Presymptomatic geographical distribution of ALS patients suggests the involvement of environmental factors in the disease pathogenesis.

BACKGROUND: Given that the pathogenetic process of ALS begins many years prior to its clinical onset, examining patients' residential histories may offer insights on the disease risk factors. Here, we analyzed the spatial distribution of a large ALS cohort in the 50 years preceding the disease onset. METHODS: Data from the PARALS register were used. A spatial cluster analysis was performed at the time of disease onset and at 1-year intervals up to 50 years prior to that. RESULTS: A total of 1124 patients were included. The analysis revealed a higher-incidence cluster in a large area (435,000 inhabitants) west of Turin. From 9 to 2 years before their onset, 105 cases were expected and 150 were observed, resulting in a relative risk of 1.49 (P = 0.04). We also found a surprising high number of patients pairs (51) and trios (3) who lived in the same dwelling while not being related. Noticeably, these occurrences were not observed in large dwellings as we would have expected. The probability of this occurring in smaller buildings only by chance was very low (P = 0.01 and P = 0.04 for pairs and trios, respectively). CONCLUSIONS: We identified a higher-incidence ALS cluster in the years preceding the disease onset. The cluster area being densely populated, many exposures could have contributed to the high incidence ALS cluster, while we could not find a shared exposure among the dwellings where multiple patients had lived. However, these findings support that exogenous factors are likely involved in the ALS pathogenesis.

Nerve conduits for treating peripheral nerve injuries: A systematic literature review.

Peripheral nerve injuries are a major public health problem. Nerve conduits have been developed in the recent years, although it is still not clear if they should replace nerve grafting and neurorrhaphy. This systematic review aims to gather evidence regarding the use of nerve conduits for peripheral nerve repair. The following electronic databases were searched: MEDLINE, Cochrane Library (CENTRAL) and Embase. Study selection and data extraction followed the PRISMA guidelines. The systematic review of the literature retrieved 6767 articles. Only 27 studies were retained accounting for 1022 patients: 10 randomized controlled trials, 15 case series and 2 cohort studies. Ten different types of tubes were described and a variety of evaluation methods were used to assess outcomes in terms of efficacy (motor and sensory recovery) and complications. The Semmes-Weinstein monofilament test and the static and moving 2-point discrimination test were the most commonly applied tests to evaluate nerve recovery. In general, outcomes showed no significant difference between groups. Synthetic conduits had more complications. Despite major methodological limitations in the studies, we can conclude that use of nerve conduits is preferable over suture repair and nerve grafting, as the functional recovery rates are above 80%. The choice of conduit is based on the surgeon's expertise, but use of synthetic conduits is discouraged due to their higher complication rates.

Influence of palatability on motivation to operate for caloric and non-caloric food in non food-deprived and food-deprived rats.

Palatability is the hedonic food component that is considered to override the homeostatic mechanisms that control food intake, and we compared how much effort non food-deprived and food-deprived rats were willing to spend in order to earn a palatable caloric (sucrose) or non-caloric (saccharin) snack. We first studied the dopaminergic response, in terms of dopamine levels and dopamine and cAMP-regulated phosphoprotein Mr 32,000 (DARPP-32) phosphorylation pattern, to two consecutive palatable caloric or non-caloric snacks in the nucleus accumbens shell (NAcS) of non food-deprived and fasted rats. We report that non food-deprived rats developed rapid habituation in the NAcS dopaminergic response to the second consumption of both caloric and non-caloric palatable food, while food-deprived rats developed rapid habituation only to saccharin. Next, we show that in self-administration experiments, non food-deprived rats spent a similar effort when operating for sucrose or saccharin. However, the same rats showed an increased response specifically for sucrose after 18-h fasting. After pre-feeding devaluation, rats reduced their response to sucrose but not for saccharin. These results strengthen the hypothesis that food intake is mainly controlled by palatability in non food-deprived rats and by caloric content in food-deprived rats. Moreover, they show that rapid habituation development was associated with a similar, basal working activity aimed at ingesting both caloric and non-caloric food, as observed in non food-deprived rats consuming sucrose or saccharin and in fasted rats consuming saccharin. Conversely, lack of habituation, as present in fasted rats consuming a caloric food, was associated with extra energy expenditure.

Subclinical pulmonary edema in endurance athletes.

Strenuous exercise may cause progressive and proportional haemodynamic overload damage to the alveolar membrane, even in athletes. Despite the high incidence of arterial desaturation reported in endurance athletes has been attributed, into other factors, also to the damage of the alveolar-capillary membrane this evidence is equivocal. Some studies demonstrated flood of the interstitial space and consequent increase in pulmonary water content, but most of them were able to show this through indirect signs of interstitial oedema. The present review illustrates the literature's data in favour or against pulmonary interstitial edema due to intense exercise in athletes.

