ABSTRACT
The discovery of a novel sphingolipid subclass, the (1-deoxy)sphingolipids, which lack the 1-hydroxy group, attracted considerable attention in the last decade, mainly due to their involvement in disease. They differed in their physico-chemical properties from the canonical (or 1-hydroxy) sphingolipids and they were more toxic when accumulated in cells, inducing neurodegeneration and other dysfunctions. (1-Deoxy)ceramides, (1-deoxy)dihydroceramides, and (1- deoxymethyl)dihydroceramides, the latter two containing a saturated sphingoid chain, have been studied in this work using differential scanning calorimetry, confocal fluorescence and atomic force microscopy, to evaluate their behavior in bilayers composed of mixtures of three or four lipids. When compared to canonical ceramides (Cer), a C16:0 (1-deoxy)Cer shows a lower miscibility in mixtures of the kind C16:0 sphingomyelin/cholesterol/XCer, where XCer is any (1-deoxy)ceramide, giving rise to the coexistence of a liquid-ordered phase and a gel phase. The latter resembles, in terms of thermotropic behavior and nanomechanical resistance, the gel phase of the C16:0 sphingomyelin/cholesterol/C16:0 Cer mixture [Busto et al., Biophys. J. 2014, 106, 621-630]. Differences are seen between the various C16:0 XCer under study in terms of nanomechanical resistance, bilayer thickness and bilayer topography. When examined in a more fluid environment (bilayers based on C24:1 SM), segregated gel phases are still present. Probably related to such lateral separation, XCer preserve the capacity for membrane permeation, but their effects are significantly lower than those of canonical ceramides. Moreover, C24:1 XCer show significantly lower membrane permeation capacity than their C16:0 counterparts. The above data may be relevant in the pathogenesis of certain sphingolipid-related diseases, including certain neuropathies, diabetes, and glycogen storage diseases.
ABSTRACT
Antecedentes y objetivo: Las recomendaciones sobre el manejo general del glaucoma y el uso de cirugías mínimamente-invasivas y microincisionales en fases tempranas son limitadas. El objetivo de este estudio fue establecer un consenso sobre el manejo del glaucoma, centrándose en el implante XEN 45 (AbbVie Inc., North Chicago, IL, EE. UU.). Métodos: Se utilizó un método Delphi. El comité científico dirigió el estudio, identificó el panel de expertos y participó en la elaboración del cuestionario. Se invitó a 51 expertos a completar, en una escala Likert de 9 puntos, un cuestionario de 89 ítems que cubría 3 bloques temáticos. Se realizaron 2 rondas Delphi. Se logró consenso si≥66,6% de los expertos llegaron a un acuerdo o desacuerdo. Resultados: Los panelistas acordaron 84 ítems relacionados con la calidad de vida, el algoritmo terapéutico y el perfil del paciente, y el manejo quirúrgico pre y postoperatorio. Los panelistas consideraron el implante XEN idóneo para tratar el glaucoma en diferentes etapas y para diferentes perfiles de pacientes: pacientes jóvenes/ancianos/con comorbilidades-significativas, glaucoma-miópico, pacientes con fracaso quirúrgico previo y con postoperatorio complejo. El implante XEN se consideró un paso terapéutico previo a la cirugía filtrante clásica y una posible primera opción quirúrgica en pacientes ancianos con comorbilidades y presión intraocular descontrolada. El implante XEN permite al paciente retomar sus actividades diarias más rápidamente que las cirugías filtrantes convencionales y reducir y/o eliminar los tratamientos tópicos. Conclusiones: Este consenso según la metodología Delphi proporcionó una serie de recomendaciones generales para el tratamiento del glaucoma, incluidas aquellas relacionadas con la calidad de vida del paciente, el algoritmo terapéutico y el perfil del paciente, y específicas con respecto al uso del implante XEN.(AU)
Background and objective: Recommendations on general glaucoma management and the use of early minimally invasive and microincisional surgeries are limited. This study aimed to establish consensus regarding glaucoma management, focusing on the XEN-45 gel stent implant. Methods: A Delphi consensus-driven process was used. The scientific committee led the study, identified the expert panel, and participated in elaborating the questionnaire. Fifty-one panelists were invited to complete, on a nine-point Likert scale, an 89-item questionnaire covering three topic blocks. Two Delphi rounds were performed. Consensus was achieved if ≥66.6% of panelists reached agreement or disagreement. Results: Panelists agreed on 84 items related to the patients quality of life, the therapeutic algorithm and patient profile, and