Short-term synaptic plasticity, simulation of nerve terminal dynamics, and the effects of protein kinase C activation in rat hippocampus

Phorbol esters are hypothesised to produce a protein kinase C (PKC)-dependent increase in the probability of transmitter release via two mechanisms: facilitation of vesicle fusion or increases in synaptic vesicle number and replenishment. We used a combination of electrophysiology and computer simulation to distinguish these possibilities. We constructed a stochastic model of the presynaptic contacts between a pair of hippocampal pyramidal cells that used biologically realistic processes and was constrained by electrophysiological data. The model reproduced faithfully several forms of short-term synaptic plasticity, including short-term synaptic depression (STD), and allowed us to manipulate several experimentally inaccessible processes. Simulation of an increase in the size of the readily releasable vesicle pool and the time of vesicle replenishment decreased STD, whereas simulation of a facilitation of vesicle fusion downstream of Ca²⁺ influx enhanced STD. Because activation of protein kinase C with phorbol ester enhanced STD of EPSCs in rat hippocampal slice cultures, we conclude that an increase in the sensitivity of the release process for Ca²⁺ underlies the potentiation of neurotransmitter release by PKC.     

Two novel mutations at exon 8 of the Sequestosome 1 (SQSTM1) gene in an Italian series of patients affected by Paget's disease of bone (PDB).

PDB is genetically heterogeneous. Mutations of the sequestosome1 gene have been reported in sporadic and familial forms of Paget's in patients of French Canadian and British descent. Mutational analyses in different ethnic groups are needed to accurately investigate hereditary diseases. We describe two novel mutations of sequestosome1 in 62 Italian sporadic patients, confirming the role of the encoded protein in this disorder. INTRODUCTION: Paget's disease of bone (PDB) is a relatively common disease of bone metabolism reported to affect up to 3% of whites over 55 years of age. The disorder is genetically heterogeneous, and at present, there is scientific evidence that at least eight different human chromosomal loci are correlated with its pathogenesis. Mutations of the sequestosome1 (SQSTM1) gene were identified as responsible for most of the sporadic and familial forms of Paget in patients of French Canadian and British descent. Such mutations were located at exon 7 and 8 levels, encoding for the ubiquitin protein-binding domain (UBA) and representing a mutational hot spot area. MATERIALS AND METHODS: To verify the involvement of this gene in Italian subjects affected by PDB, we performed mutational analysis in 62 sporadic PDB cases. RESULTS: We described three different mutations at exon 8 level: P392L, already described in the French Canadian population and families predominantly of British descendent, and two novel mutations consisting of the amino acid substitutions M404V and G425R. No significant differences in the clinical history of PDB have been observed in patients with SQSTM1 mutations in respect to those without. CONCLUSIONS: Even though our findings suggest a minor involvement of the SQSTM1 gene in the pathogenesis of sporadic Italian Paget's cases, the identification of different significant mutations within the SQSTM1 gene in unrelated, but clinically similar individuals, offers extremely convincing evidence for a causal relationship between this gene and PDB. Longitudinal studies are needed to assess the penetrance of genotype/phenotype correlations. Our findings confirm the evidence of a clustered mutation area at this level in this disorder.     

Neridronate prevents bone loss in patients receiving androgen deprivation therapy for prostate cancer.

Today, androgen deprivation therapy is a cornerstone of treatment for advanced prostate cancer, although it presents important complications such as osteoporosis. Neridronate, a relatively new bisphosphonate, is able to prevent bone loss in patients with prostate cancer during androgen ablation. INTRODUCTION: Androgen-deprivation therapy (ADT) is a cornerstone of treatment for advanced prostate cancer. This therapy has iatrogenic complications, such as osteoporosis. The aim of our study was to evaluate the efficacy of neridronate, a relatively new bisphosphonate, to prevent bone loss during androgen ablation. MATERIALS AND METHODS: Forty-eight osteoporotic patients with prostate cancer, treated with 3-month depot triptorelina, were enrolled and randomly assigned to two different treatment groups: group A (n = 24) was treated with a daily calcium and cholecalciferol supplement (500 mg of elemental calcium and 400 IU cholecalciferol), and group B (n = 24) received in addition to the same daily calcium and cholecalciferol supplement, 25 mg of neridronate given intramuscularly every month. All patients also received bicalutamide for 4 weeks. Lumbar and femoral BMD was evaluated by DXA at baseline and after 1 year of therapy; moreover, deoxypyridinoline (DPD) and bone alkaline phosphatase (BALP) were determined at the beginning, midway through, and at the end of the study. RESULTS: After 6 and 12 months, whereas patients treated only with calcium and cholecalciferol (group A) showed a marked bone loss, with increased levels of DPD and BALP compared with baseline values, patients treated also with neridronate (group B) had substantially unchanged levels of these markers. After 1 year of treatment, lumbar and total hip BMD decreased significantly in patients treated only with calcium and cholecalciferol (group A), whereas it did not change significantly at any skeletal site in patients treated also with neridronate (group B). No relevant side effects were recorded during our study. CONCLUSIONS: Neridronate is an effective treatment in preventing bone loss in the hip and lumbar spine in men receiving ADT for prostate cancer.     