Antinociceptive activity of Delta9-tetrahydrocannabinol non-ionic microemulsions.

Delta(9)-Tetrahydrocannabinol (Delta(9)-THC), the major psychoactive constituent of Cannabis sativa L., has been widely studied for its potential pharmaceutical application in the treatment of various diseases and disturbs. This sparingly soluble terpeno-phenolic compound is not easy to handle and to be formulated in pharmaceutical preparations. The aim of this work was to develop a stable aqueous Delta(9)-THC formulation acceptable for different ways of administration, and to evaluate the therapeutic properties of the new Delta(9)-THC based preparation for pain treatment. Due to the thermodynamic stability and advantages of microemulsion based systems, the study was focused on the identification of aqueous microemulsion based systems containing Delta(9)-THC. Oil in water Delta(9)-THC microemulsions were individuated through phase diagrams construction, using the non-ionic surfactant Solutol HS15, being this surfactant acceptable for parenteral administration in human. A selected microemulsion samples containing 0.2 wt% of Delta(9)-THC, stable up to 52 degrees C, was successfully assayed on animal models of pain. Significant antinociceptive activity has been detected by both intraperitoneal and intragastric administration of the new Delta(9)-THC pharmaceutical preparation. The effect has been highlighted in shorter time if compared to a preparation of the same active principle based on previously reported conventional preparation.

A comparison of continuous subcutaneous paliperidone infusion and repeated subcutaneous injection of risperidone free-base in rats.

It is proposed that to achieve a therapeutic effect in schizophrenia patients, dopamine D(2)-receptor occupancy by antipsychotics within the striatum must exceed 60-65%. However, at high levels of D(2)-receptor occupancy, the risk of extrapyramidal symptoms (EPS) is increased. Following oral dosing of antipsychotics, peaks and troughs in plasma drug concentrations may be mirrored by fluctuations in D(2)-receptor occupancy. Paliperidone, a novel antipsychotic available as extended-release tablets (paliperidone ER), is the major active metabolite of risperidone and exhibits a plasma pharmacokinetic profile with reduced peak-trough fluctuations and consistent D(2)-receptor occupancy compared with conventional oral antipsychotic formulations. Using formulations that resemble those in clinical practice, this study provides a preclinical evaluation of the pharmacological properties of paliperidone ER and risperidone immediate-release formulation in terms of consistent antipsychotic efficacy over time and extrapyramidal symptom liability. Significant fluctuations in inhibition of d-amphetamine-induced hyperlocomotion were observed for repeated subcutaneous (SC) risperidone injections, whereas stable inhibitory efficacy was demonstrated during continuous SC paliperidone infusion. Similarly, significant fluctuations in latency on-bar were observed with repeated SC risperidone injections, whereas significantly lower latency on-bar was demonstrated following continuous SC paliperidone infusion. These results in an animal model suggest that although risperidone and paliperidone demonstrate similar pharmacologic effects, continuous administration of paliperidone achieves more stable antipsychotic efficacy with reduced motor impairment, akin to the effects observed with paliperidone ER in clinical studies.

Cefditoren versus community-acquired respiratory pathogens: time-kill studies.

The time-kill method was used to determine the bactericidal activity of cefditoren compared with oral cephalosporins, amoxicillin, amoxicillin/clavulanate and levofloxacin against a randomly selected group of strains isolated from community-acquired respiratory tract infections (CARTIs). Cefditoren was the only agent showing significant bactericidal activity (>or=3 log(10 )reduction of viable cells) within 4 h against all Streptococcus pneumoniae strains, both penicillin-susceptible (PEN S) or -resistant (PEN R), as well as against Streptococcus pyogenes, and Moraxella catarrhalis. Against beta-lactamase positive strains of Haemophilus influenzae, cefditoren was comparable to the quinolone and more active than other cephalosporins at 24 h. Cefditoren showed the best killing kinetic profiles and this observation may be important when choosing an oral third-generation cephalosporin as initial or sequential therapy.

Association of rs2200733 at 4q25 with atrial flutter/fibrillation diseases in an Italian population.

