266 research outputs found

    Defining the Conformational Features of Anchorless, Poorly Neuroinvasive Prions

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    Infectious prions cause diverse clinical signs and form an extraordinary range of structures, from amorphous aggregates to fibrils. How the conformation of a prion dictates the disease phenotype remains unclear. Mice expressing GPI-anchorless or GPI-anchored prion protein exposed to the same infectious prion develop fibrillar or nonfibrillar aggregates, respectively, and show a striking divergence in the disease pathogenesis. To better understand how a prion's physical properties govern the pathogenesis, infectious anchorless prions were passaged in mice expressing anchorless prion protein and the resulting prions were biochemically characterized. Serial passage of anchorless prions led to a significant decrease in the incubation period to terminal disease and altered the biochemical properties, consistent with a transmission barrier effect. After an intraperitoneal exposure, anchorless prions were only weakly neuroinvasive, as prion plaques rarely occurred in the brain yet were abundant in extracerebral sites such as heart and adipose tissue. Anchorless prions consistently showed very high stability in chaotropes or when heated in SDS, and were highly resistant to enzyme digestion. Consistent with the results in mice, anchorless prions from a human patient were also highly stable in chaotropes. These findings reveal that anchorless prions consist of fibrillar and highly stable conformers. The additional finding from our group and others that both anchorless and anchored prion fibrils are poorly neuroinvasive strengthens the hypothesis that a fibrillar prion structure impedes efficient CNS invasion

    In vitro comparison of the effects of rough and polished stem surface finish on pressure generation in cemented hip arthroplasty

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    Background and purpose High pressures around implants can cause bone lysis and loosening. We investigated how pressures are generated around cemented femoral stems

    Association of Vitamin D Levels With Kidney Volume in Autosomal Dominant Polycystic Kidney Disease (ADPKD)

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    Vitamin D possesses renoprotective effects beyond mineral metabolism, potentially reducing arterial blood pressure and inflammation and vitamin D enzymes (CYP24A1 and CYP27B1) as well as vitamin D receptor (VDR) contribute to its homeostasis. In the present study, we aimed to determine vitamin D association with kidney volume, blood pressure parameters and inflammatory markers in ADPKD. This cross-sectional study, conducted from August 2011 through May 2016, evaluated 25(OH)D, 1,25(OH)2D and other hormonal/biochemical serum and urinary parameters, inflammatory markers and monocyte expression of VDR, CYP24A1, CYP27B1 in 74 ADPKD patients. The height-adjusted total kidney volume (htTKV) was determined by MRI and blood pressure (BP) measured through 24-h ambulatory BP monitoring (ABPM).Vitamin D insufficiency was present in 62% of patients and CYP24A1 was overexpressed in this group, raising a hypothesis of 25(OH)D increased catabolism. Serum 25(OH)D levels and VDR expression were negatively correlated with htTKV as was VDR with IL-6, IL-10, CRP, and NFκB. A multiple linear regression analysis with htTKV as dependent variable, including hypertension, CRP, eGFR, age, time since diagnosis, VDR, and 25(OH)D adjusted for season of the year showed that only the first three parameters were independent predictors of the former. There has been no association of serum 25(OH)D and VDR expression with ABPM parameters. Present findings suggested that low levels of serum 25(OH)D and VDR expression are associated with a higher kidney volume in ADPKD patients, but do not represent independent risk factors for htTKV

    In vitro influence of stem surface finish and mantle conformity on pressure generation in cemented hip arthroplasty

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    Background and purpose Under physiological loads, debonded cemented femoral stems have been shown to move within their cement mantle and generate a fluid pump that may facilitate peri-prosthetic osteolysis by pressurizing fluid and circulating wear debris. The long-term physiological loading of rough and polished tapered stems in vitro has shown differences in performance, with greater interface pressures generated by the rough stems. In this study we investigated the individual effects of stem surface finish, degree of mantle wear, and mode of loading on the stem pump mechanism

    Clinical profile, outcomes and improvement in symptoms and productivity in rhinitic patients in Karachi, Pakistan