surgical and pre- and post-operative management. Panelists agreed on the suitability of XEN stent implants to treat glaucoma at different stages and for different patient profiles: young patients, elderly or with significant comorbidities, and with myopic glaucoma, patients who failed previous surgeries, and with previous poor post-operative experience. XEN surgery was considered a therapeutic step prior to classic filtering surgery and a possible first surgical option in elderly patients with comorbidities and uncontrolled intraocular pressure. XEN surgery allows the patient to return to routine daily activities faster than conventional filtering surgeries and to reduce and/or eliminate topical treatments. Conclusions: This Delphi-driven consensus resulted in a series of general recommendations for glaucoma management, including those related to patient quality of life, therapeutic algorithm, and patient profile, and specific ones regarding the use of XEN stent gel surgery.(AU)
Subject(s)
Humans , Male , Female , Delphi Technique , Glaucoma/surgery , Minimally Invasive Surgical Procedures , Algorithms , OphthalmologyABSTRACT
BACKGROUND AND OBJECTIVE: Recommendations on general glaucoma management and the use of early minimally invasive and microincisional surgeries are limited. This study aimed to establish consensus regarding glaucoma management, focusing on the XEN-45 gel stent implant. METHODS: A Delphi consensus-driven process was used. The scientific committee led the study, identified the expert panel, and participated in elaborating the questionnaire. Fifty-one panelists were invited to complete, on a nine-point Likert scale, an 89-item questionnaire covering three topic blocks. Two Delphi rounds were performed. Consensus was achieved if ≥66.6% of panelists reached agreement or disagreement. RESULTS: Panelists agreed on 84 items related to the patients' quality of life, the therapeutic algorithm and patient profile, and surgical and pre- and post-operative management. Panelists agreed on the suitability of XEN stent implants to treat glaucoma at different stages and for different patient profiles: young patients, elderly or with significant comorbidities, and with myopic glaucoma, patients who failed previous surgeries, and with previous poor post-operative experience. XEN surgery was considered a therapeutic step prior to classic filtering surgery and a possible first surgical option in elderly patients with comorbidities and uncontrolled intraocular pressure. XEN surgery allows the patient to return to routine daily activities faster than conventional filtering surgeries and to reduce and/or eliminate topical treatments. CONCLUSIONS: This Delphi-driven consensus resulted in a series of general recommendations for glaucoma management, including those related to patient quality of life, therapeutic algorithm, and patient profile, and specific ones regarding the use of XEN stent gel surgery.
Subject(s)
Glaucoma Drainage Implants , Glaucoma , Humans , Aged , Delphi Technique , Quality of Life , Treatment Outcome , Glaucoma/surgeryABSTRACT
BACKGROUND: Oral cancer represents the sixth most common cancer in the world and is associated with 40-50% survival at 5 years. Within oral malignancies, oral squamous cell carcinoma (OSCC) is commonly preceded by potentially malignant lesions, which, according to histopathological criteria, are referred to as oral dysplasia and their diagnosis are associated with higher rates of malignant transformation towards cancer. We recently reported that aberrant activation of the Wnt/ßcatenin pathway is due to overexpression of Wnt ligands in oral dysplasia. However, the expression of other regulators of this pathway, namely components of the ß-catenin destruction complex has not been explored in oral dysplasia. MATERIAL AND METHODS: Using immunohistochemical analyses, we evaluated nuclear expression of ßcatenin and its association with Wnt3a and Wnt5a. Likewise, components of the ß-catenin destruction complex, including Adenomatous Polyposis Coli (APC), Axin and Glycogen Synthase Kinase 3 beta (GSK-3ß) were also evaluated in oral dysplasia and OSCC biopsies. RESULTS: We found that moderate and severe dysplasia samples, which harbored increased expression of nuclear ßcatenin, depicted augmented cytoplasmic expression of GSK3ß, Axin and APC, in comparison with OSCC samples. Also, GSK-3ß was found nuclear in mild dysplasia and OSCC samples, when compared with other study samples. CONCLUSIONS: Cytoplasmic levels of components of the ß-catenin destruction complex are increased in oral dysplasia and might be responsible of augmented nuclear ßcatenin.
