Advances in modelling alpha-synuclein-induced Parkinson's diseases in rodents: Virus-based models versus inoculation of exogenous preformed toxic species.

Aggregates of alpha-synuclein (αSyn) have been described in Parkinson's disease (PD) patients, and recent evidence has suggested that the most toxic αSyn species in PD are small soluble aggregates including oligomers, prefibrils, protofibrils. The physiological function of αSyn is still highly debated, with a possible role in synaptic vesicle trafficking and release at the presynaptic compartment, and in the regulation of gene expression in the nucleus. Emerging evidence indicate that most of αSyn functions are related with the crucial ability to bind biological membranes, which is associated with structural conversion from a disordered monomer to an α-helical enriched structure. Conformational properties of αSyn can be modulated by a number of factors including post-translational modifications, gene duplication and triplication-driven overexpression, single point mutations, environmental changes, which affect membrane binding and the protein propensity to aggregate in toxic species. The recognized toxic role of αSyn in PD has laid the rational for purposing of αSyn-based, neuropathologically relevant preclinical models of PD. Different approaches have led to the establishment of transgenic models, viral vector-based models, and more recently models based on the intracerebral inoculation of exogenous αSyn preformed fibrils/oligomers. Here, we overview and compare viral vector-based models of αSyn overexpression and models obtained by direct intracerebral infusion of in vitro preformed αSyn species. The advantages and pitfalls associated with these different approaches are discussed.

Efficacy and safety of NEPA, an oral combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy: a randomized dose-ranging pivotal study.

BACKGROUND: NEPA is a novel oral fixed-dose combination of netupitant (NETU), a new highly selective neurokinin-1 (NK1) receptor antagonist (RA) and palonosetron (PALO), a pharmacologically and clinically distinct 5-hydroxytryptamine type 3 (5-HT3) RA. This study was designed to determine the appropriate clinical dose of NETU to combine with PALO for evaluation in the phase 3 NEPA program. PATIENTS AND METHODS: This randomized, double-blind, parallel group study in 694 chemotherapy naïve patients undergoing cisplatin-based chemotherapy for solid tumors compared three different oral doses of NETU (100, 200, and 300 mg) + PALO 0.50 mg with oral PALO 0.50 mg, all given on day 1. A standard 3-day aprepitant (APR) + IV ondansetron (OND) 32 mg regimen was included as an exploratory arm. All patients received oral dexamethasone on days 1-4. The primary efficacy endpoint was complete response (CR: no emesis, no rescue medication) during the overall (0-120 h) phase. RESULTS: All NEPA doses showed superior overall CR rates compared with PALO (87.4%, 87.6%, and 89.6% for NEPA100, NEPA200, and NEPA300, respectively versus 76.5% PALO; P < 0.050) with the highest NEPA300 dose studied showing an incremental benefit over lower NEPA doses for all efficacy endpoints. NEPA300 was significantly more effective than PALO and numerically better than APR + OND for all secondary efficacy endpoints of no emesis, no significant nausea, and complete protection (CR plus no significant nausea) rates during the acute (0-24 h), delayed (25-120 h), and overall phases. Adverse events were comparable across groups with no dose response. The percent of patients developing electrocardiogram changes was also comparable. CONCLUSIONS: Each NEPA dose provided superior prevention of chemotherapy-induced nausea and vomiting (CINV) compared with PALO following highly emetogenic chemotherapy; however, NEPA300 was the best dose studied, with an advantage over lower doses for all efficacy endpoints. The combination of NETU and PALO was well tolerated with a similar safety profile to PALO and APR + OND.

Efficacy and safety of repeated dosing of netupitant, a neurokinin-1 receptor antagonist, in treating overactive bladder.

