Development of the Italian Version of the National Institutes of Health Stroke Scale It-NIHSS

Background and Purpose-The National Institutes of Health Stroke Scale (NIHSS) is a basic component of the assessment of patients with acute stroke. To foster and standardize the use of the NIHSS among Italian health professionals, we translated the scale, dubbed into Italian the training and test videotapes devised by the National Institutes of Health researchers, and conducted a series of certification courses using the translated videos. Methods-Translation, text adaptation, video dubbing, and editing of the Italian NIHSS videotapes relied on a team of bilingual stroke neurologists. Three waves of training courses were organized for mixed classes of medical and nonmedical health professionals. The certification test was based on the usual set of 5 videotaped patients. Scoring rules were those provided by the National Institutes of Neurological Disorders and Stroke. Reliability of the Italian NIHSS was assessed using kappa statistics and compared with that of the original NIHSS. Results-During 3 years, 850 nurses, 460 nonneurologist physicians, and 246 neurologists were trained. Pass rates were respectively 44%, 75%, and 87%, respectively. Overall, 80% of scale items showed moderate to excellent reliability. Independent significant predictors of test failure at multivariate logistic regression were nurse profession (OR, 5.41; 95% CI, 4.07 to 7.20), older age (OR, 1.03; 95% CI, 1.02 to 1.05), and first edition of the course (OR, 3.13; 95% CI, 2.43 to 4.05). The agreement across all items between NIHSS and the Italian NIHSS was 80% (kappa = 0.70 +/- 0.18, z < 0.001). Conclusions-The Italian translation, supervised by experienced vascular neurologists, did not influence the clinimetric characteristics of the NIHSS. Our findings support the implementation of NIHSS video training in languages other than English. (Stroke. 2009; 40: 2557-2559.

Human papillomavirus (HPV) DNA in penile carcinomas in Argentina: Analysis of primary tumors and lymph nodes

Among sexually transmitted diseases, infection by human papillomavirus (HPV) has become one of the most important. On the other hand, though epidemiological data show that some HPV types are closely associated with cervical cancer, few reports have been found with reference to penile carcinoma because of its rare occurrence. The aim of this study was to investigate the relationship between HPV infection and penile cancer in Argentina. A retrospective study was carried out on 38 white men with penile squamous-cell carcinoma. Sixty-five archival fixed biopsies taken from 34 primary penile tumors, 25 nodal metastases, 1 skin “satellite” metastasis and 5 histologically normal lymph nodes were used as specimens. HPV detection and typing were carried out by the polymerase chain reaction (PCR) using generic primers, combined with single-stranded conformational polymorphism (SSCP) analysis. HPV DNA was found in 71% patients, corresponding 81% of them to “high risk” types, with predominance of HPV 18. Both primary tumors and metastases showed concordance of HPV occurrence and type in both lesions. In 3 patients, HPV 16 was detected not only in primary tumors and metastases, but also in histologically normal lymph nodes. Our data indicate that most penile carcinomas in Argentine patients are etiologically related to HPV, especially to “high risk” genital types. The agreement in HPV detection between primary tumors and metastases suggests a potential viral role in tumor progression. HPV detection in otherwise histologically normal lymph nodes might be useful as early marker of a metastatic process.Fil: Picconi, María A.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C.G. Malbrán”; ArgentinaFil: Eijan, Ana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad de Buenos Aires; ArgentinaFil: Distéfano, Angélica L.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C.G. Malbrán”; ArgentinaFil: Pueyo, Silvia. Provincia de Buenos Aires. Ministerio de Salud. Hospital Materno Infantil de San Isidro. Servicio de Dermatología; ArgentinaFil: Alonio, Lidia Virginia. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C.G. Malbrán”; ArgentinaFil: Gorostidi, Susana. Universidad de Buenos Aires; ArgentinaFil: Teyssié, Angélica R.. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorio e Instituto de Salud “Dr. C.G. Malbrán”; ArgentinaFil: Casabone, Bernardo Adalberto. Universidad de Buenos Aires; Argentin

Derangement of Ras-Guanine Nucleotide-Releasing Factor 1 (Ras-GRF1) and Extracellular Signal-Regulated Kinase (ERK) Dependent Striatal Plasticity in L-DOPA-Induced Dyskinesia

