Forced swimming differentially affects male and female brain corticosteroid receptors

Corticosteroid receptors are key mediators of the neuroendocrine response to stress. Previously, we have determined the effects of restraint stress on the regulation of corticosteroid receptor genes in the brain and pituitary of male and female rats. Significant gender- and regional-specific regulation of receptor mRNAs was observed. To further investigate the stressor specificity in the same context, we have determined glucocorticoid receptor (GR) and mineralocorticoid receptor (MR) mRNAs following exposure to swimming stress paradigms applied alone, or in combination with restraint stress. Our data revealed stressor-specific alterations in GR or MR mRNA levels, which were more pronounced in males, the gender most affected by swimming stress. No alterations in GR or MR mRNA levels were detected in the female hippocampus and hypothalamus upon exposure to swimming paradigms, while in males the same stressors down-regulated GR mRNA in the hippocampus (chronic exposure) and up-regulated both genes in the hypothalamus (acute exposure). In the frontal cortex, acute swimming stress caused a reciprocal change in GR mRNA levels in the two sexes. The above difference is not due to circulating ovarian steroids, since ovariectomy did not change the female pattern of GR gene expression following acute stress. Our results further showed a hypothalamic-pituitary-adrenal axis facilitation to a novel superimposed stressor expressed at the level of limbic corticosteroid receptors: When chronically restrained rats of both sexes were exposed to acute swimming stress, a reduced GR/MR mRNA ratio, implying reduced feedback axis sensitivity, was detected in both the hippocampus and the hypothalamus. In conclusion, our work provides additional evidence on stressor, gender and region specificity in the regulation of brain corticosteroid receptors.     

The association of diabetic microvascular and macrovascular disease with cutaneous circulation in patients with type 2 diabetes mellitus

Aims

To study the impact of diabetic neuropathy, both peripheral sensorimotor (DPN) and cardiac autonomic neuropathy (CAN), on transcutaneous oxygen tension (TcPO₂) in patients with type 2 diabetes mellitus (T2DM).

Plasma levels of MMP-2, MMP-9 and TIMP-1 are not associated with arterial stiffness in subjects with type 2 diabetes mellitus

ObjectiveIncreased arterial stiffness is a marker of atherosclerosis and is recognised early in the course of type 2 diabetes mellitus (T2DM). Matrix metalloproteinases (MMP) and their tissue inhibitors (TIMP) are a family of proteolytic enzymes which are essential for the structure and function of large arteries. In this study, we examined for relationships between MMP and TIMP-1 and indices of arterial stiffness in subjects with T2DM.Research Design and MethodsA total of 60 subjects with T2DM and 60 nondiabetic subjects were recruited. Aortic distensibility (AD) was assessed noninvasively by ultrasonography and augmentation index by pulse wave analysis.ResultsThe values of AD were lower in subjects with T2DM than in controls (P<.001), while those of augmentation index were not significantly different between the two groups. Plasma concentrations of MMP-2 and MMP-9 were not different between diabetic and nondiabetic participants, while those of TIMP-1 were lower in the diabetic patients (P=.005). In the diabetes group, no significant associations were found between either AD or augmentation index and MMPs as well as TIMP-1, while duration of diabetes emerged as the strongest predictor of AD (P<.001). In the nondiabetic group, nonsignificant associations were also found between AD or augmentation index and MMPs as well as TIMP-1.ConclusionIn patients with T2DM, plasma levels of MMP and TIMP-1 are not associated with arterial stiffness assessed by either AD or augmentation index.     

Comparative effects of sevoflurane and propofol based general anaesthesia for elective surgery on memory

Introduction

Unconscious processing of words during general anaesthesia has been suggested. We used the process dissociation procedure (PDP) to test memory performance during sevoflurane and propofol anaesthesia in relation to hypnotic depth.

Material and methods

One hundred participants anaesthetised for elective surgery (50 with propofol and 50 with sevoflurane) and 50 non-anaesthetized listened to a list of words. The bispectral index (BIS) of the anaesthetised patients was recorded. Within 36 h after word presentation, memory was assessed using a word stem completion task, based on Buchner''s model applied on the PDP.

Results

There was evidence of memory for words presented during light (BIS 61-80) (p = 0.001) and adequate (BIS 41-60) (p = 0.008) but not deep anaesthesia (BIS 21-40) (p = 0.09). The PDP showed a significant implicit but not explicit memory contribution (mean total explicit memory scores: 0.04 ±0.07 in all BIS categories; mean implicit memory scores: 0.01 ±0.04, 0.1 ±0.08, and 0.05 ±0.09 at BIS = 21-40, 41-60, and 61-80, respectively). There was a statistically significant difference between the mean implicit memory score (I) of the propofol and sevoflurane group in the BIS category 41-60 in general (p = 0.016), and after incision (I_A.I.) (p = 0.005) in particular, with propofol depressing I more than sevoflurane in both cases. Memory performance of nonanaesthetized participants was better, with a higher contribution of explicit and a comparable contribution of implicit memory.

Conclusions

During general anaesthesia, implicit memory persists even in adequate hypnotic states. Sevoflurane affects the implicit memory of adequately anaesthetised subjects less than propofol.     

