How much effort is required to accurately describe the complex ecology of a rodent‐borne viral disease?

We use data collected on 18, 1-ha live trapping grids monitored from 1994 through 2005 and on five of those grids through 2013 in the mesic northwestern United States to illustrate the complexity of the deer mouse (Peromyscus maniculatus)/Sin Nombre virus (SNV) host-pathogen system. Important factors necessary to understand zoonotic disease ecology include those associated with distribution and population dynamics of reservoir species as well as infection dynamics. Results are based on more than 851,000 trap nights, 16,608 individual deer mice and 10,572 collected blood samples. Deer mice were distributed throughout every habitat we sampled and were present during every sampling period in all habitats except high altitude habitats over 1900 m. Abundance varied greatly among locations with peak numbers occurring mostly during fall. However, peak rodent abundance occurred during fall, winter and spring during various years on three grids trapped 12 months/yr. Prevalence of antibodies to SNV averaged 3.9% to 22.1% but no grids had mice with antibodies during every month. The maximum period without antibody-positive mice ranged from 1 to 52 months, or even more at high altitude grids where deer mice were not always present. Months without antibody-positive mice were more prevalent during fall than spring. Population fluctuations were not synchronous over broad geographic areas and antibody prevalences were not well spatially consistent, differing greatly over short distances. We observed an apparently negative, but nonstatistically significant relationship between average antibody prevalence and average deer mouse population abundance and a statistically significant positive relationship between the average number of antibody positive mice and average population abundance. We present data from which potential researchers can estimate the effort required to adequately describe the ecology of a rodentborne viral system. We address different factors affecting population dynamics and hantavirus antibody prevalence and discuss the path to understanding a complex rodent-borne disease system as well as the obstacles in that path.Fil: Douglass, Richard J.. University of Montana; Estados UnidosFil: Vadell, María Victoria. Universidad Nacional de San Martín. Instituto de Investigaciones e Ingeniería Ambiental. Laboratorio de Ecología de Enfermedades Transmitidas por Vectores; Argentina. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Departamento de Ecología, Genética y Evolución; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Exogenous LRRK2G2019S induces parkinsonian-like pathology in a nonhuman primate

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease among the elderly. To understand pathogenesis and to test therapies, animal models that faithfully reproduce key pathological PD hallmarks are needed. As a prelude to developing a model of PD, we tested the tropism, efficacy, biodistribution, and transcriptional impact of canine adenovirus type 2 (CAV-2) vectors in the brain of Microcebus murinus, a nonhuman primate that naturally develops neurodegenerative lesions. We show that introducing helper-dependent (HD) CAV-2 vectors results in long-term, neuron-specific expression at the injection site and in afferent nuclei. Although HD CAV-2 vector injection induced a modest transcriptional response, no significant adaptive immune response was generated. We then generated and tested HD CAV-2 vectors expressing LRRK2 (leucine-rich repeat kinase 2) and LRRK2 carrying a G2019S mutation (LRRK2G2019S), which is linked to sporadic and familial autosomal dominant forms of PD. We show that HD-LRRK2G2019S expression induced parkinsonian-like motor symptoms and histological features in less than 4 months

Anti-tumour necrosis factor discontinuation in inflammatory bowel disease patients in remission: study protocol of a prospective, multicentre, randomized clinical trial

