Effects of voluntary ethanol consumption on emotional state and stress responsiveness in socially isolated rats

Social isolation of rats immediately after weaning is thought to represent an animal model of anxiety-like disorders. This mildly stressful condition reduces the cerebrocortical and plasma concentrations of 3α-hydroxy-5α-pregnan-20-one (3α,5α-TH PROG) as well as increases the sensitivity of rats to the effects of acute ethanol administration on the concentrations of this neuroactive steroid. We further investigated the effects of voluntary consumption of ethanol at concentrations increasing from 2.5 to 10% over 4 weeks of isolation. Isolated rats showed a reduced ethanol preference compared with group-housed animals. Ethanol consumption did not affect the isolation-induced down-regulation of BDNF or Arc, but it attenuated the increase in the cerebrocortical concentration of 3α,5α-TH PROG induced by foot-shock stress in both isolated and group-housed animals as well as increased the percentage of number of entries made by socially isolated rats into the open arms in the elevated plus-maze test. Ethanol consumption did not affect expression of the α₄ subunit of the GABA_A receptor in the hippocampus of group-housed or isolated rats, whereas it up-regulated the δ subunit throughout the hippocampus under both conditions. The results suggest that low consumption of ethanol may ameliorate some negative effects of social isolation on stress sensitivity and behavior.     

Multi-target strategy for Parkinsonian patients: the role of deep brain stimulation in the centromedian-parafascicularis complex

The intra-laminar (IL) thalamic complex, composed of centromedian (CM) and parafascicular (Pf) nucleus, is a strategic crossroad for the activity of the basal ganglia and is recently regaining its position has a putative neurosurgical target for Parkinsonian syndromes. The multi-target approach we have encouraged since the late nineties has allowed the combined implantation of a standard target (the subthalamic nucleus-STN or the internal pallidus-GPi) plus an innovative one (CM/Pf) in well-identified Parkinson's disease (PD) patients; hence, it is possible to study, in the same PD patients, the specific target-mediated effects on different clinical signs. Here, we focus on the potential usefulness of implanting the CM/Pf complex when required in the management of contra-lateral tremor (resistant to standard deep brain stimulation-DBS - in STN - , n=2) and disabling involuntary movements, partially responsive to GPi-DBS (n=6). When considering global UPDRS scores, CM/Pf-DBS ameliorate extra-pyramidal symptoms but not as strongly as STN (or GPi) does. Yet, CM/Pf acts very powerfully on tremor and contributes to the long-term management of l-Dopa-induced involuntary movements. The lack of cognitive deficits and psychic impairment associated with the improvement of their quality of life, in our small cohort of CM/Pf implanted patients, reinforces the notion of CM/Pf as a safe and attractive area for surgical treatment of advanced PD, possibly affecting not only motor but also associative functions.     

Genetic analysis and evaluation of resistance to thyrotropin and growth hormone-releasing hormone in pseudohypoparathyroidism type Ib

CONTEXT: Pseudohypoparathyroidism (PHP) types Ia and Ib, are caused by mutations in GNAS exons 1-13 and GNAS methylation defects, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO and hormone resistance is limited to PTH and, as reported in one paper, TSH. No study addressed the question of GH deficiency in PHP-Ib patients. OBJECTIVES: The objective of the study was to screen patients with clinically diagnosed PHP-Ib for genetic defects and investigate the presence of resistance to TSH and GHRH. PATIENTS/METHODS: We investigated GNAS differential methylation and STX16 microdeletions in genomic DNA from 10 patients with clinical diagnosis of sporadic PHP-Ib, i.e. PTH resistance without AHO. Resistance to GHRH was assessed by GH response to GHRH plus arginine. Thyroid function and ultrasonography were also evaluated. RESULTS: Molecular analysis showed GNAS cluster imprinting defects in all PHP-Ib patients and the first de novo STX16 deletion in one apparently sporadic patient. Subclinical or clinical hypothyroidism due to resistance to TSH was present in nine of 10 patients, whereas a preserved GH response to a GHRH plus arginine test was present in all patients, with one exception. CONCLUSIONS: We report the first molecular analysis of Italian patients with PHP-Ib. Clinical investigation shows that, like PHP-Ia patients, PHP-Ib patients are resistant to TSH, whereas they maintain a normal responsiveness to GHRH, at variance with PHP-Ia patients. These data provide new information on this rare disease and emphasize the clinical heterogeneity of genetic defects within GNAS.     

Surgical options in the treatment of GIST of the upper portion of the stomach. Report of two cases

Gastrointestinal stromal tumors are rare neoplasms arising from mesenchymal precursor cells of the gastrointestinal tract that may differentiate towards the interstitial cells of Cajal, pacemaker cells regulating autonomous motility of G.I. tract. Grading of GIST has been proven to be as difficult as their classification. Two thirds of GISTs are located in the stomach, 20-50% in the small bowel (one third in the duodenum), and 5-15% in colon and rectum; GISTs, however, may rarely be found also in the oesophagus, omentum, mesentery or the retroperitoneum. The distribuition of these tumors in the stomach is: pars media, 40%; antrum, 25%; pylorus, 20%; in less than 15%, GISTs location is next to the EGJ, in the cardia and in the iundus. The upper gastric third location of GISTs is not common, so their surgical management has been not yet well investigated. Total gastrectomy is considered the therapy of choice for the GIST located next to the EGJ, but wedge resection could be considered a surgical option in selected cases. The Authors describe 2 cases of GIST located just under the upper portion of the stomach and discuss about the different surgical options for GISTs of this region.     

Myasthenia gravis during pregnancy

Myasthenia gravis (MG) affects women in the second and third decades of life, overlapping with the childbearing years. During pregnancy, the course of this disease is unpredictable; worsening of symptoms occurs more likely during the first half of pregnancy and postpartum. MG can be well managed during pregnancy with relatively safe and effective therapies. Cesarean section is recommended only for obstetric reasons; epidural anesthesia is advised to reduce physical and emotional stress. Anticholinesterase drugs are the mainstay of treatment, when MG symptoms are not satisfactorily controlled, corticosteroids, azathioprine and in some cases cyclosporin A may be used. Life-threatening conditions (e.g., respiratory insufficiency) may occur during pregnancy; therefore, intensive check-ups by a gynecologist and a neurologist are necessary.     

Reversine, a novel Aurora kinases inhibitor, inhibits colony formation of human acute myeloid leukemia cells

The demonstration that the small synthetic molecule reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine] promotes the dedifferentiation of committed cells into multipotent progenitor-type cells has raised hopes on the exploitation of this small chemical tool for the generation of stem cells. Here, we show that reversine causes a failure in cytokinesis and induces polyploidization. These effects of reversine are due to the inhibition of Aurora A and B, two related kinases that are implicated in several aspects of mitosis and that are frequently amplified and overexpressed in human tumors. Reversine inhibits the phosphorylation of histone H3, a direct downstream target of Aurora kinases. Similarly to the Aurora kinase inhibitor VX-680, which has recently entered phase II clinical trials for cancer treatment, reversine inhibited colony formation of leukemic cells from patients with acute myeloid leukemia but was significantly less toxic than VX-680 on cells from healthy donors. The crystal structure of the reversine-Aurora B kinase complex shows that reversine is a novel class of ATP-competitive Aurora kinase inhibitors. Thus, although our studies raise serious doubts on the application of reversine in regenerative medicine, they support the paradigm that reversine might be a useful agent in cancer chemotherapy.