic bone loss.     

Nutrient Intakes among Brazilian Children Need Improvement and Show Differences by Region and Socioeconomic Level

Brazil is the most populous country in South America. Using 24 h dietary data, we compared the nutrient intakes of 4–13-year-olds to reference values and tested for regional and socioeconomic (SES) differences. A considerable proportion reported intakes below the Estimated Average Requirements (EAR) for vitamins E (78.1%, 96.5%), D (100% for both), and calcium (80.5%, 97.7%) for 4–8 and 9–13-year-olds, respectively. Few exceeded Adequate Intakes (AI) for potassium or fiber. Older children reported greater inadequacies and, while there was regional variability, patterns of inadequacy and excess tended to be similar. For vitamin C, the percent of children below EAR in the Northeast and Southeast was lower than in the South. Most children, regardless of SES, had energy intakes within the Acceptable Macronutrient Distribution Ranges (AMDRs) for carbohydrates and protein. Over a quarter reported total energy from fat less than the AMDR, and inversely associated with SES (low 50.9%, moderate 26.0%, and high 15.0%), but also exceeding the percentage of energy recommendation for saturated fat, increasing with SES (low 18.1%, moderate 38.9%, and high 48.8%). The contrast observed between the diets of young Brazilians and recommendations underscores the need for individual and regional environmental interventions to promote healthier dietary patterns.     

Risk Factors for Development of Rectal Neuroendocrine Tumors Longer Than 9 mm: Retrospective Cohort

BackgroundRectal neuroendocrine tumors (R-NET) represent the most frequent of gastroenteropancreatic neuroendocrine neoplasms (NEN-GEP) according to the United States Surveillance, Epidemiology, and End Results database. With an annual percentage of occurrence increasing to 8.2% of all rectal neoplasms, R-NET affect less than 2% and are reported in only 0.05% to 0.07% of patients undergoing colorectal cancer (CRC) screening. The primary objective of this study was to assess the risk factors associated with R-NET greater than 10 mm. As a secondary objective, it was also aimed to evaluate the response to endoscopic treatment.Methods: This was a retrospective study, using data collected through the analysis of medical records of colonoscopies performed from January 2008 to December 2014. Records of polypectomies were identified, and the results were searched for pathological findings of R-NET. We also gathered epidemiological data and outcomes as risk factors for lesions greater than or equal to 10 mm, with local and distant recurrence.Results: During the study period, 18 218 colonoscopies were performed and 10 865 polypoid lesions were detected and removed, 20 with R-NET anatomopathology. The detection rate was 0.1%. The risk factors associated with major lesions were Japanese ethnicity, the lack of previous cancer diagnosis, and a Ki67 index > 2%. The mean follow-up was 56.6 months, and there was no local lymph node recurrence or distant relapse.ConclusionThis study concludes that endoscopic resection is a good and effective method for treatment of Grade 1 rectal NET smaller than 11 mm, with high cure rates and low rates of local or distant relapse.