68 research outputs found
Niemann-Pick Type C Disease Reveals a Link between Lysosomal Cholesterol and PtdIns(4,5)P2 That Regulates Neuronal Excitability.
There is increasing evidence that the lysosome is involved in the pathogenesis of a variety of neurodegenerative disorders. Thus, mechanisms that link lysosome dysfunction to the disruption of neuronal homeostasis offer opportunities to understand the molecular underpinnings of neurodegeneration and potentially identify specific therapeutic targets. Here, using a monogenic neurodegenerative disorder, NPC1 disease, we demonstrate that reduced cholesterol efflux from lysosomes aberrantly modifies neuronal firing patterns. The molecular mechanism linking alterations in lysosomal cholesterol egress to intrinsic tuning of neuronal excitability is a transcriptionally mediated upregulation of the ABCA1 transporter, whose PtdIns(4,5)P2-floppase activity decreases plasma membrane PtdIns(4,5)P2. The consequence of reduced PtdIns(4,5)P2 is a parallel decrease in a key regulator of neuronal excitability, the voltage-gated KCNQ2/3 potassium channel, which leads to hyperexcitability in NPC1 disease neurons. Thus, cholesterol efflux from lysosomes regulates PtdIns(4,5)P2 to shape the electrical and functional identity of the plasma membrane of neurons in health and disease
Analysis, Research, and Communication in Skills-Focused Courses
Since the Carnegie Report and Best Practices for Legal Education were published, a new focus has emerged on building studentsâ traditional foundational skills through increased opportunities for experiential education, including legal research and writing instruction. Although the Carnegie Report explored legal writing pedagogy in some detail, Best Practices devoted little attention to how foundational analytical, research, and writing skills are or should be taught with specificity, which provided the impetus for more extended treatment here. This section identifies some âbetter practicesâ being used and urges adoption of best practices.
In skills-focused courses, legal analysis, research, and writing should be taught as a fluid and recursive process in a client-centered context, giving students the opportunity to write, reflect, and revise. To build and retain fundamental skills, law students should have at least one significant writing experience each semester of law school. It could take the form of practice-related or âinstrumentalâ writing, âwriting to learnâ exercises, or other forms. Although the ABA requires two rigorous writing courses in the J.D. curriculum, many schools require that only one be practice-related. Some schools have addressed the inadequacy of the ABA requirements by expanding their legal writing programs from two to three or four semesters. The best practice is also to offer advanced, upper-level courses in analysis, research, and writing. For maximum effectiveness, all foundational writing, research, and analysis courses taught in the first year should be taught in small classes by full-time law teachers with practice experience and equal status
Analysis, Research, and Communication in Skills-Focused Courses
Since the Carnegie Report and Best Practices for Legal Education were published, a new focus has emerged on building studentsâ traditional foundational skills through increased opportunities for experiential education, including legal research and writing instruction. Although the Carnegie Report explored legal writing pedagogy in some detail, Best Practices devoted little attention to how foundational analytical, research, and writing skills are or should be taught with specificity, which provided the impetus for more extended treatment here. This section identifies some âbetter practicesâ being used and urges adoption of best practices.
In skills-focused courses, legal analysis, research, and writing should be taught as a fluid and recursive process in a client-centered context, giving students the opportunity to write, reflect, and revise. To build and retain fundamental skills, law students should have at least one significant writing experience each semester of law school. It could take the form of practice-related or âinstrumentalâ writing, âwriting to learnâ exercises, or other forms. Although the ABA requires two rigorous writing courses in the J.D. curriculum, many schools require that only one be practice-related. Some schools have addressed the inadequacy of the ABA requirements by expanding their legal writing programs from two to three or four semesters. The best practice is also to offer advanced, upper-level courses in analysis, research, and writing. For maximum effectiveness, all foundational writing, research, and analysis courses taught in the first year should be taught in small classes by full-time law teachers with practice experience and equal status
Implementing Effective Education in Specific Contexts
This chapter of Building on Best Practices: Transforming Legal Education in a Changing World includes contributions from many authors: Section A, The Socratic Method, is by Elizabeth G. Porter Section B, Analysis, Research, and Communication in Skills-Focused Courses, is by Ruth Anne Robbins, Amy Sloan & Kristen K. Tiscione Section C, Use of Technology in Teaching, is by Michele Pistone and Warren Binford Section D, Law Libraries and Legal Education, is by Jonathan Franklin Section E, Cross-Border Teaching and Collaboration, is by Kimberly D. Ambrose, William H. D. Fernholz, Catherine F. Klein, Dana Raigrodski, Stephen A. Rosenbaum & Leah Wortham Section F, Experiential Education, includes: Incorporating Experiential Education Throughout the Curriculum, by Deborah Maranville with Cynthia Batt, Lisa Radtke Bliss & Corolyn Wilkes Kaas Delivering Effective Education in In-House Clinics, by Lisa Radtke Bliss & Donald C. Peters Delivering Effective Education in Externship Programs, by Carolyn Wilkes Kaas with Cynthia Batt, Dena Bauman & Daniel Schaffzin, and Ensuring Effective Education in Alternative Clinical Models, by Deborah Maranvill
Present situation and new perspectives for vaccination against Neisseria meningitidis in Tuscany, Central Italy
Background. In Italy one third of bacterial meningitis are caused by Neisseria meningitidis. In March 2005, the Regional Health Authority of Tuscany included the meningococcal serogroup C conjugate (MCC) vaccine in the recommended vaccination pro- gram with a schedule of three doses to all newborns at 3, 5 and 13 months of age (from 2008 amended to a single dose at 13 months) and a single catch-up dose until age 6.