BACKGROUND: Bidirectional long-term plasticity at the corticostriatal synapse has been proposed as a central cellular mechanism governing dopamine-mediated behavioral adaptations in the basal ganglia system. Balanced activity of medium spiny neurons (MSNs) in the direct and the indirect pathways is essential for normal striatal function. This balance is disrupted in Parkinson's disease and in L-3,4-dihydroxyphenylalanine (L-DOPA)-induced dyskinesia (LID), a common motor complication of current pharmacotherapy of Parkinson's disease. METHODS: Electrophysiological recordings were performed in mouse cortico-striatal slice preparation. Synaptic plasticity, such as long-term potentiation (LTP) and depotentiation, was investigated. Specific pharmacological inhibitors or genetic manipulations were used to modulate the Ras-extracellular signal-regulated kinase (Ras-ERK) pathway, a signal transduction cascade implicated in behavioral plasticity, and synaptic activity in different subpopulations of striatal neurons was measured. RESULTS: We found that the Ras-ERK pathway, is not only essential for long-term potentiation induced with a high frequency stimulation protocol (HFS-LTP) in the dorsal striatum, but also for its reversal, synaptic depotentiation. Ablation of Ras-guanine nucleotide-releasing factor 1 (Ras-GRF1), a neuronal activator of Ras proteins, causes a specific loss of HFS-LTP in the medium spiny neurons in the direct pathway without affecting LTP in the indirect pathway. Analysis of LTP in animals with unilateral 6-hydroxydopamine lesions (6-OHDA) rendered dyskinetic with chronic L-DOPA treatment reveals a complex, Ras-GRF1 and pathway-independent, apparently stochastic involvement of ERK. CONCLUSIONS: These data not only demonstrate a central role for Ras-ERK signaling in striatal LTP, depotentiation, and LTP restored after L-DOPA treatment but also disclose multifaceted synaptic adaptations occurring in response to dopaminergic denervation and pulsatile administration of L-DOPA

P07-05. HIV and STI prevalence among men who have sex with men (MSM) recruited through respondent driven sampling (RDS) in Buenos Aires, Argentina

Fil: Pando, María A. Centro Nacional de Referencia para el SIDA; Argentina.Fil: Marone, Rubén. Nexo Asociación Civil; Argentina.Fil: Balán, Iván C. Columbia University. HIV Center for Clinical and Behavioral Studies; Estados Unidos.Fil: Dolezal, Curtis. Columbia University. HIV Center for Clinical and Behavioral Studies; Estados Unidos.Fil: Squiquera, Luis. Nexo Asociación Civil; Argentina. Fil: Balan, Iván C. Columbia University. HIV Center for Clinical and Behavioral Studies; Estados Unidos.Fil: Picconi, María Alejandra. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina.Fil: Gonzales, J. ANLIS Dr.C.G.Malbrán. Instituto Nacional de Enfermedades Infecciosas. Servicio Virus Oncogénicos; Argentina.Fil: Rey, Jorge. Hospital de Clínicas José de San Martín; Argentina.Fil: Fernandez Toscano, M. Hospital de Clínicas José de San Martín; Argentina.Fil: Rodriguez Fermepín, Marcelo. UBA. Laboratorio de Inmunología Clínica; Argentina.Fil: Gallo Vaulet, Lucia. UBA. Laboratorio de Inmunología Clínica; Argentina.Fil: Carballo Dieguez, Alex. Columbia University. HIV Center for Clinical and Behavioral Studies; Estados Unidos.Fil: Avila, María M. Centro Nacional de Referencia para el SIDA; Argentina.Background MSM constitute one of the populations most affected by HIV and other STIs in Argentina. Previous prevalence studies were based on convenience samples. RDS, a methodology designed to access hidden populations, is being used for the first time in Argentina to recruit MSM. Methods RDS recruitment started in November 2007 with 16 first generation participants (seeds) who were selected for their potential to tap in MSM networks. Recruitment is ongoing. Men must be 18 years of age or older, be residents of Buenos Aires, self-report having sex with men at least 10 times in their lives and at least once in the past six months. They must have a coupon indicating they have been referred by a study participant. Specimens are being collected for HIV and STI diagnosis. All data are weighted using the RDS Analysis Tool (RDSAT). Results To date, 333 MSM were recruited through RDS showing a prevalence of 11.3, 16.6, 7.9, 17.6, 4.0 and 88.3% for HIV, HBV, HCV, T. pallidum, Chlamydia and HPV, respectively. Chlamydia and HPV diagnoses were only performed in 73 and 79 participants, respectively. Among HPV positive individuals, 47.8% had almost one of these high risk types (16, 58, 33, 45, 18 and 31) and 32% had multiple infections with 2 or more types. Conclusion Compared with previous studies, these results show similar HIV, HBV and T. pallidum prevalences but higher HCV prevalence. For the first time, an elevated prevalence of HPV was detected on MSM, with high frequency of types associated with ano-genital cancer. Preliminary analyses of socio demographic data show that RDS helps recruit a diversity of MSM, particularly of lower socio-economic level usually missed with other recruitment methods. The high prevalence of coinfections in this population should be taken into account if MSM are part of vaccine trials given that STI may increase HIV sexual transmission