Subject(s)
Carcinoma, Squamous Cell , Mouth Neoplasms , Axin Signaling Complex , Glycogen Synthase Kinase 3 beta , Humans , Squamous Cell Carcinoma of Head and Neck , Wnt Signaling Pathway , beta CateninABSTRACT
Staphylococcus epidermidis has emerged as one of the major nosocomial pathogens associated with infections of implanted medical devices. The most important factor in the pathogenesis of these infections is the formation of bacterial biofilms. Bacteria grown in biofilms are more resistant to antibiotics and to the immune defence system than planktonic bacteria. In these infections, the antimicrobial therapy usually fails and the removal of the biofilm-coated implanted device is the only effective solution. In this study, three proteomic approaches were performed to investigate membrane proteins associated to biofilm formation: (i) sample fractionation by gel electrophoresis, followed by isotopic labelling and LC-MS/MS analysis, (ii) in-solution sample preparation, followed by isotopic labelling and LC-MS/MS analysis and (iii) in-solution sample preparation and label-free LC-MS/MS analysis. We found that the commensal strain S. epidermidis CECT 231 grown in biofilms expressed higher levels of five membrane and membrane-associated proteins involved in pathogenesis: accumulation-associated protein, staphylococcal secretory antigen, signal transduction protein TRAP, ribonuclease Y and phenol soluble modulin beta 1 when compared with bacteria grown under planktonic conditions. These results indicate that a commensal strain can acquire a pathogenic phenotype depending on the mode of growth.
Subject(s)
Bacterial Outer Membrane Proteins/metabolism , Biofilms , Staphylococcus epidermidis/physiology , Bacterial Outer Membrane Proteins/genetics , Bacterial Proteins/metabolism , Gene Expression , Gene Expression Regulation, Bacterial , Tandem Mass Spectrometry , Up-Regulation , Virulence , Virulence Factors/genetics , Virulence Factors/metabolismABSTRACT
Organochlorine pesticides and polychlorinated biphenyls (PCBs) are consistently found in human tissues. Serum levels of organochlorine compounds (OC) in pregnant women in particular have raised concern about possible harm to humans in the early phases of physical and behavioural development. The objective of the present study was to evaluate the association between concentration of OCs in serum of two cohorts of pregnant women from Gipuzkoa and Sabadell in Spain and socioeconomic, reproductive and dietary variables. Concentration of polychlorinated biphenyls (PCBs: 28, 52, 101, 118, 138, 153 and 180), hexachlorobenzene (HCB), beta and gamma-hexachlorocyclohexane (ß-HCH and γ-HCH), heptachlor epoxide, dichlorodiphenyl dichloroethylene (p,p'-DDE) and dichlorodiphenyl trichloroethane (p,p'-DDT) were measured in the serum of 1259 pregnant women. Associations between OCs and potential predictor variables were assessed using linear regression models adjusted for potential confounders. The compounds most commonly found in the serum were p,p'-DDE (99% of the samples) and PCB-153 (95% of the samples). Geometric means of serum concentrations (ng g⻹ lipid) of organochlorine pesticides were 110.0, 19.1, and 33.5 for p,p'-DDE, ß-HCH, and HCB respectively, while the geometric means of PCBs were 21.8, 38.9 and 26.9 for PCB 138, 153, and 180 respectively. The levels of all OCs increased with age. BMI was positively associated with the concentration of organochlorine pesticides but inversely related to PCB concentrations. The serum levels of OCs fell only after a cumulative period of breastfeeding of over a year. Levels of PCBs were related to fish intake, but in general dietary factors did not improve the explained variability of the concentrations of OCs. Overall, the levels of OCs found in the study are at the lower end of the range reported in Spain and other countries.