AIM: NK-1 receptors in sensory nerves, the spinal cord and bladder smooth muscle participate in complex sensory mechanisms that regulate bladder activity. This study was designed to assess the efficacy and safety of a new NK-1 receptor antagonist, netupitant, in patients with OAB. METHODS: This was a phase II, multicenter, double-blind study in which adults with OAB symptoms >6 months were randomized to receive 1 of 3 doses of netupitant (50, 100, 200 mg) or placebo once daily for 8 weeks. The primary efficacy endpoint was percentage change from baseline in average number of daily micturitions at week 8. Urinary incontinence, urge urinary incontinence (UUI), and urgency episodes were also assessed. RESULTS: The primary efficacy endpoint was similar in the treatment groups (-13.85 for placebo to -16.17 in the netupitant 200 mg group) with no statistically significant differences between netupitant and placebo. The same was true for most secondary endpoints although a significant difference for improvement in UUI episodes and a trend for the greatest decrease in urgency episodes were seen in the netupitant 100 mg group. Netupitant was well tolerated with most treatment emergent adverse events (AEs) being mild. While the overall incidence of AEs increased with netupitant dose, there was no evidence for this dose dependency based on relationship to treatment, intensity, or time to onset. CONCLUSIONS: The study failed to demonstrate superiority of netupitant versus placebo in decreasing OAB symptoms, despite a trend favoring netupitant 100 mg. There were no safety concerns with daily administration of netupitant over 8 weeks.

Health status and 6 years survival of 552 90+ Italian sib-ships recruited within the EU Project GEHA (GEnetics of Healthy Ageing).

In a scenario of increasing life expectancy worldwide, it is mandatory to identify the characteristics of a healthy aging phenotype, including survival predictors, and to disentangle those related to environment/lifestyle versus those related to familiarity/genetics. To this aim we comprehensively characterised a cohort of 1,160 Italian subjects of 90 years and over (90+, mean age 93 years; age range 90-106 years) followed for 6 years survival, belonging to 552 sib-ships (familiar longevity) recruited (2005-2008) within the EU-funded GEHA project in three Italian geographic areas (Northern, Central and Southern Italy) different for urban/rural and socio-economical characteristics. On the whole, the following factors emerged as significant predictors of survival after 90 years of age: absence of cognitive impairment and physical disability, high hand grip strength scores and body mass index (BMI) values, "excellent/good" self-reported health, high haemoglobin and total cholesterol levels and low creatinine levels. These parameters, excluding BMI values, were also significantly associated within sib-ships, suggesting a strong familial/genetic component. Geographical micro-heterogeneity of survival predictors emerged, such as functional and physical status being more important in Southern than in Central and Northern Italy. In conclusion, we identified modifiable survival predictors related to specific domains, whose role and importance vary according to the geographic area considered and which can help in interpreting the genetic results obtained by the GEHA project, whose major aim is the comprehensive evaluation of phenotypic and genetic data.

Does the longevity of one or both parents influence the health status of their offspring?

According to the findings of some recent studies, the centenarians' offspring appear to represent a promising model for research on longevity and healthy aging. This study compares the health status and the functional status of three groups of subjects: 1. individuals with two long-lived parents (one of whom centenarian), 2. individuals with only one long-lived (centenarian) parent, and 3. individuals with no long-lived parents. The goal is to verify whether the centenarians' offspring display any advantage over the offspring of both non-long-lived parents and to evaluate whether the longevity of the non-centenarian parent provides a further advantage. A total of 374 subjects (mean age approximately 70 years) was examined. A threshold for longevity was established for non-centenarian parents through demographic data available for Italy (males surviving to at least 81 years of age and females to 87 years). The participants were assessed for their health and functional status by means of a standardized questionnaire and tests of physical performance. Data were analyzed using multivariate regression models adjusted for socio-demographic characteristics and risk factors for age-related pathologies. The results of the study show that centenarians' offspring have a better functional status, a reduced risk for several age-related pathologies and reduced drug consumption than the offspring of non-long-lived parents. In addition, the health status of centenarians' offspring does not appear to be influenced by the longevity of the second parent. It therefore seems possible to conclude that at ages around 70 years the genetic contribution to health status deriving from having one centenarian parent is not substantially improved if the other parent is also long-lived.