Background: Patients with inflammatory bowel disease who achieve remission with anti-tumour necrosis factor (anti-TNF) drugs may have treatment withdrawn due to safety concerns and cost considerations, but there is a lack of prospective, controlled data investigating this strategy. The primary study aim is to compare the rates of clinical remission at 1?year in patients who discontinue anti-TNF treatment versus those who continue treatment. Methods: This is an ongoing, prospective, double-blind, multicentre, randomized, placebo-controlled study in patients with Crohn?s disease or ulcerative colitis who have achieved clinical remission for ?6?months with an anti-TNF treatment and an immunosuppressant. Patients are being randomized 1:1 to discontinue anti-TNF therapy or continue therapy. Randomization stratifies patients by the type of inflammatory bowel disease and drug (infliximab versus adalimumab) at study inclusion. The primary endpoint of the study is sustained clinical remission at 1?year. Other endpoints include endoscopic and radiological activity, patient-reported outcomes (quality of life, work productivity), safety and predictive factors for relapse. The required sample size is 194 patients. In addition to the main analysis (discontinuation versus continuation), subanalyses will include stratification by type of inflammatory bowel disease, phenotype and previous treatment. Biological samples will be obtained to identify factors predictive of relapse after treatment withdrawal. Results: Enrolment began in 2016, and the study is expected to end in 2020. Conclusions: This study will contribute prospective, controlled data on outcomes and predictors of relapse in patients with inflammatory bowel disease after withdrawal of anti-TNF agents following achievement of clinical remission. Clinical trial reference number: EudraCT 2015-001410-1

Experience with continuous levodopa enteral infusion (Duodopa®)in patients with advanced Parkinson's disease in a secondary level hospital

Introduction: Continuous levodopa delivery by enteral infusion (Duodopa®) is an alternative to deep brain stimulation and subcutaneous apomorphine to control motor fluctuations and dyskinesias in advanced Parkinson's disease (PD). We report our experience with Duodopa® therapy in 11 patients with advanced PD. Methods: We retrospectively assessed clinical and quality of life changes in all patients with PD with severe motor fluctuations and dyskinesias who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy from September 2006 (Duodopa® was approved for advanced PD treatment in Spain at that date) until April 2010 at the A. Marcide Hospital of Spain. Results: Nine patients received Duodopa® [62.7±10.6 (44–74) years, 63.6% male)]. Pre- Duodopa® clinical characteristics of patients were: disease duration 14.5±8.9 (3–34) years, oral levodopa dose 918.2±277.7 (450–1300) mg/day, and Hoehn and Yahr staging 3.7±0.5 (3–4). Nine patients are still receiving Duodopa®. Patients improved motor fluctuations (72.7% significant improvement), dyskinesia (55.5% significant improvement), daily off-time (90.9%) and daily duration dyskinesia (66.6%) after total infusion time of 170.5 months (3–31). The improvement in Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39) and Schwab&England Capacity for Daily Living Scale were 38.5±19.8 and 24±12.5 respectively (P<0.05). Equivalent daily dose of levodopa (April 2010) was 1683.4±295.8 (1234–2216) mg/day. Conclusions: Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease Resumen: Introducción: La infusión continua de levodopa intraduodenal (Duodopa®) constituye una alternativa a la infusión subcutánea de apomorfina y a la cirugía en pacientes con enfermedad de Parkinson (EP) avanzada. Describimos nuestra experiencia con Duodopa® en pacientes con EP avanzada. Métodos: Realizamos un estudio epidemiológico, observacional, no intervencionista, poblacional, descriptivo, y retrospectivo, en el que se incluyen todos aquellos pacientes con EP avanzada tratados con Duodopa® por parte de la Sección de Neurología del Hospital A. Marcide de Ferrol hasta abril de 2010. Resultados: Once de un total de 12 pacientes seleccionados fueron tratados con Duodopa® [63,6% varones; edad media 62,7 ± 10,6 (44–74) años]. En el momento de ser seleccionados para recibir Duodopa® presentaban: tiempo medio de evolución de enfermedad de 14,5 ± 8,9 (3–34) años, dosis media de levodopa oral de 918,2 ± 277,7 (450–1300) mg/ día, y un estadio de Hoehn y Yahr de 3,7 ± 0,5 (3–4). Nueve pacientes mantienen el tratamiento con Duodopa®. Hubo mejoría en las fluctuaciones motoras (72,7% gran mejoría) y discinesias (55,5% gran mejoría) con reducción del tiempo off/día (90,9%) y tiempo con discinesias/día (66,6%) después de un tiempo total de seguimiento con Duodopa® de 170,5 (3–31) meses. La mejoría en las escalas PDQ-39 y Schwab&England fue de 38,5 ± 19,8 y 24 ± 12,5 puntos respectivamente (p < 0,05). La dosis media equivalente oral de levodopa (abril 2010) fue de 1683,4 ± 295,8 (1234–2216) mg/día. Conclusiones: Duodopa® pudiera ser un tratamiento efectivo, seguro, y bien tolerado alternativo a la cirugía y apomorfina subcutánea en pacientes con EP avanzada adecuadamente seleccionados. Keywords: Dyskinesias, Duodopa, Parkinson's disease, Motor fluctuations, Continuous enteral infusion, Levodopa, Palabras clave: Discinesias, Duodopa, Enfermedad de Parkinson, Fluctuaciones motoras, Infusión continua enteral, Levodop