Subject(s)
Diet/statistics & numerical data , Environmental Pollutants/blood , Hydrocarbons, Chlorinated/blood , Maternal Exposure/statistics & numerical data , Pesticides/blood , Pregnancy/blood , Adult , Demography , Dichlorodiphenyl Dichloroethylene/blood , Female , Heptachlor/blood , Hexachlorobenzene/blood , Humans , Polychlorinated Biphenyls/blood , Socioeconomic Factors , Spain , Surveys and QuestionnairesABSTRACT
PURPOSE: This review aims to provide guidance in managing glaucoma patients more effectively. It focuses on the importance of detecting progression and measuring its rate within the management of primary open-angle glaucoma today. Recent findings strongly indicate that continued monitoring of visual fields (VFs) and reassessment of target intraocular pressures (IOPs) depending on VF progression rates are mandatory in the management of glaucoma. METHODS: Data on glaucoma progression from older as well as most recent literature findings are summarized in this article. In addition, the article elaborates on the scientific content from a series of lectures given by experts in the field during several international symposia on 'rate of progression' in 2008. RESULTS: This review summarizes key findings on the natural history of glaucoma and known factors for disease progression. It highlights the visual function changes observed as glaucoma progresses and discusses disease impact on patients' quality of life. Findings support the need to obtain information on rate of progression and its importance for clinical management. Practical ways to measure rate of progression are given by new software options to help measure major parameters. Finally, on the basis of a patient's individual rate of progression therapeutic options are assessed, such as maximum medical therapy with fixed combinations. CONCLUSIONS: Estimating a patient's individual rate of VF progression by using newly developed analyses will be helpful to forecast the potential future development of the glaucoma. An individualized treatment approach then requires that in patients in whom the risk of becoming visually impaired or blind during their lifetime is higher, a more intensive medical IOP-lowering therapy such as fixed combinations can be considered as treatment option.
Subject(s)
Glaucoma/diagnosis , Disease Progression , Glaucoma/physiopathology , Humans , Intraocular Pressure , Quality of Life , Risk Factors , Visual Field Tests , Visual Fields/physiologyABSTRACT
Levels of PCDD/Fs and dioxin-like PCBs were measured in 16 pooled samples of serum from a total of 322 adults in the general population, to coincide with the start-up of a new municipal solid urban waste treatment plant in Biscay, Basque Country (Spain). Two hundred and eighty-three individual serum samples were also obtained, in which the most common PCBs (28, 52, 101, 118, 138, 153 and 180) were quantified. The samples were taken from four geographical zones: two from the metropolitan area of Bilbao, located less than 2 km from the plant and with high traffic density (Zones E1 and E2), a third located 5 km from the plant in an urban area of Bilbao, also with high traffic density (Zone C1) and the fourth located 20 km from the plant, in a municipality with minimal industrial activity and low traffic density (Zone C2), the latter two being out of the path of the prevailing winds. The median levels of dioxins+furans were similar by zone: E1=24.3, E2=27.3, C1=21.3, C2=18.8 pg g(-1) lipid (p=0.362); by sex: 20.2 vs. 22.6 pg g(-1) lipid in men and women (p=0.328); and by age: 20.8 vs. 21.3 pg g(-1) lipid in subjects aged 20-44 and 45-69 (p=0.505). No detectable levels of PCBs 52 and 101 were found. Significant differences by zone were found only for PCB 180 (p=0.041), with higher values in Zone C2, the zone with the lowest presumed contamination levels. Dioxin-like PCBs (p<0.001) and the most common PCBs (138, 153, 180) (p<0.001) were both statistically associated with age, higher values being found in the 45-69 age group.