BACKGROUND: Atrial fibrillation (AF) and atrial flutter (AFL) are common cardiac conduction disorders affecting many people. Recent studies on sporadic cases of AF/AFL showed a significant association of the single nucleotide polymorphism rs2200733T with the disease, suggesting a genetic factor in the development of the disease. OBJECTIVES: To determine the association of rs2200733 with AF/AFL derived from an Italian population sample. SUBJECTS: 78 patients with AF/AFL and 348 controls took part in the study. DESIGN: Genetic case-control study. RESULTS: The results indicate that there is a positive, significant association between the rs2200733 T allele and patients with AF/AFL of Italian origin (allelic p<0.001 with OR = 2.17). CONCLUSION: These results derived from a sample of the Italian population agree with previously reported findings from an Icelandic study, which also found that the minor allele rs2200733 was associated with AF/AFL disease.

Cyclosporin is safe and effective in severe atopic dermatitis of childhood. Report of three cases.

Severe atopic dermatitis causes major impairment in the life of both children and their parents. Generally, symptoms can be controlled with emollients, topical steroids, antibiotics, antihistaminic but some patients remain intensely ill and may require treatment with systemic steroids and so on. Cyclosporin has been found to be effective in a variety of inflammatory skin disorders since it reduces the number of activated T-cells expressing interleukin 2 (IL-2) receptors. In order to monitor the safety and clinical efficacy of therapy and days of remission we performed Cyclosporin on 3 children with severe atopic dermatitis, refractory to all traditional therapies. Cyclosporin suspension at dosage of 5 mg/kg daily, in 2 doses for 8 weeks has been used. Cyclosporin blood levels, liver and kidney function, blood pressure and some immunological parameters (eosinophils, IgE, IL-2 receptors) were monitored. All patients showed a marked clinical improvement with reduction of pruritus, erythema, papules, vesciculation, excoriation, scaly crusts and lichenification. No clinical or haematological side effects were demonstrated. The soluble IL-2 receptor concentration decreased even after 8 weeks of treatment in all 3 patients, regardless of IgE levels (case 1: low IgE level; case 2: very high IgE level) as in several others T-cell mediated non IgE-related skin disease. The authors suggest that courses of 8 weeks seem effective and safe as well as longer time in producing early remission with the advantage of a low cumulative exposure to the drug. The main question is whether a prolonged remission will permain as well as continuous therapy. This study underscores the potential value of systemic administration of this powerful immuno-suppressive agent in the treatment of many cases of severe atopic dermatitis working regardless of the IgE values. Although 3 cases report does not justify any definitive conclusion however it does a contribute to understand the heterogeneity of atopic dermatitis and it adds information to its current treatment guidelines.

The role of limbic and cortical regions in schizophrenia: focus on dopamine.

Dopamine is implicated in the pathogenesis of both the positive and the negative symptoms of schizophrenia. Clinical efficacy of antipsychotic drugs, without the production of side-effects, may be achieved by a dose-response separation of pharmacological function, regional (i.e., anatomical) selectivity of action, or by the selective targeting of neuroreceptors. The atypical antipsychotics have many different ways of acting on receptors in the brain, but they have in common a decreased likelihood of producing extrapyramidal side-effects. Patients respond well to them by showing improvements of both positive and negative symptoms. The preclinical profile of amisulpride shows specificity for D2/D3 dopamine receptors and selective activity in the limbic system. There is evidence that amisulpride is effective in treating both the negative and positive symptoms of schizophrenia, and that it has a low propensity to induce motor side-effects. Therefore, both positive and negative symptoms can be treated, without inducing these side-effects, by selectively targeting dopamine receptors.

Double-blind multicenter study on the efficacy and tolerability of cetirizine compared with oxatomide in chronic idiopathic urticaria in preschool children.

BACKGROUND: There are no studies on the use of cetirizine in children under the age of 6. OBJECTIVE: We compared the efficacy and tolerability of cetirizine in patients with idiopathic chronic urticaria to the more widely used antihistamine, oxatomide. METHODS: This double-blind study was performed on 62 patients (38 male and 24 female) with idiopathic chronic urticaria, recruited from four different medical centers of the national territory (Ancona, Cagliari, Catania, and Messina). The children's ages ranged from 2 to 6 years (mean 3.85). The patients were randomly assigned to two treatment groups: one group treated 31 children with cetirizine at a dosage of 5 mg q.d., and a second group treated 31 children for the same amount of time with oxatomide, at a dosage of 25 mg q.d. Sixty-two children began the treatment, but five did not finish the study (three in the cetirizine and two in the oxatomide group). Thus, the clinical study and the statistical evaluation were conducted on 57 children (28 cetirizine and 29 oxatomide). The Student's t test was used to compare severity of the illness and changes in the hematochemical tests. RESULTS: Overall, the effectiveness of the two medications in treating erythema, papules, edema, and itching showed comparable therapeutic activity (P < 0.001). Neither medication produced significant side effects. CONCLUSIONS: The results of the present study suggest that cetirizine may represent an effective and safe pharmacologic therapy for chronic urticaria in preschool children. There was no evidence for changes in hematochemical and urinary values, demonstrating the safety and the tolerability of the two antihistamines, even when given to young children.