Generation and quality control of lipidomics data for the alzheimers disease neuroimaging initiative cohort.

Alzheimers disease (AD) is a major public health priority with a large socioeconomic burden and complex etiology. The Alzheimer Disease Metabolomics Consortium (ADMC) and the Alzheimer Disease Neuroimaging Initiative (ADNI) aim to gain new biological insights in the disease etiology. We report here an untargeted lipidomics of serum specimens of 806 subjects within the ADNI1 cohort (188 AD, 392 mild cognitive impairment and 226 cognitively normal subjects) along with 83 quality control samples. Lipids were detected and measured using an ultra-high-performance liquid chromatography quadruple/time-of-flight mass spectrometry (UHPLC-QTOF MS) instrument operated in both negative and positive electrospray ionization modes. The dataset includes a total 513 unique lipid species out of which 341 are known lipids. For over 95% of the detected lipids, a relative standard deviation of better than 20% was achieved in the quality control samples, indicating high technical reproducibility. Association modeling of this dataset and available clinical, metabolomics and drug-use data will provide novel insights into the AD etiology. These datasets are available at the ADNI repository at http://adni.loni.usc.edu/

Distinct Changes in cAMP and Extracellular Signal-Regulated Protein Kinase Signalling in L-DOPA-Induced Dyskinesia

Background: In rodents, the development of dyskinesia produced by L-DOPA in the dopamine-depleted striatum occurs in response to increased dopamine D1 receptor-mediated activation of the cAMP- protein kinase A and of the Rasextracellular signal-regulated kinase (ERK) signalling pathways. However, very little is known, in non-human primates, about the regulation of these signalling cascades and their association with the induction, manifestation and/or maintenance of dyskinesia. Methodology/Results: We here studied, in the gold-standard non-human primate model of Parkinson’s disease, the changes in PKA-dependent phosphorylation of DARPP-32 and GluR1 AMPA receptor, as well as in ERK and ribosomal protein S6 (S6) phosphorylation, associated to acute and chronic administration of L-DOPA. Increased phosphorylation of DARPP-32 and GluR1 was observed in both L-DOPA first-ever exposed and chronically-treated dyskinetic parkinsonian monkeys. In contrast, phosphorylation of ERK and S6 was enhanced preferentially after acute L-DOPA administration and decreased during the course of chronic treatment. Conclusion: Dysregulation of cAMP signalling is maintained during the course of chronic L-DOPA administration, while abnormal ERK signalling peaks during the initial phase of L-DOPA treatment and decreases following prolonged exposure

Pathophysiology of L-dopa-induced motor and non-motor complications in Parkinson's disease

Involuntary movements, or dyskinesia, represent a debilitating complication of levodopa (L-dopa) therapy for Parkinson's disease (PD). L-dopa-induced dyskinesia (LID) are ultimately experienced by the vast majority of patients. In addition, psychiatric conditions often manifested as compulsive behaviours, are emerging as a serious problem in the management of L-dopa therapy. The present review attempts to provide an overview of our current understanding of dyskinesia and other L-dopa-induced dysfunctions, a field that dramatically evolved in the past twenty years. In view of the extensive literature on LID, there appeared a critical need to re-frame the concepts, to highlight the most suitable models, to review the central nervous system (CNS) circuitry that may be involved, and to propose a pathophysiological framework was timely and necessary. An updated review to clarify our understanding of LID and other L-dopa-related side effects was therefore timely and necessary. This review should help in the development of novel therapeutic strategies aimed at preventing the generation of dyskinetic symptoms

Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART.

