Stereotaxical Infusion of Rotenone: A Reliable Rodent Model for Parkinson's Disease

A clinically-related animal model of Parkinson's disease (PD) may enable the elucidation of the etiology of the disease and assist the development of medications. However, none of the current neurotoxin-based models recapitulates the main clinical features of the disease or the pathological hallmarks, such as dopamine (DA) neuron specificity of degeneration and Lewy body formation, which limits the use of these models in PD research. To overcome these limitations, we developed a rat model by stereotaxically (ST) infusing small doses of the mitochondrial complex-I inhibitor, rotenone, into two brain sites: the right ventral tegmental area and the substantia nigra. Four weeks after ST rotenone administration, tyrosine hydroxylase (TH) immunoreactivity in the infusion side decreased by 43.7%, in contrast to a 75.8% decrease observed in rats treated systemically with rotenone (SYS). The rotenone infusion also reduced the DA content, the glutathione and superoxide dismutase activities, and induced alpha-synuclein expression, when compared to the contralateral side. This ST model displays neither peripheral toxicity or mortality and has a high success rate. This rotenone-based ST model thus recapitulates the slow and specific loss of DA neurons and better mimics the clinical features of idiopathic PD, representing a reliable and more clinically-related model for PD research

Parkinson’s disease mouse models in translational research

Animal models with high predictive power are a prerequisite for translational research. The closer the similarity of a model to Parkinson’s disease (PD), the higher is the predictive value for clinical trials. An ideal PD model should present behavioral signs and pathology that resemble the human disease. The increasing understanding of PD stratification and etiology, however, complicates the choice of adequate animal models for preclinical studies. An ultimate mouse model, relevant to address all PD-related questions, is yet to be developed. However, many of the existing models are useful in answering specific questions. An appropriate model should be chosen after considering both the context of the research and the model properties. This review addresses the validity, strengths, and limitations of current PD mouse models for translational research

Ontwerp en uitvoering stuw te braddock

Het United States Army Corps of Engineers (USACE) heeft in 1998 een openbare aanbesteding gehouden voor de sloop van de huidige en de bouw van de nieuwe stuw 2 in de Monongahela River (Pennsylvania, Verenigde Staten) op basis van een door henzelf vervaardigd ontwerp. De nieuwe stuw 2 bestaat in het ontwerp van het USACE uit een vaste drempel aan de rechteroever, drempels in het middengedeelte en een nooddrempel aan de Iinkeroever (zie Figuur 1). Het middengedeelte bestaat uit een hoge drempel en drie lage drempels. Vier segmentschuiven tussen vijf pijlers vormen de bovenbouw van de drempels in het middengedeelte. De nieuwe stuw 2 wordt in twee constructie-elementen geprefabriceerd in een bouwdok te Leetsdale, getransporteerd over de Ohio en Monongahela River en op de projectlocatie afgezonken. Het eerste constructie-element bestaat uit de vaste drempel, de hoge drempel en een lage drempel. Het tweede constructie-element bestaat uit de overige twee lage drempels. De joint venture bestaande uit Misener, Lane en Interbeton heeft een aanbieding gedaan op de openbare aanbesteding. Delta Marine Consultants bv. (DMC) hebben namens de joint venture het ontwerp van het USACE kritisch bekeken om de aanbieding te doen. De voornaamste punten van kritiek betroffen het constructief ontwerp, het afbouwen aan een steiger en het afzinken op een paalfundering van de twee constructie elementen. In de uitvoeringsplanning van de joint venture wordt het eerste constructie-element in april 2000 en het tweede constructie-element in mei 2001 afgezonken. Het project zou 1 oktober 2002 aan de klant overgeleverd worden. Door het constructief systeem en de uitvoeringsmethode binnen de randvoorwaarden aan te passen wordt in dit afstudeerrapport getracht de door DMC gesignaleerde problemen op te lossen en de totale bouwtijd te verkorten. De randvoorwaarden voor dit afstudeerproject worden gevormd door het ruimtelijk functioneel ontwerp, de hydraulische vormgeving en het stuwprogramma van het USAGE. De basisgedachte van prefabricage van het USAGE wordt aangehouden. Gezien de problematiek rond de paalfundering in het ontwerp van het USAGE wordt er gestreefd naar een fundering op staal. Dit systeem voldoet, na enige constructieve aanpassingen, gevuld met ballastbeton ruim aan alle grenstoestanden voor een fundering op staal. Scheefstand door ongelijke zettingen kan worden opgevangen door de U-vormen, zodat het functioneren van de segmentschuiven mogelijk blijft. De U-vormen worden afgezonken op grindribben. De grindribben fungeren als fundering en in de uitvoeringsfasen als bodembescherming. Door de grindribben wordt voldoende oppervlakte verkregen om het gewicht over te brengen naar de rivierbodem zonder dat de spanningen in de U-vormen en de ondergrond te hoog worden. Een 100% aansluiting tussen het funderingsvlak van de U-vormen en de grindribben wordt gerealiseerd door de holle kamers tussen de grindribben te vullen met mortel. Piping wordt voorkomen door een damwand bovenstrooms tot in de (ondoorlatende) siltsteenlaag en een korte damwand benedenstrooms. Tussen twee U-vormen worden aan de boven- en benedenstroomse zijde damwanden in sponningen geplaatst. De ruimte tussen de damwanden wordt volgegrout.Hydraulic EngineeringCivil Engineering and Geoscience