Metabolic syndrome in the offspring of centenarians: focus on prevalence, components, and adipokines.

With aging, an increased prevalence of a clustering of metabolic abnormalities has been observed. These abnormalities include obesity, dyslipidemia, hypertension, and insulin resistance and are collectively known as metabolic syndrome (MetS), a low-grade, systemic, inflammatory condition associated with an increased risk of cardiovascular disease, diabetes, and other adverse health outcomes. A number of studies have demonstrated that centenarians' offspring have a significant survival advantage and a lower risk of developing the most important age-related diseases. They therefore represent one of the best models with which to study the familiar component of human longevity. The aim of this study was to determine if the offspring of centenarians (n = 265 subjects) showed a different prevalence of MetS in comparison to the offspring of non-long-lived parents (controls, n = 101 subjects). In addition, we assessed whether centenarians' offspring showed particular features of MetS and a distinct regulation of circulating adipokines, cytokines, and metabolic mediators. Although the prevalence of MetS was quite similar both in the offspring of centenarians and the controls, MetS-affected centenarians' offspring seemed healthier, more functionally fit, and had lower resistin levels. MetS prevalence did not change in centenarians' offspring across resistin, IGF-1, and resistin/IGF-1 ratio tertiles. On the other hand, in controls, MetS prevalence strongly increased across resistin tertiles and in the third resistin/IGF-1 ratio tertile, indicating a dramatic increase in MetS prevalence when the ratio between these two factors is unbalanced, with high levels of resistin and low levels of IGF-1.

Age-related inflammation: the contribution of different organs, tissues and systems. How to face it for therapeutic approaches.

A typical feature of ageing is a chronic, low-grade inflammation characterized by a general increase in the production of pro-inflammatory cytokines and inflammatory markers ("inflamm-ageing"). This status may slowly damage one or several organs, especially when unfavorable genetic polymorphisms and epigenetic alterations are concomitant, leading to an increased risk of frailty together with the onset of age-related chronic diseases. The contribution of different tissues (adipose tissue, muscle), organs (brain, liver), immune system and ecosystems (gut microbiota) to age-related inflammation ("inflamm-ageing") will be discussed in this review in the context of its onset/progression leading to site-restricted and systemic effects. Moreover, some of the possible strategies and therapies to counteract the different sources of molecular mediators which lead to the age-related inflammatory phenotype will be presented.

Bitter taste study in a sardinian genetic isolate supports the association of phenylthiocarbamide sensitivity to the TAS2R38 bitter receptor gene.

Recently, a major locus on chromosome 7q was found in association with the taste sensitivity to phenylthiocarbamide (PTC) in humans. This region contains the TAS2R38 gene that encodes a member of the TAS2R bitter taste receptor family. Three SNPs within this gene demonstrated a strong association with taster status in Utah families and in an additional sample of 85 unrelated individuals. We studied a small isolated village in eastern Sardinia and carried out a genome-wide scan to map the genetic basis of PTC perception in this population. We performed both qualitative and quantitative PTC-taste linkage analysis. Qualitative analysis was carried out by defining a cut-off from the bimodal distribution of the trait and classifying subjects as tasters and non-tasters (75 and 25%, respectively). Linkage analysis on 131 subjects belonging to a unique large multi-generation pedigree comprising 239 subjects confirmed significant evidence for linkage at 7q35 also in our population. Haplotype analyses of the three SNPs inside the PTC gene allowed us to identify only two haplotypes that were associated with the non-taster phenotype (80% AVI homozygous) and to taster phenotype (40% PAV homozygous and 56% PAV/AVI heterozygous). Sex, age and haplotype effect explained 77.2 % of the total variance in PTC sensitivity.

Family-based association study between bipolar disorder and DRD2, DRD4, DAT, and SERT in Sardinia.