Experiencia con la infusión continua de levodopa intraduodenal (Duodopa®) en pacientes con enfermedad de Parkinson avanzada en un hospital de segundo nivel asistencial

Resumen: Introducción: La infusión continua de levodopa intraduodenal (Duodopa®) constituye una alternativa a la infusión subcutánea de apomorfina y a la cirugía en pacientes con enfermedad de Parkinson (EP) avanzada. Describimos nuestra experiencia con Duodopa® en pacientes con EP avanzada. Métodos: Realizamos un estudio epidemiológico, observacional, no intervencionista, poblacional, descriptivo, y retrospectivo, en el que se incluyen todos aquellos pacientes con EP avanzada tratados con Duodopa® por parte de la Sección de Neurología del Hospital A. Marcide de Ferrol hasta abril de 2010. Resultados: Once de un total de 12 pacientes seleccionados fueron tratados con Duodopa® [63,6% varones; edad media 62,7 ± 10,6 (44-74) años]. En el momento de ser seleccionados para recibir Duodopa® presentaban: tiempo medio de evolución de enfermedad de 14,5 ± 8,9 (3-34) años, dosis media de levodopa oral de 918,2 ± 277,7 (450-1300) mg/día, y un estadio de Hoehn y Yahr de 3,7 ± 0,5 (3-4). Nueve pacientes mantienen el tratamiento con Duodopa®. Hubo mejoría en las fluctuaciones motoras (72,7% gran mejoría) y discinesias (55,5% gran mejoría) con reducción del tiempo off/día (90,9%) y tiempo con discinesias/día (66,6%) después de un tiempo total de seguimiento con Duodopa® de 170,5 (3-31) meses. La mejoría en las escalas PDQ-39 y Schwab&England fue de 38,5 ± 19,8 y 24 ± 12,5 puntos respectivamente (p < 0,05). La dosis media equivalente oral de levodopa (abril 2010) fue de 1683,4 ± 295,8 (1234-2216) mg/día. Conclusiones: Duodopa® pudiera ser un tratamiento efectivo, seguro, y bien tolerado alternativo a la cirugía y apomorfina subcutánea en pacientes con EP avanzada adecuadamente seleccionados. Abstract: Introduction: Continuous levodopa delivery by enteral infusion (Duodopa®) is an alternative to deep brain stimulation and subcutaneous apomorphine to control motor fluctuations and dyskinesias in advanced Parkinson's disease (PD). We report our experience with Duodopa® therapy in 11 patients with advanced PD. Methods: We retrospectively assessed clinical and quality of life changes in all patients with PD with severe motor fluctuations and dyskinesias who started continuous daily levodopa duodenal infusion through percutaneous endoscopic gastrostomy from September 2006 (Duodopa® was approved for advanced PD treatment in Spain at that date) until April 2010 at the A. Marcide Hospital of Spain. Results: Nine patients received Duodopa® [62.7 ± 10.6 (44-74) years, 63.6% male)]. Pre-Duodopa® clinical characteristics of patients were: disease duration 14.5 ± 8.9 (3-34) years, oral levodopa dose 918.2 ± 277.7 (450-1300) mg/day, and Hoehn and Yahr staging 3.7 ± 0.5 (3-4). Nine patients are still receiving Duodopa®. Patients improved motor fluctuations (72.7% significant improvement), dyskinesia (55.5% significant improvement), daily off-time (90.9%) and daily duration dyskinesia (66.6%) after total infusion time of 170.5 months (3-31). The improvement in Parkinson's Disease Quality of Life Questionnaire-39 (PDQ-39) and Schwab&England Capacity for Daily Living Scale were 38.5 ± 19.8 and 24 ± 12.5 respectively (P < 0.05). Equivalent daily dose of levodopa (April 2010) was 1683.4 ± 295.8 (1234-2216) mg/day. Conclusions: Intraduodenal infusion of levodopa offers an important alternative in treating patients with advanced Parkinson disease. Palabras clave: Discinesias, Duodopa, Enfermedad de Parkinson, Fluctuaciones motoras, Infusión continua enteral, Levodopa, Keywords: Dyskinesias, Duodopa, Parkinson's disease, Motor fluctuations, Continuous enteral infusion, Levodop