A study of the behaviour of and the forces in a bed protecting mattress: The falling apron

In many cases the bottom around a structure that is exposed to current has to be protected by a mattress. The purpose of the mattress is to protect the soil besides the structure from erosion and scour, thus preserving the strength of the foundation of the structure. Examples are the bottom protection around bridge piers, along guide bunds and behind discharge sluices. At the edge of the bottom protection parallel to the current (e.g. along guide bunds) or at the trailing edge (e.g. behind discharge sluice) scourholes will be formed in the unprotected bed. The slopes of these scourholes may be so steep that local soil failure follows. In that case the mattress has to span the local depression caused by the slope failure and maintain its protective function (see Figure 2-1). The mattress should therefore be able to withstand the tension forces that build up in the fabric. In this report a sequence of models is proposed and verified to estimate the maximum force in a mattress spanning a local soil failure. The study was commisioned by CUR in Gouda as a contribution to the design of the guide bunds of the Jamuna Bridge.Hydraulic EngineeringCivil Engineering and Geoscience

Staphyloma-induced Serous Maculopathy:Natural Course and Treatment Effects

Purpose: To study the natural course of staphyloma-induced serous maculopathy (SISM) and the effects of treatments. Design: Retrospective case series. Participants: This retrospective analysis included 26 eyes of 20 patients with SISM and at least 12 months of follow-up. Methods: Medical records were reviewed for patient demographics, such as age, sex, spherical equivalent, best-corrected visual acuity (BCVA), type of staphyloma, and imaging characteristics. Spectralis OCT B-scans were evaluated for the presence and height of the serous retinal detachment (SRD) at each follow-up visit. An SRD episode was defined as a period with SRD in 1 patient. Main Outcome Measures: Changes in SRD height and BCVA. Results: Twenty-six eyes of 20 patients (70% female) were included. The mean age was 54 ± 11 years, and the mean spherical equivalent was −4.8 ± 3.3 diopters at baseline. The staphyloma was located inferior in 12 eyes (46%), inferonasal in 7 eyes (27%), and nasal in 7 eyes (27%). The mean follow-up duration was 73 ± 34 months. During follow-up, the SRD height fluctuated in all eyes, with a mean change of 125 ± 56 μm. The SRD disappeared completely during follow-up in 13 eyes (50%) and then reappeared in 7 eyes (35%). Resolution occurred spontaneous in 8 eyes (31%). The median time of an SRD episode was 25 (interquartile range 14–57) months. Treatment was performed in 20 eyes (77%) and led to resolution of SRD in 3 of the 15 photodynamic therapy treatments (21%), 2 of 5 (40%) anti-VEGF series, and 2 of 4 eyes (50%) treated with topical prednisolone. Best-corrected visual acuity at the final visit (0.42 ± 0.25) was not significantly different from BCVA at baseline (0.34 ± 0.27 logarithm of the minimum angle of resolution, P = 0.07), nor was BCVA change significantly different between treated eyes (n = 19) and nontreated eyes (n = 7, P = 0.3). Conclusion: Serous retinal detachment in patients with SISM fluctuated over time and resolved without treatment in 31% of the eyes. Because treatment does not change the course of BCVA, a wait-and-see policy is advocated in these patients on the exclusion of treatable causes of SRD. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.</p