Subject(s)
Benzofurans/blood , Environmental Exposure , Environmental Pollutants/blood , Polychlorinated Biphenyls/blood , Polychlorinated Dibenzodioxins/analogs & derivatives , Adult , Aged , Benzofurans/isolation & purification , Chemical Fractionation , Demography , Dibenzofurans, Polychlorinated , Environmental Pollutants/isolation & purification , Female , Humans , Male , Middle Aged , Polychlorinated Biphenyls/isolation & purification , Polychlorinated Dibenzodioxins/blood , Polychlorinated Dibenzodioxins/isolation & purification , Refuse Disposal , Spain , Urban PopulationSubject(s)
Diagnostic Techniques, Ophthalmological , Lysosomal Storage Diseases/diagnosis , Microscopy/methods , Diagnostic Techniques, Ophthalmological/instrumentation , Fabry Disease/blood , Fabry Disease/diagnosis , Germany/epidemiology , Humans , Lysosomal Storage Diseases/blood , Lysosomal Storage Diseases/epidemiology , Mass Screening , Mucopolysaccharidosis I/blood , Mucopolysaccharidosis I/diagnosis , SpainABSTRACT
Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (C for cellular), to a toxic and infectious form, PrP(Sc) (Sc for scrapie). None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrP(Sc), such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrP(Sc) scrapie strain 139A. These methodological refinements led to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer immunoglobulin (Ig) A and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (log-rank test P<0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrP(Sc) infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route.
Subject(s)
Antibodies/blood , Prions/immunology , Scrapie/prevention & control , Vaccines/administration & dosage , Administration, Oral , Animals , Blotting, Western , Brain/pathology , Enzyme-Linked Immunosorbent Assay , Immunoglobulin A/blood , Immunoglobulin A/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Mice , Scrapie/pathology , Vaccination/methods , Vaccines/immunology , Vaccines, Synthetic/administration & dosage , Vaccines, Synthetic/immunologyABSTRACT
To date, there has been a lack of evidence-based guidance on the frequency of visual field examinations required to identify clinically meaningful rates of change in glaucoma. The objective of this perspective is to provide practical recommendations for this purpose. The primary emphasis is on the period of time and number of examinations required to measure various rates of change in mean deviation (MD) with adequate statistical power. Empirical data were used to obtain variability estimates of MD while statistical modelling techniques derived the required time periods to detect change with various degrees of visual field variability. We provide the frequency of examinations per year required to detect different amounts of change in 2, 3 and 5 years. For instance, three examinations per year are required to identify an overall change in MD of 4 dB over 2 years in a patient with average visual field variability. Recommendations on other issues such as examination type, strategy and quality are also made.
Subject(s)
Glaucoma/physiopathology , Visual Fields , Cataract/complications , Diagnostic Techniques, Ophthalmological , Disease Progression , Evidence-Based Medicine , Glaucoma/complications , Humans , Macular Degeneration/complications , Visual Field Tests/methodsABSTRACT
INTRODUCTION: No studies have yet been performed to evaluate the prevalence of gastrointestinal (GI) complications in solid organ transplant recipients in Spain. MATERIALS AND METHODS: An observational, cross-sectional study to evaluate the prevalence and management of GI complications in transplanted patients was conducted via a written questionnaire given to doctors at their practice. RESULTS: A total of 58 lung transplant recipients were included. Their mean age was 52.6 +/- 10.8 years; 65% of the patients were men; and the mean time since the transplant was 2.1 +/- 2.3 years. GI complications were seen in 48.6% of the lung transplant patients. Regarding the management, the most frequently used measure was the prescription of gastric protectors (70.5%). In seven patients, the immunosuppressive treatment was also modified (reduced, discontinued temporarily, or discontinued permanently); however, the figure is so low that no conclusions can be drawn from this result. CONCLUSIONS: The prevalence of GI complications in lung transplant was over 50%, and these complications affected patients' daily activities in most cases. In lung transplant recipients, there was a higher prevalence of nausea and abdominal pain and a lower of diarrhea and dyspepsia than what was observed in other type of transplant recipients.