Association analysis of candidate genes may represent a strategy for clarifying the genetic components involved in bipolar disorder. Polymorphism at dopamine receptor genes DRD2, DRD4, and dopamine and serotonin transporter genes (DAT, SERT) has been used in previous association studies. Some authors have reported positive association between certain alleles and bipolar disorder, using the case-control design. In this family-based association study of DRD2, DRD4, DAT, and SERT, the distribution of parental nontransmitted alleles was compared with that of alleles transmitted to 53 Sardinian probands suffering from bipolar disorder. The transmission disequilibrium test (TDT) was used to detect any disproportionate transmission of alleles by heterozygous parents to affected children. No differences were found between the allele distribution of polymorphisms at DRD2, DRD4, DAT, and SERT in probands and parental nontransmitted chromosomes. TDT did not reveal any difference between transmitted and nontransmitted alleles. Our results do not support the hypothesis of a role for DRD2, DRD4, DAT, or SERT in bipolar disorder. Previously reported positive associations between DRD2 or SERT and bipolar disorder were conceivably due to stratification dependent on the case-control design, even though our sample might have failed to detect small associations due to limited power.

Association between dopamine receptor genes and migraine without aura in a Sardinian sample.

BACKGROUND: Migraine seems to be caused by a combination of environmental and genetic factors. Clinical and pharmacologic evidence supports the hypothesis that dopaminergic transmission is involved in the pathogenesis of migraine. OBJECTIVE: The current report concerns a genetic study to test the involvement of genes for dopamine (DA) receptors D2 (DRD2), D3 (DRD3), and D4 (DRD4) in migraine without aura, particularly in a subgroup with enhanced DA sensitivity. METHODS: For the first time, a family-based association method--the Transmission Disequilibrium Test (TDT)--was used to examine an isolated population, such as Sardinians. We studied 50 nuclear families of patients affected by migraine without aura. The subgroup of dopaminergic migraineurs was selected based on the presence of both nausea and yawning immediately before or during the pain phase of migraine. RESULTS: No association was detected using the TDT between DRD3, DRD4, and migraine without aura either in the overall sample or in the subgroup. No difference was observed in DRD2 allelic distribution in the overall sample, although the allelic distribution at the DRD2 locus differed significantly in the subgroup of dopaminergic migraineurs (p = 0.004). Allele 1 of the TG dinucleotide intronic noncoding polymorphism of the DRD2 locus was the individual allele that appeared to be in disequilibrium with migraine without aura (p = 0.02). CONCLUSIONS: Our data suggest that a genetic approach could be useful in providing molecular support to the hypothesis that hypersensitivity of the dopaminergic system may represent the pathophysiologic basis of migraine, at least in a subgroup of patients.

No evidence of association between dopamine D3 receptor gene and bipolar affective disorder.

A recent study reported a possible association between allele 1 of the dopamine D3 receptor gene and bipolar affective disorder using the haplotype relative risk approach. In attempt to replicate these findings, we used similar family-based methods, such as the Haplotype-Based Haplotype Relative Risk method and the Transmission Disequilibrium Test, in a sample of 44 bipolar probands from Sardinia with both parents available. Using the Bal I restriction enzyme site polymorphism of Lannfelt et al. (1992), no differences were found between transmitted and non-transmitted alleles and no evidence of linkage disequilibrium was observed.

The influence of diabetes mellitus on primary open angle glaucoma perimetry.

We have carried out a study into retinal sensitivity alterations in the course of primary open angle glaucoma to see if their appearance and evolution might be influenced by concomitant diabetes mellitus. The visual field examination (Perimeter Octopus 500 EZ, programme G1) indicated prevalent sensitivity defects in the superior hemifield, both in glaucoma only subjects and in those with diabetes as well. As to the inferior hemifield, a greater, statistically significant, retinal sensitivity defect was found in the inferior temporal quadrant of the left eye in the group of diabetics.