Optimización del manejo clínico de opicapona en la enfermedad de Parkinson. Recomendaciones de expertos españoles

[EN] Motor fluctuations are frequently seen in Parkinson disease patients on chronic treatment with levodopa. Management of motor fluctuation includes the addition of catechol-O-methyl transferase (COMT) inhibitors. Opicapone is a recent and selective third-generation COMT inhibitor which achieves marked increase in the bioavailability of levodopa. We present a consensus of a group of Spanish neurologists with extensive experience in the clinical management of motor fluctuations. The clinical experience of this group of experts is in line with clinical trials and confirms that opicapone is an effective drug in the control of motor fluctuations, regardless of the daily levodopa dose, or the use of other antiparkinsonian drugs. However, in the opinion of these experts, the ideal patient with Parkinson’s disease to initiate treatment with opicapone is the one with mild motor fluctuations, since the ratio between clinical efficacy and adverse effects is more favorable. In general, it is an easy-to-use drug both in those first treated with a COMT inhibitor or those already on entacapone. In any case, the secondary side effects are easily managed.[ES] Las fluctuaciones motoras constituyen una importante complicación en los pacientes con enfermedad de Parkinson tratados con levodopa. Entre las opciones terapéuticas para el manejo de las fluctuaciones motoras se cuenta con los inhibidores de la catecol-O-metil-transferasa (COMT), incluyendo la opicapona. La opicapona muestra una elevada afinidad por la COMT y consigue un aumento marcado de la biodisponibilidad de la levodopa. Se presenta el consenso de un grupo de expertos españoles en la enfermedad de Parkinson con experiencia en el tratamiento clínico de fluctuaciones motoras y el empleo de opicapona. La experiencia de este grupo de expertos, en consonancia con los ensayos clínicos, confirma que la opicapona es un fármaco eficaz en el control de las fluctuaciones motoras de la enfermedad de Parkinson, con independencia de la dosis de levodopa recibida o de la utilización de otros fármacos antiparkinsonianos. No obstante, a juicio de estos expertos, el paciente ideal para iniciar el tratamiento con opicapona es el que presenta fluctuaciones motoras leves, ya que muestra una mejor relación entre eficacia clínica y efectos adversos. En general, la opicapona es un fármaco de fácil manejo, tanto en pacientes que requieren opicapona como primer inhibidor de la COMT como en los previamente tratados con entacapona, o en los que están en tratamiento concomitante con otros fármacos antiparkinsonianos. En cualquier caso, los efectos secundarios son fácilmente corregibles