Subject(s)
Gastrointestinal Diseases/epidemiology , Lung Transplantation/adverse effects , Postoperative Complications/epidemiology , Adolescent , Adult , Aged , Cadaver , Child , Cross-Sectional Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Prevalence , Retrospective Studies , Spain , Surveys and Questionnaires , Tissue DonorsABSTRACT
Prion diseases are a unique category of illness, affecting both animals and humans, where the underlying pathogenesis is related to a conformation change of the cellular form of a normal, self-protein called a prion protein (PrP(c) [C for cellular]) to a pathological and infectious conformation known as scrapie form (PrPsc [Sc for scrapie]). Currently, all prion diseases are without effective treatment and are universally fatal. The emergence of bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease has highlighted the need to develop possible therapies. In Alzheimer's disease (AD), which has similarities to prion diseases, both passive and active immunisation have been shown to be highly effective at preventing disease and cognitive deficits in model animals. In a human trial of active vaccination in AD, despite indications of cognitive benefits in patients with an adequate humoral response, 6% of patients developed significant complications related to excessive cell-mediated immunity. This experience highlights that immunotherapies designed to be directed against a self-antigen have to finely balance an effective humoral immune response with potential autoimmune toxicity. Many prion diseases have the gut as a portal of infectious agent entry. This makes mucosal immunisation a potentially very attractive method to partially or completely prevent prion entry across the gut barrier and to also produce a modulated immune response that is unlikely to be associated with any toxicity. The authors' recent results using an attenuated Salmonella vaccine strain expressing the prion protein show that mucosal vaccination can partially protect against prion infection from a peripheral source, suggesting the feasibility of this approach.
Subject(s)
Immunity, Mucosal , Prion Diseases/veterinary , Vaccination/veterinary , Animals , Cattle , Creutzfeldt-Jakob Syndrome/prevention & control , Creutzfeldt-Jakob Syndrome/transmission , Creutzfeldt-Jakob Syndrome/veterinary , Encephalopathy, Bovine Spongiform/prevention & control , Encephalopathy, Bovine Spongiform/transmission , Humans , Prion Diseases/prevention & control , Prion Diseases/transmission , Scrapie/prevention & control , Scrapie/transmission , ZoonosesSubject(s)
Glaucoma/diagnosis , Glaucoma/physiopathology , Humans , Intraocular Pressure , Risk AssessmentABSTRACT
No disponible
Subject(s)
Humans , Glaucoma/diagnosis , Risk Adjustment/methods , Risk Factors , Intraocular PressureABSTRACT
PURPOSE: To evaluate the efficacy and safety of fixed-combination brimonidine tartrate 0.2%/timolol 0.5% ophthalmic solution dosed BID and demonstrate non-inferiority to concomitant use of brimonidine tartrate 0.2% BID and timolol 0.5% BID in glaucoma and ocular hypertension patients with intraocular pressure (IOP) uncontrolled on monotherapy. METHODS: Randomized, multicenter, double-masked, parallel-group study involving 371 patients with inadequate IOP control (IOP from 22 to 34 mmHg) after > or =3 weeks of run-in on any monotherapy. Patients were treated with fixed-combination brimonidine/timolol BID (fixed-combination group, n = 188) or concomitant brimonidine BID and timolol BID (concomitant group, n = 183). IOP was assessed pre-dose and 2 hours after morning dosing at weeks 2, 6, and 12. RESULTS: A total of 355 patients (96%) completed the study. Patient demographics, run-in monotherapy, and baseline mean IOP on monotherapy were comparable between treatment groups. During follow-up, the mean reduction from baseline IOP was significant (p < 0.001) at all time points and ranged from 4.4 to 5.3 mmHg in each group. Brimonidine/timolol fixed combination was as effective as concomitant therapy with respect to mean IOP and mean change from baseline IOP at all time points and visits. Between-group differences were < or =0.35 mmHg for mean IOP and < or 0.30 mmHg for mean change from baseline IOP; none were significant. No unexpected side effects were associated with the fixed combination. Both treatments were well tolerated with no difference in adverse events between groups. CONCLUSIONS: Brimonidine/timolol fixed-combination therapy is as safe and effective as concomitant treatment with the individual components. Its simplified dosing regimen has the potential to improve compliance.
Subject(s)
Antihypertensive Agents/therapeutic use , Glaucoma/drug therapy , Quinoxalines/therapeutic use , Timolol/therapeutic use , Antihypertensive Agents/adverse effects , Brimonidine Tartrate , Double-Blind Method , Drug Combinations , Drug Therapy, Combination , Female , Follow-Up Studies , Humans , Intraocular Pressure/drug effects , Male , Middle Aged , Ocular Hypertension/drug therapy , Ophthalmic Solutions/adverse effects , Ophthalmic Solutions/therapeutic use , Patient Compliance , Quinoxalines/adverse effects , Timolol/adverse effects , Treatment OutcomeABSTRACT
In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP(C) (prion protein cellular), to a toxic and infectious form, PrP(Sc) (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk.