Valor diagnóstico de la centellografía de las glándulas salivales en Síndrome de Sjögren / Scintigraphy salyvary glans in Sjögren Syndrome.Diagnostic value

La Centellografía Salival es un método sensitivo para la evaluación de las glándulas salivales.Ha sido descripta una correlación entre la centellografía salival,el flujo salival,la sialografía e histología.Nosotros realizamos un estudio prospectivo en 22 pacientes con Síndrome de Sjögren para confirmar el rol de la Centellografía Salival.En 14 pacientes la Centellografía mostró un patrón de captación anormal.La Centellografía mostró ser un método sensible para evaluar el compromiso glandular.No hubo correlación entre el patrón histológico y la duración de la enfermedad

Valor diagnóstico de la centellografía de las glándulas salivales en Síndrome de Sj÷gren / Scintigraphy salyvary glans in Sj÷gren Syndrome.Diagnostic value

La Centellografía Salival es un método sensitivo para la evaluación de las glándulas salivales.Ha sido descripta una correlación entre la centellografía salival,el flujo salival,la sialografía e histología.Nosotros realizamos un estudio prospectivo en 22 pacientes con Síndrome de Sj÷gren para confirmar el rol de la Centellografía Salival.En 14 pacientes la Centellografía mostró un patrón de captación anormal.La Centellografía mostró ser un método sensible para evaluar el compromiso glandular.No hubo correlación entre el patrón histológico y la duración de la enfermedad

Ecografía de glándulas submandibulares y parótida en Sindrome de Sjögren.Nuestra Experiencia / Echography saluvary gland submandibular and parotid in Sjögren Syndrome

Se realizó Ecografía de glándulas salivales, parótida y submandibulares a 22 pacientes con diagnóstico de Sindrome de Sjögren.El estudio fué realizado con un ecógrafo de alta resolución con transductor de 7,5 MHz.Dieciseis de los 22 pacientes presentaron un Sindrome de Sejögren Definido(evidencias objetivas de sequedad ocular, bucal y en los pacientes clasificados como Sindrome de Sjögren secundario una enfermedad autoinmune sistémica, incluyendo en todos una biopsia característica de glándulas salivales menores).En estos 16 pacientes se observaron alteraciones ecográficas del parénquima y del tamaño glandular.Doce de los 16 pacientes (75 por ciento) tuvieron un patrón heterogéneo y cuatro patrón homogéneo (25 por ciento).El estudio ultrasonográfico mostró una sensibilidad del 75 por ciento , comparable a la del test de Shirmer y a la sialografía.La Ecografía de glándulas salivales mayores y menores es un método auxiliar, simple y no envasivo cuya información refleja indirectamente el grado de infiltración de las glándulas salivales

Ecografía de glándulas submandibulares y parótida en Sindrome de Sj÷gren.Nuestra Experiencia / Echography saluvary gland submandibular and parotid in Sj÷gren Syndrome

Se realizó Ecografía de glándulas salivales, parótida y submandibulares a 22 pacientes con diagnóstico de Sindrome de Sj÷gren.El estudio fué realizado con un ecógrafo de alta resolución con transductor de 7,5 MHz.Dieciseis de los 22 pacientes presentaron un Sindrome de Sej÷gren Definido(evidencias objetivas de sequedad ocular, bucal y en los pacientes clasificados como Sindrome de Sj÷gren secundario una enfermedad autoinmune sistémica, incluyendo en todos una biopsia característica de glándulas salivales menores).En estos 16 pacientes se observaron alteraciones ecográficas del parénquima y del tamaño glandular.Doce de los 16 pacientes (75 por ciento) tuvieron un patrón heterogéneo y cuatro patrón homogéneo (25 por ciento).El estudio ultrasonográfico mostró una sensibilidad del 75 por ciento , comparable a la del test de Shirmer y a la sialografía.La Ecografía de glándulas salivales mayores y menores es un método auxiliar, simple y no envasivo cuya información refleja indirectamente el grado de infiltración de las glándulas salivales