Objective. To evaluate the impact of the current national and regional immunization strategies against N. meningitidis and to highlight new perspectives for meningococcal disease prevention with the existing tetravalent meningococcal vaccine (ACWY) and with the future incoming meningococcal B vaccines.
Methods. Meningitis incidence rates in Italy and in Tuscany were calculated for the period 1994-2011 and 2005-2011,respectively. Immunization coverage with MCC vaccine in Tuscany and vacci- nation status of meningitis cases were reported. Literature review on meningococcal conjugate vaccine use and recommendation was performed.
Results. A decrease in incidence rates of meningococcal menin- gitis was observed in all age groups involved in the immunization campaign. Immunization coverage with MCC increased progres- sively year by year in Tuscany. A herd immunity effect was meas- ured in unvaccinated age groups. Since 2006 no cases of invasive meningococcal C infection in vaccinated subjects were observed in Tuscany.
Conclusions. Implementation of MCC vaccination in Tuscany was effective in preventing meningococcal C disease, confirming the effectiveness of the vaccine. A new tetravalent (ACWY) con- jugate vaccine is now available and its use in all Italian Regions should be considered.
The full article is free available on www.jpmh.or
Oral administration and intralesional injection of hyaluronic acid Versus intralesional injection alone in peyronie's disease: Results from a phase III study
Purpose: The aim of this study was to compare the effect of combined oral administration and intralesional injection of hyaluronic acid (HA) with intralesional injections alone, in patients with early onset of Peyronie's disease (PD). Materials and Methods: For this prospective, randomized phase III clinical trial we included patients with recent diagnosis of PD. Eighty-one patients were randomized into two groups. Group A consisted of 41 patients receiving oral administration of HA in combination with weekly intralesional injection of HA for 6 weeks. Group B consisted of 40 patients group B who received weekly intralesional injections of HA for 6 weeks, only. The main outcome measures were the changes from baseline to the end of therapy after three months in penile curvature (°) and changes in the international index of erectile function (IIEF-5) score and patient's global impressions of improvement (PGI-I) score. Results: Group A had a significantly larger reduction in penile curvature as compared with group B (Group A: -7.8°, Group B: -4.1° [p<0.001]). Group A also showed a higher improvement in IIEF-5 and PGI-I scores in comparison with Group B (Group A: +4 IIEF-5, Group B: +2 IIEF-5 [p<0.001]; Group A: 3 PGI-I, Group B: 1 PGI-I, [p<0.001]). At three months both groups had a significant reduction of penile curvature from baseline (p<0.001). Conclusions: Oral administration combined with intralesional treatment with HA shows greater efficacy to improve penile curvature and overall sexual satisfaction in comparison with intralesional HA treatment alone
NPC1 regulates the distribution of phosphatidylinositol 4âkinases at Golgi and lysosomal membranes
Cholesterol and phosphoinositides (PI) are two critically important lipids that are found in cellular membranes and dysregulated in many disorders. Therefore, uncovering molecular pathways connecting these essential lipids may offer new therapeutic insights. We report that loss of function of lysosomal Niemann-Pick Type C1 (NPC1) cholesterol transporter, which leads to neurodegenerative NPC disease, initiates a signaling cascade that alters the cholesterol/phosphatidylinositol 4-phosphate (PtdIns4P) countertransport cycle between Golgi-endoplasmic reticulum (ER), as well as lysosome-ER membrane contact sites (MCS). Central to these disruptions is increased recruitment of phosphatidylinositol 4-kinases-PI4KIIα and PI4KIIIÎČ-which boosts PtdIns4P metabolism at Golgi and lysosomal membranes. Aberrantly increased PtdIns4P levels elevate constitutive anterograde secretion from the Golgi complex, and mTORC1 recruitment to lysosomes. NPC1 disease mutations phenocopy the transporter loss of function and can be rescued by inhibition or knockdown of either key phosphoinositide enzymes or their recruiting partners. In summary, we show that the lysosomal NPC1 cholesterol transporter tunes the molecular content of Golgi and lysosome MCS to regulate intracellular trafficking and growth signaling in health and disease
IP3R-driven increases in mitochondrial Ca2+ promote neuronal death in NPC disease