The 5-HT2 antagonist ritanserin blocks dopamine re-uptake in the rat frontal cortex.

The effect of ritanserin on dopamine (DA) re-uptake and efflux was studied in rat frontal cortex synaptosomes. When compared to other 5HT2 receptor antagonists such as ketanserin and risperidone or DA D2 receptor antagonists such as haloperidol and raclopride, the effect of ritanserin proved to be more potent. Ritanserin blocked the DA transporter with a Ki of 0.18 +/- 0.06 microM, similar to cocaine (0.11 +/- 0.005 microM), while ketanserin had a Ki of 0.93 +/- 0.045; haloperidol of 2.07 +/- 0.12; risperidone of 18.01 +/- 0.62 and raclopride of 24.01 +/- 1.55. In addition, 15 min from its local application to the synaptosomes, ritanserin potently released [3]H-DA leaving only 29.6 +/- 1.6% of DA content, while ketanserin effect was equal to 46.5 +/- 0.9%; haloperidol to 70.4 +/- 2.2% and risperidone to 73.9 +/- 1.5%, all tested at the dose of 10 microM. Cocaine had no effect on DA efflux. These results suggest that ritanserin has a intrinsic dopaminergic effect which may help to explain its reported improvement on mood, cognition and negative symptoms of schizophrenia.

Loss of presynaptic and postsynaptic structures is accompanied by compensatory increase in action potential-dependent synaptic input to layer V neocortical pyramidal neurons in aged rats.

Reduction in both presynaptic and postsynaptic structures in the aging neocortex may significantly affect functional synaptic properties in this area. To directly address this issue, we combined whole-cell patch-clamp recording of spontaneously occurring postsynaptic currents (PSCs) with morphological analysis of layer V pyramidal neurons in the parietal cortex of young adult (1- to 2-month-old) and aged (28- to 37-month-old) BN x F344 F(1) hybrid rats. Analysis of spontaneous PSCs was used to contrast functional properties of basal synaptic input with structural alterations in the dendritic tree of pyramidal neurons and density of terminals in contact with these cells. We observed significant changes in a number of morphological parameters of pyramidal neurons in aged rats. These include smaller cell body size and fewer basal dendritic branches (but not of oblique dendrites and dendritic tufts) and spines. Ultrastructural analysis also revealed a lower density of presynaptic terminals per unit length of postsynaptic membrane of labeled pyramidal neurons in the aged brain. This reduction in both presynaptic and postsynaptic elements was paralleled by a significant decrease in frequency of tetrodotoxin-insensitive miniature (action potential-independent) PSCs (mPSCs). The frequency of excitatory and inhibitory mPSCs was reduced to the same extent. In contrast, no significant change was observed in the frequency of spontaneous PSCs recorded in absence of tetrodotoxin (sPSCs), indicating an increase in action potential-dependent (frequency(sPSCs) - frequency(mPSCs)) input to pyramidal neurons in the aged group. This functional compensation may explain the lack of drastic loss of spontaneous neuronal activity in normal aging.

[Efficacy and tolerability of paroxetine in the treatment of the depressive phase of bipolar disorders]. / La paroxetina nel disturbo bipolare in fase depressiva.

Eighty patients aged between 20-65 years and suffering from bipolar disease according to DSM IV criteria, were treated with paroxetine for os at the single dosage of 20-40 mg/die. At regular intervals psychometric reagents were administered for the evaluation and the variations in the bipolar disease. Tolerability was excellent and side-effects mild, with a tendency to regress after the second week of therapy. The clinical assessment and the psychometric findings both suggest that paroxetina has a useful action on the bipolar disease.

Different affinity of cortical GHB binding sites in sardinian alcohol-preferring (sP) and -non preferring (sNP) rats.

Specific gamma-hydroxybutyric acid (GHB) binding sites in cortical membranes of selectively bred alcohol-preferring sP and alcohol-non preferring sNP rats were compared using [2,3(-3)H]GHB ligand. The sP rat line showed an increased affinity (approximately 40% lower Kd) of both the high- and low-affinity sites in comparison with the sNP line. No significant difference in GHB receptor density (Bmax) was detected between the two rat lines. The results raise the possibility that differences in GHB binding sites may play a role in the genetic predisposition to ethanol preference in our rat line.

Expression of the 170-kDa and 180-kDa isoforms of DNA topoisomerase II in resting and proliferating human lymphocytes.