Diagnóstico del cáncer de próstata mediante ecografía transrectal y antígeno prostático específico / Prostatic cancer: PS antigen and transrectal ultrasound

Se estudia un grupo de 64 pacientes con sospecha de cáncer de próstata, mediante ecografía prostática transrectal (EPT), biopsia prostática transrectal y dosaje sérico de antígeno prostático específico (APE). La combinación de hallazgo ecográfico de nódulo hipoecoico con elevación del APE (>=10ng/ml) aportó los mejores resultados diagnósticos para cáncer de próstata: sensibilidad, 78,9 por ciento, especificidad, 75 por ciento y valor predictivo positivo del 88,2 por ciento

Diagnóstico del cáncer de próstata mediante ecografía transrectal y antígeno prostático específico / Prostatic cancer: PS antigen and transrectal ultrasound

Se estudia un grupo de 64 pacientes con sospecha de cáncer de próstata, mediante ecografía prostática transrectal (EPT), biopsia prostática transrectal y dosaje sérico de antígeno prostático específico (APE). La combinación de hallazgo ecográfico de nódulo hipoecoico con elevación del APE (>=10ng/ml) aportó los mejores resultados diagnósticos para cáncer de próstata: sensibilidad, 78,9 por ciento, especificidad, 75 por ciento y valor predictivo positivo del 88,2 por ciento (AU)

The role of laparoscopy in the treatment of endometriosis.

The aim of the present study was to evaluate the role of laparoscopy not only in the diagnosis but also in the therapy of pelvic endometriosis. Ninety-four patients underwent laparoscopy between May 1991 and May 1993. The patients were divided into 2 groups, according to the indication for laparoscopy: group I (benign ovarian cysts n = 47); group II (chronic pelvic pain, n = 47). All laparoscopies were performed by 2 surgeons only. When present, endometriosis was scored according to the American Fertility Society revised classification 1985 (AFS 1985). Endometriosis was present in 37 (39.4%) of the 94 patients included in the study: 19 out of 47 (40.4%) in group I, 18 out of 47 (38.3%) in group II. In 29 patients with endometriosis (78.3%), the score was reduced surgically during the diagnostic procedure. In 24 cases (82.8%) by laparoscopy and in 5 cases (17.2%) only, by laparotomy. Therefore, the careful selection of cases, the use of appropriate instruments and the experience in endoscopic surgery, combined with a good knowledge of pelvic anatomy, may allow the treatment of endometriosis immediately after diagnosis by laparoscopy, resulting in shorter hospitalization, less physical trauma, and a lower number of post-operative adhesions.

Experimental cultivation of cannabis plants in the Mediterranean area.

In research carried out in 1982, which included the cultivation of cannabis plants with low, medium and high levels of delta 9-tetrahydrocannabinol (THC), the authors have determined the parameters for individualization and classification of cannabis plants according to their intoxicant potential. This can help to provide courts of law with valid supportive expertise on cannabis trafficking cases. The parameters are the percentages of THC in cannabinoids and in the dried substance of a plant, as well as the percentage of cannabinoids in the dried substance. On the basis of these parameters, the authors have found that a cannabis plant in which the percentage of THC exceeds 50 per cent of the total amount of cannabinoids of the extractable resin and 0.3 per cent of the total amount of dried substance, and in which the amounts of resin and cannabinoids are substantial, has a considerable intoxicant potential and is liable to be used for illicit production of cannabis for abuse. On the contrary, a plant with a THC level below 50 per cent of the cannabinoids and 0.3 per cent of the dried substance, in addition to a low level of total cannabinoids, has low intoxicant potential and can be used in industry for the production of oil and rope. On the basis of these parameters it is also possible to predict the intoxicant potential of a young cannabis plant harvested at a relatively early stage of its development.