Ca2+ is the most ubiquitous second messenger in neurons whose spatial and temporal elevations are tightly controlled to initiate and orchestrate diverse intracellular signaling cascades. Numerous neuropathologies result from mutations or alterations in Ca2+ handling proteins; thus, elucidating molecular pathways that shape Ca2+ signaling is imperative. Here, we report that loss-of-function, knockout, or neurodegenerative disease-causing mutations in the lysosomal cholesterol transporter, Niemann-Pick Type C1 (NPC1), initiate a damaging signaling cascade that alters the expression and nanoscale distribution of IP3R type 1 (IP3R1) in endoplasmic reticulum membranes. These alterations detrimentally increase Gq-protein coupled receptor-stimulated Ca2+ release and spontaneous IP3R1 Ca2+ activity, leading to mitochondrial Ca2+ cytotoxicity. Mechanistically, we find that SREBP-dependent increases in Presenilin 1 (PS1) underlie functional and expressional changes in IP3R1. Accordingly, expression of PS1 mutants recapitulate, while PS1 knockout abrogates Ca2+ phenotypes. These data present a signaling axis that links the NPC1 lysosomal cholesterol transporter to the damaging redistribution and activity of IP3R1 that precipitates cell death in NPC1 disease and suggests that NPC1 is a nanostructural disease
Antimicrobial prophylaxis for transrectal ultrasound-guided prostate biopsy: fosfomycin trometamol, an attractive alternative
OBJECTIVE:
To compare fosfomycin trometamol (FT) and ciprofloxacin (CIP) for antibiotic prophylaxis in transrectal prostate biopsy (TR-PB).
PATIENTS AND METHODS:
Data for 1109 patients (mean age 66.7 \ub1 8.45) who underwent TR-PB between March to September 2015 in seven Italian urological institutions were retrospectively reviewed, of which 632 received FT (Group 1) and 477 received CIP (Group 2) for prophylaxis. We reviewed all urine culture results obtained after the procedure, all adverse drug reactions (ADRs) related to the drug and all febrile and/or symptomatic urinary tract infections (UTIs) occurring within 1 month after TR-PB. The rate of symptomatic UTIs and the rate of ADRs were considered the main outcome measures.
RESULTS:
In the total study population, 72/1109 (6.5 %) patients experienced symptomatic UTIs and among these 11 (0.9 % of total) had urosepsis. Out of 72, 53 (73.6 %) symptomatic UTIs were caused by fluoroquinolone-resistant strains. Out of 632, 10 (1.6 %) patients in Group 1 and 62/477 (12.9 %) patients in Group 2 had symptomatic UTIs (p < 0.001); in particular, 2/632 (0.3 %) patients in Group 1 and 9/477 (1.8 %) patients in Group 2 had urosepsis (p < 0.001). No differences were reported in terms of adverse events (0.6 vs 0.4 %; p = 0.70). A Charlson comorbidity index 641 and type of antimicrobial prophylaxis (FT) were found to be associated with a lower probability of symptomatic UTIs in the multivariate model.
CONCLUSIONS:
Antibiotic prophylaxis with FT for TR-PB had a lower rate of adverse events and a lower rate of symptomatic UTIs as compared with CIP. Fosfomycin trometamol appears as an attractive alternative prophylactic regimen in prostate biopsies
Has VZV epidemiology changed in Italy? Results of a seroprevalence study
The aim of the study was to evaluate if and how varicella prevalence has changed in Italy. In particular a seroprevalence study was performed, comparing it to similar surveys conducted in pre-immunization era. During 2013â2014, sera obtained from blood samples taken for diagnostic purposes or routine investigations were collected in collaboration with at least one laboratory/center for each region, following the approval of the Ethics Committee. Data were stratified by sex and age. All samples were processed in a national reference laboratory by an immunoassay with high sensitivity and specificity. Statutory notifications, national hospital discharge database and mortality data related to VZV infection were analyzed as well. A total of 3707 sera were collected and tested. In the studied period both incidence and hospitalization rates decreased and about 5 deaths per year have been registered. The seroprevalence decreased in the first year of life in subjects passively protected by their mother, followed by an increase in the following age classes. The overall antibody prevalence was 84%. The comparison with surveys conducted with the same methodology in 1996â1997 and 2003â2004 showed significant differences in age groups 1â19 y. The study confirms that in Italy VZV infection typically occurs in children. The impact of varicella on Italian population is changing. The comparison between studies performed in different periods shows a significant increase of seropositivity in age class 1â4 years, expression of vaccine interventions already adopted in some regions
- âŠ