Although HAART suppresses HIV replication, it is often unable to restore immune homeostasis. Consequently, non-AIDS-defining diseases are increasingly seen in treated individuals. This is attributed to persistent virus expression in reservoirs and to cell activation. Of note, in CD4(+) T cells and monocyte-macrophages of virologically-suppressed individuals, there is continued expression of multi-spliced transcripts encoding HIV regulatory proteins. Among them, Tat is essential for virus gene expression and replication, either in primary infection or for virus reactivation during HAART, when Tat is expressed, released extracellularly and exerts, on both the virus and the immune system, effects that contribute to disease maintenance. Here we report results of an ad hoc exploratory interim analysis (up to 48 weeks) on 87 virologically-suppressed HAART-treated individuals enrolled in a phase II randomized open-label multicentric clinical trial of therapeutic immunization with Tat (ISS T-002). Eighty-eight virologically-suppressed HAART-treated individuals, enrolled in a parallel prospective observational study at the same sites (ISS OBS T-002), served for intergroup comparison. Immunization with Tat was safe, induced durable immune responses, and modified the pattern of CD4(+) and CD8(+) cellular activation (CD38 and HLA-DR) together with reduction of biochemical activation markers and persistent increases of regulatory T cells. This was accompanied by a progressive increment of CD4(+) T cells and B cells with reduction of CD8(+) T cells and NK cells, which were independent from the type of antiretroviral regimen. Increase in central and effector memory and reduction in terminally-differentiated effector memory CD4(+) and CD8(+) T cells were accompanied by increases of CD4(+) and CD8(+) T cell responses against Env and recall antigens. Of note, more immune-compromised individuals experienced greater therapeutic effects. In contrast, these changes were opposite, absent or partial in the OBS population. These findings support the use of Tat immunization to intensify HAART efficacy and to restore immune homeostasis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00751595

Optostimulation of striatonigral terminals in substantia nigra induces dyskinesia that increases after L‐DOPA in a mouse model of Parkinson's disease

Background and Purpose: L-DOPA-induced dyskinesia (LID) remains a major complication of L-DOPA therapy in Parkinson's disease. LID is believed to result from inhibition of substantia nigra reticulata (SNr) neurons by GABAergic striatal projection neurons that become supersensitive to dopamine receptor stimulation after severe nigrostriatal degeneration. Here, we asked if stimulation of direct medium spiny neuron (dMSN) GABAergic terminals at the SNr can produce a full dyskinetic state similar to that induced by L-DOPA. Experimental Approach: Adult C57BL6 mice were lesioned with 6-hydroxydopamine in the medial forebrain bundle. Channel rhodopsin was expressed in striatonigral terminals by ipsilateral striatal injection of adeno-associated viral particles under the CaMKII promoter. Optic fibres were implanted on the ipsilateral SNr. Optical stimulation was performed before and 24 hr after three daily doses of L-DOPA at subthreshold and suprathreshold dyskinetic doses. We also examined the combined effect of light stimulation and an acute L-DOPA challenge. Key Results: Optostimulation of striatonigral terminals inhibited SNr neurons and induced all dyskinesia subtypes (optostimulation-induced dyskinesia [OID]) in 6-hydroxydopamine animals, but not in sham-lesioned animals. Additionally, chronic L-DOPA administration sensitised dyskinetic responses to striatonigral terminal optostimulation, as OIDs were more severe 24 hr after L-DOPA administration. Furthermore, L-DOPA combined with light stimulation did not result in higher dyskinesia scores than OID alone, suggesting that optostimulation has a masking effect on LID. Conclusion and Implications: This work suggests that striatonigral inhibition of basal ganglia output (SNr) is a decisive mechanism mediating LID and identifies the SNr as a target for managing LID.Fil: Keifman, Ettel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentina. Consejo Superior de Investigaciones Científicas; EspañaFil: Ruiz De Diego, Irene. Consejo Superior de Investigaciones Científicas; EspañaFil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Paz, Rodrigo Manuel. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Solís, Oscar. Consejo Superior de Investigaciones Científicas; EspañaFil: Murer, Mario Gustavo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Moratalla, Rosario. Consejo Superior de Investigaciones Científicas; Españ