Subject(s)
Immunotherapy , Mucous Membrane/immunology , PrPC Proteins/immunology , Prion Diseases/immunology , Prion Diseases/prevention & control , Vaccination , Administration, Oral , Analysis of Variance , Animals , Blotting, Western/methods , Female , Gene Expression Regulation, Viral/physiology , Immunoglobulin A/metabolism , Immunoglobulin G/metabolism , Mice , PrPC Proteins/chemistry , Prion Diseases/virology , Protein Conformation , Time FactorsABSTRACT
No disponible
Subject(s)
Humans , Postoperative Care/methods , Lung Transplantation/methods , Preoperative Care/methods , Physician's Role , Graft Rejection/epidemiology , Patient SelectionABSTRACT
PURPOSE: To evaluate the efficacy and safety of fixed-combination brimonidine tartrate 0.2%/timolol 0.5% ophthalmic solution dosed BID and demonstrate non-inferiority to concomitant use of brimonidine tartrate 0.2% BID and timolol 0.5% BID in glaucoma and ocular hypertension patients with intraocular pressure (IOP) uncontrolled on monotherapy. METHODS: Randomized, multicenter, double-masked, parallel-group study involving 371 patients with inadequate IOP control (IOP from 22 to 34 mmHg) after >=3 weeks of run-in on any monotherapy. Patients were treated with fixed-combination brimonidine/timolol BID (fixed-combination group, n=188) or concomitant brimonidine BID and timolol BID (concomitant group, n=183). IOP was assessed pre-dose and 2 hours after morning dosing at weeks 2, 6, and 12. RESULTS: A total of 355 patients (96%) completed the study. Patient demographics, run-in monotherapy, and baseline mean IOP on monotherapy were comparable between treatment groups. During follow-up, the mean reduction from baseline IOP was significant (p<0.001) at all time points and ranged from 4.4 to 5.3 mmHg in each group. Brimonidine/timolol fixed combination was as effective as concomitant therapy with respect to mean IOP and mean change from baseline IOP at all time points and visits. Between-group differences were <=0.35 mmHg for mean IOP and <=0.30 mmHg for mean change from baseline IOP; none were significant. No unexpected side effects were associated with the fixed combination. Both treatments were well tolerated with no difference in adverse events between groups. CONCLUSIONS: Brimonidine/timolol fixed-combination therapy is as safe and effective as concomitant treatment with the individual components. Its simplified dosing regimen has the potential to improve compliance. (Eur J Ophthalmol 2005; 15: 581-90).
ABSTRACT
Bacillus cereus sphingomyelinase activity was assayed on large unilamellar vesicles composed of sphingomyelin (SM)/cholesterol (Ch) mixtures at varying proportions. Natural (egg) SM was used with a gel-fluid transition temperature at ca. 40 degrees C. When the enzyme was assayed at 37 degrees C, the activity on pure SM was exceedingly low, but a small increase was observed as soon as some Ch was added, and a large enhancement of activity occurred with Ch proportions above 25 mol%. The data were interpreted in terms of sphingomyelinase activity being higher in the cholesterol-induced liquid-ordered phase than in the gel phase. The abrupt increase in activity above 25 mol% Ch would occur as a result of a change in domain connectivity, when the Ch-rich liquid-ordered domains coalesced. In equimolar SM/Ch mixtures, that were in the liquid-ordered state in a wide range of temperatures, sphingomyelinase activity was virtually constant in the 30-70 degrees C range. The results demonstrate that at the mammalian and bird physiological temperatures Ch modulates sphingomyelinase activity, and that this can occur precisely because most SM have a gel-fluid transition temperature above the physiological temperature range. In addition, Ch activation of sphingomyelinase and the strong affinity of Ch for SM allow the rapid, localised and self-contained production of the metabolic signal ceramide in specific microdomains (rafts).