Significance of estrogen receptor 1 (ESR-1) gene imbalances in colon and hepatocellular carcinomas based on tissue microarrays analysis

Estrogen receptor alpha–encoded by ESR1 gene–overexpression correlates with prognosis and response to specific chemotherapy in breast adenocarcinoma cases. Mechanisms of ESR-1 deregulation in carcinomas remain under investigation. To analyze ESR1 in carcinomas of different histogenesis. Using tissue microarray technology, 172 primary carcinomas including breast ductal adenocarcinomas (n = 60), hepatocellular carcinomas (n = 52), and colon adenocarcinomas (n = 60) were cored and re-embedded in three paraffin blocks. Initial diagnosis was based on liquid based cytology (LiquiPrep/ThinPrep). Immunohistochemistry and fluorescence in situ hybridization were performed. Quantitative evaluation of ER-a protein levels was assessed by applying digital image analysis. ER-a overexpression was observed in 41/60 (68.3%), 23/52 (44.2%) and 4/60 (6.6%) cases, respectively. ESR1 gene multiple copies were confirmed in 13/60 (21.6%) breast adenocarcinomas, but high amplification only in 8/13 (62.8%). Allelic absence was identified in 3/52 (5.7%) hepatocellular carcinomas, whereas colon adenocarcinomas demonstrated gene gains in 5/60 (8.3%) cases referred to chr 6 aneuploidy and not to amplification. ER-a overall expression was associated strongly to ESR1 gene copies only in breast carcinoma (P = 0.036). ESR-1 gene overexpression happens frequently in breast cancer, but only a subset of them are high amplified cases correlated to increased response rates in hormonal therapy (tamoxifen). Absence of this mechanism in hepatocellular and colon carcinomas maybe is a negative factor for applying this therapy. This is a pattern of histo-genetic depended targeted therapeutic strategy.     

Brooke-Spiegler syndrome with parotid gland involvement

Salivary gland involvement in Brooke-Spiegler syndrome (BSS), an autosomal dominantly inherited disease, is known though not frequent. A case of familial cylindromatosis with parotid gland adenoma is herein reported. A 67-year-old lady presented with multiple scalp nodules and papular coalescent lesions over the nasolabial folds and the forehead. The clinical examination also revealed a left preauricular lump. Multiple biopsies of the scalp lesions and the nasolabial papules revealed cylindromas and trichoepitheliomas respectively. CT scan and FNA of the preauricular lump were suggestive of parotid gland adenoma. The patient underwent excision of the scalp cylindromas and total left parotidectomy. There is no evidence of recurrence after 4 years. The association of BSS with salivary gland tumours, emphasizes the necessity of thorough salivary gland examination in all patients with skin lesions. Knowledge of the genetic background of BSS allows for genetic counseling of patients.     

A non-catecholamine-producing sympathetic paraganglioma of the spermatic cord: the importance of performing candidate gene mutation analysis

Background  

Catecholamine-producing tumours are called pheochromocytomas when they are located in the adrenal gland and sympathetic paragangliomas when they are located elsewhere in the abdomen. Rarely these tumours do not produce catecholamines and even more rarely they arise in the spermatic cord. Over the past decade, systematic mutation analysis of apparently sporadic cases of pheochromocytomas and paragangliomas has elucidated the frequent presence of germ line mutations in one of five candidate genes, including RET, VHL, SDHB, SDHC, and SDHD.     

Intravenous fosfomycin for the treatment of multidrug-resistant pathogens: what is the evidence on dosing regimens?

Introduction: The intravenous (IV) formulation of fosfomycin has been re-introduced in clinical practice mainly to overcome treatment failures against multidrug-resistant (MDR) bacteria. Appropriate dosing schedules of the IV formulation have not yet been established.

Areas covered: The mechanism of action and resistance development, commercial IV formulations, pharmacokinetic/pharmacodynamic (PK/PD) properties, IV dosing regimens for the treatment of MDR infections along with efficacy and safety issues were reviewed. Data regarding specific MDR pathogens, daily doses and patients’ outcomes, gaps in the current literature, and in progress research agenda are presented.

Expert opinion: The doses of fosfomycin IV range between 12 and 24 grams/day depending on the severity of infection. The efficacy and safety of the commonly administered doses have been shown mainly in observational non-comparative trials. The optimal dose ensuring maximal efficacy with minimal toxicity along with the most appropriate co-administered antibiotic(s) need further evaluation. The pharmacokinetic/pharmacodynamic parameter associated with maximum efficacy has not yet been established, although, the ratio of the area under the concentration-time curve (AUC) for the free unbound fraction of fosfomycin versus the MIC (fAUC/MIC) may be linked to optimal treatment. RCTs and other comparative studies are underway to address gaps of knowledge in adult patients and neonates.     

Eleven Patients With Testicular Leydig Cell Tumors

We present the sonographic and magnetic resonance imaging findings of Leydig cell tumors in a series of patients, along with a brief review of the literature. We evaluated the sonographic features of 11 cases of Leydig cell tumors, including echogenicity, size, margins, and patterns of vascularity. The magnetic resonance imaging characteristics of 9 patients were also assessed, with special attention to the appearance of the tumors on T2-weighted imaging and postcontrast T1-weighted imaging. Seven tumors were hypoechoic, and 4 were almost isoechoic. Ten patients showed various patterns of hypervascularity in the tumors, combined in some cases with feeding vessels. One case presented with a single feeding vessel. The tumors showed homogeneous or heterogeneous low signal intensity on T2-weighted imaging and marked enhancement on postcontrast T1-weighted imaging. The small size of these tumors, the various patterns of vascularity on color and power Doppler sonography, and the marked enhancement on postcontrast T1-weighted imaging are considered valuable but generally nonspecific for identification of these tumors.