Immunohistological study of grumose degeneration of the dentate nucleus in progressive supranuclear palsy

The grumose degeneration observed in the dentate nuclei of 7 cases of progressive supranuclear palsy (PSP) was studied with a panel of antibodies which included 2 neurofilaments, Tau and ubiquitin. Dentate nucleus neurons were negative with all antibodies except ubiquitin which showed a slightly positive homogeneous pattern of staining. The amorphous material surrounding swollen or normal neurons was strongly positive for neurofilament and subunits and numerous torpedoes were observed in the granular layer of the cerebellar cortex. Our results confirm that grumose degeneration consists in degeneration of terminal axons of Purkinje cells in the dentate nucleus. The positivity of dentate nucleus neurons for ubiquitin may support the concept of synaptic dysfunction between Purkinje cells and dentate nucleus neurons.     

Clobetasol vs. testosterone in the treatment of lichen sclerosus of the vulvar region]

The paper describes a study carried out in 40 patients affected by lichen sclerosus (LS) of the vulva. The mean age of patients was 60.9 years (range 27-83) and 31 were in menopause. Patients were divided randomly into two groups of 20. The symptoms (itching, burning, pain, dyspareunia), clinical aspects (atrophy, hyperkeratosis, sclerosis) and histological alterations (atrophy of the epithelium, edema, inflammatory infiltrate, fibrosis) were quantified in each patient by a score. The mean scores relating to the three parameters examined were then calculated for each group. One group was treated with testosterone propionate 2% and the other with a strong synthetic corticosteroid, clobetasol dipropionate 0.05%. After 24 weeks of treatment patients were again evaluated in relation to clinical (symptoms and clinical aspects) and histological parameters, following the procedure used before the start of treatment. The mean scores obtained were then compared with those before the start of treatment. Statistical analyses were performed using Student's t-test. Testosterone was found to be effective in relation to symptoms but no significant change was observed in relation to clinical aspects and histological alterations. It also caused major secondary effects which led to the suspension of treatment in one patient. Clobetasol was shown to be highly effective both in relation to symptoms and in terms of clinical aspects and histological alterations, and did not cause any noteworthy collateral effects, especially contact dermatitis. In the context of the objective parameters examined in this study, sclerosis and hyperkeratosis were easily modified by corticosteroid treatment in comparison to atrophy, especially in those patients with a longer duration of disease.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of climacteric transition and hormone replacement therapy on body weight and body fat distribution.

In the present study we evaluated the effects of climacteric modifications on body weight and fat distribution. From women attending a menopause clinic we selected 2175 untreated, normal healthy women who were divided into three groups: premenopausal (n = 540), perimenopausal (n = 750) and postmenopausal (n = 885), and compared them with 354 postmenopausal women receiving different forms of hormone replacement therapy (HRT). The total body fat tissue mass and distribution were analyzed using dual-energy X-ray absorptiometry. Body weight and body mass index (BMI) were significantly higher in perimenopausal and postmenopausal than in premenopausal women. Mean total body fat and fat as a percentage of soft tissue were significantly (p < 0.05) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. Fat tissue and regional fat tissue as a percentage of total fat tissue were higher in the trunk (p < 0.0001) and arms (p < 0.0001) in perimenopausal and postmenopausal than in premenopausal women. In postmenopausal women, leg fat tissue was significantly (p < 0.05) lower than in premenopausal and perimenopausal groups. Total body and leg lean tissue were significantly lower (p < 0.05) in postmenopausal than in premenopausal and perimenopausal women. In age-matched women with similar BMI, total body fat as a percentage of soft tissue was significantly (p < 0.001) higher in the perimenopausal and postmenopausal groups than in the premenopausal group. As for body fat distribution, fat as a percentage of total fat tissue was significantly higher in the trunk (p < 0.0001) region in perimenopausal and postmenopausal women compared with the premenopausal group. In the legs, fat as a percentage of total fat tissue was significantly higher (p < 0.05) in the premenopausal than in the postmenopausal group. In the arms a slight but not significant (p < 0.18) difference was shown in fat distribution between the three untreated groups. In age-matched HRT-treated postmenopausal women, the fat tissue was similar to that in the premenopausal group. The present results confirm that endocrine changes during the menopausal transition, rather than the aging process, are related to changes in body weight and fat distribution. Perimenopausal and postmenopausal women show a shift to a central, android fat distribution that can be counteracted by HRT.     

Determining the Alveolar Component of Nitric Oxide in Exhaled Air: Procedures and Reference Values for Healthy Persons

Nitric oxide (NO) production has been described using a 2-compartment model for the synthesis and movement of NO in both the alveoli and the airways. The alveolar concentration of NO (Ca_NO), an indirect marker of the inflammatory state of the distal portions of the lung, can be deduced through exhalation at multiple flow rates. Our objective was to determine reference values for Ca_NO. The fraction of exhaled NO (Fe_NO) was measured in 33 healthy individuals at a rate of 50 mL/s; the subjects then exhaled at 10, 30, 100, and 200 mL/s to calculate Ca_NO. A chemiluminescence analyzer (NIOX Aerocrine) was used to perform the measurements. The mean (SD) Fe_NO was 15 (6) ppb. The mean Ca_NO was 3.04 (1.30) ppb. These values of Ca_NO measured in healthy individuals will allow us to analyze alveolar inflammatory behavior in respiratory and systemic processes.