Agonistas dopaminérgicos en la enfermedad de Parkinson

Resumen: Introducción: Los agonistas dopaminérgicos no ergóticos (AD) son tratamientos útiles en la enfermedad de Parkinson (EP). Revisamos la farmacología, el grado de evidencia en cuanto a eficacia y tolerabilidad de pramipexol, ropinirol y rotigotina, y proponemos algunas recomendaciones para su uso en la práctica clínica. Desarrollo: En el momento actual se dispone de formas de liberación prolongada (LP) de pramipexol y ropinirol y de administración transdérmica de rotigotina, que contribuyen a una mayor estabilidad plasmática de los valores del fármaco. En la EP inicial los 3 fármacos mejoran de forma significativa las escalas de incapacidad de los pacientes, retrasan la aparición de discinesias y permiten retrasar la introducción de levodopa. En la EP avanzada reducen el tiempo off, mejoran la Unified Parkinson's Disease Rating Scale (UPDRS) en on y en off y permiten reducir la dosis total de levodopa. Además, los 3 han sido capaces de inducir una mejora significativa en las escalas de la calidad de vida relacionada con la salud. Las fórmulas de LP han demostrado la no inferioridad frente a las de liberación inmediata, e incluso una mejor tolerabilidad (ropinirol). A pesar de su buen perfil de seguridad, entre los efectos adversos graves cabe destacar el trastorno de control de impulsos, cuya aparición puede ser precoz, y los accesos de sueño (sleep attacks). Aunque la terapia combinada no ha sido estudiada específicamente, algunas asociaciones (como la de apomorfina y otros AD) pueden ser beneficiosas. El cambio de un AD a otro es factible de un día para otro, aunque en los primeros días puede haber una sumación de efectos adversos dopaminérgicos que debe tenerse en cuenta. La suspensión brusca del tratamiento con AD puede inducir un síndrome de deprivación dopaminérgica. La retirada de cualquier AD, en particular pramipexol, se ha asociado a aparición de apatía que puede ser grave. Conclusiones: Los nuevos AD no ergóticos constituyen una opción válida de tratamiento de la EP tanto inicial como avanzada. A pesar de su buen perfil de tolerabilidad, no están exentos de efectos adversos graves, que pueden tener un efecto patoplástico en la EP y que deben monitorizarse. Abstract: Background: Non-ergoline dopamine agonists (DA) are effective treatments for Parkinson's disease (PD). This review presents the pharmacology, evidence of efficacy and safety profile of pramipexole, ropinirole, and rotigotine, and practical recommendations are given regarding their use in clinical practice. Results: Extended-release formulations of pramipexole and ropinirole and transdermal continuous delivery rotigotine patches are currently available; these may contribute to stabilising of plasma levels.In early PD, the three drugs significantly improve disability scales, delay time to dyskinesia and allow a later introduction of levodopa. In late PD they reduced total 'off'-time, improved Unified Parkinson's Disease Rating Scale (UPDRS) in both 'on' and 'off' state and allowed a reduction in total levodopa dosage. A significant improvement in quality of life scales has also been demonstrated. Extended-release formulations have proved to be non-inferior to the immediate release formulations and are better tolerated (ropinirole). Despite a generally good safety profile, serious adverse events, such as impulse control disorder and sleep attacks, need to be routinely monitored. Although combination therapy has not been addressed in scientific literature, certain combinations, such as apomorphine and another DA, may be helpful. Switching from one DA to another is feasible and safe, although in the first days an overlap of dopaminergic side effects may occur. When treatment with DA is stopped abruptly, dopamine withdrawal syndrome may present. Suspending any DA, especially pramipexole, has been linked to onset of apathy, which may be severe. Conclusions: New non-ergotine DAs are a valuable option for the treatment of both early and late PD. Despite their good safety profile, serious adverse effects may appear; these effects may have a pathoplastic effect on the course of PD and need to be monitored. Palabras clave: Agonistas dopaminérgicos, Pramipexol, Ropinirol, Rotigotina, Liberación prolongada, Equivalencia, Keywords: Dopamine agonists, Pramipexole, Ropinirole, Rotigotine, Prolonged release, Equivalenc