The expression of the 170-kDa (alpha) and the 180-kDa (beta) isoforms of DNA topoisomerase II (topo II) was investigated with two specific monoclonal antibodies (MoAbs) in human peripheral blood lymphocytes (PBL), before and after phytohaemoagglutinin (PHA) stimulation. Binding of each MoAb was detected by indirect immunofluorescence labelling and quantified with flow cytometry. In resting PBL, the intensity of immunostaining was very low for both isozymes; however, topo IIbeta-associated immunofluorescence was about 2.5 times significantly higher (P<0.001) than that associated with the alpha isoform. Between 48 and 72 h of PHA stimulation, when the highest percentage of cells in S and G2+M phases was found, the levels of topo IIalpha and beta increased up to about 30 and 10 times the value measured in resting PBL, respectively. Thus, the two isoforms reached comparable immunofluorescence values. At longer stimulation periods (96-120 h), topo IIalpha immunofluorescence was not significantly changed, while that relative to topo IIbeta declined to about 50% of the peak value (P<0.02). At this time however, topo IIalpha-associated immunofluorescence was not significantly different from that related to the beta isozyme. These results suggest that in resting PBL topo IIalpha is required at levels lower than topo IIbeta, while in proliferating lymphocytes both isoforms are expressed to significantly higher levels.

Attraction of Chironomus salinarius (Diptera: Chironomidae) to artificial light on an island in the saltwater lagoon of Venice, Italy.

The attraction of adult Chironomus salinarius to incandescent 3-W lamps of 7 different colors used in CDC traps was studied on a small island in the lagoon of Venice, Italy. An ANOVA indicated that the lamp type was a highly significant (P < 0.01) factor associated with differences in light trap catch (28% of total variation), as well as catch per lux (18% of total variation). The white lamp attracted higher numbers of adults than the other 6 color lamps. Yellow was the second most preferred, and red was the least attractive. There was a strong linear relationship (r = 0.93) between the catch and light intensity, which suggested that intensity was the primary factor influencing catch. However, catch per unit brightness (lux) tended to be inversely proportional to the peak wavelength associated with the lamp color (e.g., the violet lamp had the highest catch/lux, and the red lamp had the lowest). The corresponding regression model, Catch = 49 + [(48,013/lambda) - 63] . L, in which the slope associated with light intensity in lux (L) is inversely proportional to the peak wavelength in nm (lambda) explained 97% of the variation among lamp catch means. Manipulating light intensity and color could be useful to divert adult C. salinarius populations from midge-affected areas for control purposes.

The effect of mesoglycan in patients with cerebrovascular disease: a psychometric evaluation.

Mesoglycan is a preparation of natural glycosaminoglycans, containing mainly heparan sulphate and dermatan sulphate. A clinical trial was conducted to evaluate the efficacy and the tolerability of once-daily mesoglycan in 30 patients with clinical evidence of cerebrovascular insufficiency. Clinical effectiveness was assessed using psychometric and neurological scales: Sandoz Clinical Assessment for Geriatric Patients (SCAG); Parkside Behaviour Rating Scale Modified; Geriatric Depression Scale; and Anxiety Evaluation. Mesoglycan was given as a single oral once-daily dose of 100 mg for a period of 6 months. This treatment was shown to have positive effects on the cognitive and behavioural parameters evaluated. The effects on SCAG were already evident after 3 months' treatment and a significant improvement was observed after 6 months in those patients with a moderate to severe disease. During the treatment period only one patient suffered an adverse reaction attributed to the drug investigated.

Efficacy of two temephos formulations against Chironomus salinarius (Diptera: Chironomidae) in the saltwater lagoon of Venice, Italy.

Two formulations of the organophosphorus insecticide, temephos (Abathion Granulare, 1% AI granular and Tambro Compresse, 2% AI tablet) were evaluated against Chironomus salinarius midge larvae in 50 x 50 m experimental plots in the saltwater lagoon of Venice, Italy. Each formulation was applied at 0.2 and 0.4 kg AI/ha. Abathion Granulare produced 56 to 73% larval reduction at 0.2 kg AI/ha and 69 to 83% reduction at 0.4 kg AI/ha during 3 wk after treatment. Abathion Granulare lost effectiveness at 4 wk after application at both rates. Posttreatment larval reductions resulting from Tambro Compresse applications ranged from 77 to 86% for 3 wk, and 82 to 92% for 4 wk at rates of 0.2 and 0.4 kg AI/ha, respectively. The tablet formulation (Tambro Compresse) gave better control of C. salinarius (magnitude and duration) than the granular formulation (Abathion Granulare) in these evaluations.