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    <p>Abstract</p> <p>Background</p> <p>Rhinitis can cause a heavy toll on patients because of its bothersome effects on productivity. This retrospective study was conducted to explore the clinical profile, outcomes and improvement in the symptoms and productivity resulting from treatment of allergic rhinitis in Pakistan.</p> <p>Methods</p> <p>We carried out a retrospective file review of all allergic rhinitis patients who presented to the Ear, Nose, Throat Consulting Clinic from January, 2006 to June, 2008 using a structured proforma especially designed for this purpose. Data was entered and analyzed using SPSS v. 16.0.</p> <p>Results</p> <p>The charts of 169 patients were reviewed. The mean age of the patients was 35.2 ± 9.1 years. Sixty percent patients were male. Ninety eight patients (58%) reported allergy symptoms to be present at both home and work. One hundred and two patients (60.4%) had symptoms severe enough to cause absence from work or academic activities. Up to seventy one percent patients were spending between 1000 - 3000 Pakistani Rupees (1 US$= 83.3 Pakistani rupees) on the treatment of allergic rhinitis per year. One hundred and fifty one patients (89.3%) reported an improvement in rhinitic symptoms and productivity while 18 patients (10.7%) didn't. This improvement was significantly associated with satisfaction with treatment (p < 0.001).</p> <p>Conclusion</p> <p>Allergic rhinitis, a ubiquitous disease, was seen to cause a strain on patients in the form of recurrent treatment-related expenses as well as absenteeism from work or other daily activities. Symptoms and productivity improved significantly after treatment.</p

    Congenital hip dysplasia treated by total hip arthroplasty using cementless tapered stem in patients younger than 50 years old: results after 12-years follow-up

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    Background Congenital hip dysplasia may lead to severe acetabular and femoral abnormalities that can make total hip arthroplasty a challenging procedure. We assessed a series of patients affected by developmental hip dysplasia treated with total hip arthroplasty using cementless tapered stem and here we report the outcomes at long-term follow-up. Materials and methods Twenty-eight patients (24 women and 4 men) aged between 44 and 50 years (mean 47 years) were observed. Clinical evaluation was rated with the Harris Hip Score. Radiographic evaluation consisted in standard anteroposterior and axial view radiographs of the hip. According to Crowe’s classification, 16 hips presented dysplasia grade 1, 14 grade 2, and 4 grade 3. All patients were treated with total hip arthroplasty using a cementless tapered stem (Wagner Cone Prosthesis). Six patients were operated bilaterally, with a totally of 34 hips operated. After surgery, the patients were clinically and radiographically checked at 3, 6, and 12 months and yearly thereafter until an average follow-up of 12 years (range 10–14 years). Results Average Harris Hip Score was 56 ± 9 (range 45–69) preoperatively, 90 ± 9 (range 81–100) 12 months after surgery, and 91 ± 8 (range 83–100) at last follow-up. Radiographic evaluation demonstrated excellent osteointegration of the implants. Signs of bone resorption were present in 6 hips, nevertheless no evidence of loosening was observed and none of the implants has been revised. Conclusions Even in dysplasic femur, the tapered stem allowed adequate stability and orientation of the implant. We consider tapered stem a suitable option for total hip arthroplasty in developmental hip dysplasia, also in case of young patients, thanks to the favourable long-term results

    Neutralizing and non-neutralizing monoclonal antibodies against dengue virus E protein derived from a naturally infected patient

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    <p>Abstract</p> <p>Background</p> <p>Antibodies produced in response to infection with any of the four serotypes of dengue virus generally provide homotypic immunity. However, prior infection or circulating maternal antibodies can also mediate a non-protective antibody response that can enhance the course of disease in a subsequent heterotypic infection. Naturally occurring human monoclonal antibodies can help us understand the protective and pathogenic roles of the humoral immune system in dengue virus infection.</p> <p>Results</p> <p>Epstein-Barr Virus (EBV) transformation of B cells isolated from the peripheral blood of a human subject with previous dengue infection was performed. B cell cultures were screened by ELISA for antibodies to dengue (DENV) envelope (E) protein. ELISA positive cultures were cloned by limiting dilution. Three IgG1 human monoclonal antibodies (HMAbs) were purified and their binding specificity to E protein was verified by ELISA and biolayer interferometry. Neutralization and enhancement assays were conducted in epithelial and macrophage-like cell lines, respectively. All three HMAbs bound to E from at least two of the four DENV serotypes, one of the HMAbs was neutralizing, and all were able to enhance DENV infection.</p> <p>Conclusions</p> <p>HMAbs against DENV can be successfully generated by EBV transformation of B cells from patients at least two years after naturally acquired DENV infections. These antibodies show different patterns of cross-reactivity, neutralizing, and enhancement activity.</p
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