Bruit des circuits de transport de gaz dans l'industrie siderurgique Inventaire des sources sonores potentielles

Available at INIST (FR), Document Supply Service, under shelf-number : 18477, issue : a.1991 n.82 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueSIGLEFRFranc

Efficacy and safety of paliperidone palmitate three-monthly formulation in East Asian patients with schizophrenia: subgroup analysis of a global, randomized, double-blind, Phase III, noninferiority study

Adam J Savitz,1 Haiyan Xu,2 Srihari Gopal,1 Isaac Nuamah,2 Paulien Ravenstijn,3 David Hough,1 Maju Mathews,4 Yu Feng,5 Lu Yu,6 Masayoshi Takahashi,7 Dennis Liu,8 Gang Wang,9 Jin-Sang Yoon,10 Jiahn-Jyh Chen11 1Department of Central Nervous System, 2Department of Clinical Biostatistics, Janssen Research &amp; Development, LLC, Titusville, NJ, USA; 3Department of Clinical Pharmacology, Janssen Research &amp; Development, Beerse, Belgium; 4Global Medical Affairs, Neurosciences, Janssen Research &amp; Development, NY, USA; 5Medical Affairs, Neurosciences, Janssen Pharmaceutical Companies of Johnson and Johnson, Singapore; 6Department of Clinical Development, Janssen Research &amp; Development, Beijing, China; 7Department of Central Nervous System, Janssen Pharmaceutical KK, Tokyo, Japan; 8Playford Community Team, Northern Adelaide Local Health Network, Adelaide, SA, Australia; 9National Clinical Research Center for Mental Disorders, Beijing Anding Hospital, Affiliated Capital University of Medical Science, Beijing, China; 10Department of Psychiatry, Chonnam National University Hospital, Gwangju, South Korea; 11Department of Geriatric Psychiatry, Taoyuan Mental Hospital, Taoyuan, Taiwan Objective: To demonstrate the efficacy and safety of paliperidone palmitate three-monthly (PP3M) formulation in an East Asian population with schizophrenia by subgroup analysis of a double-blind (DB), multicenter, noninferiority study. Patients and methods: Of 1,429 patients who entered the open-label (OL) phase, 510 were East Asian (China: 296 [58%], Japan: 175 [34%], South Korea: 19 [4%] and Taiwan: 20 [4%]). In the 17-week OL phase, patients received paliperidone palmitate once-monthly (PP1M) formulation on day 1 (150 mg eq.), day 8 (100 mg eq.) and once-monthly thereafter (50&ndash;150 mg eq., flexible). Following the OL phase, patients (n=344 East Asian) entered DB phase and were randomized (1:1) to PP1M (n=174) or PP3M (n=170). Primary efficacy endpoint was the percentage of patients who remained relapse free at the end of the 48-week DB phase, using Kaplan&ndash;Meier cumulative survival estimate. Secondary efficacy endpoints included change from DB baseline to endpoint in Positive and Negative Syndrome Scale, Clinical Global Impression Severity, Personal and Social Performance scores and symptomatic remission. Additional assessments included caregiver burden and safety. Results: A total of 285/344 (83%) randomized East Asian patients completed the DB phase. The percentage of patients who had a relapse event was similar on comparing PP3M (17 [10.2%]) to PP1M (20 [11.8%]), and also for Japan (PP3M: 9 [17.6%], PP1M: 13 [23.2%]) and China (PP3M: 6 [5.9%], PP1M: 7 [6.9%]). Mean change from baseline in secondary efficacy parameters was similar to the global population, regardless of treatment. Symptomatic remission was attained by 50% of the treated patients. Caregiver burden was significantly reduced (P&lt;0.001) following treatment with PP3M/PP1M. Frequency of treatment-emergent adverse events in PP3M group during DB phase was greater in the East Asian subgroup (81%) than the global population (68%) and was higher in Japan (92%) than China (75%). Conclusion: Results suggest that PP3M is efficacious in the East Asian subgroup. Although treatment-emergent adverse events were slightly higher in the East Asian subgroup versus the global population, no new safety signals were identified. Keywords: antipsychotic, caregiver burden, depot paliperidone palmitate, East Asia, long-acting injectable, paliperidone palmitate once-monthly, paliperidone palmitate three-monthly, schizophrenia, symptom remissio