Brain-reactive autoantibodies prevalent in human sera increase intraneuronal amyloid-β(1-42) deposition

Previous studies have reported immunoglobulin-positive neurons in Alzheimer's disease (AD) brains, an observation indicative of blood-brain barrier (BBB) breakdown. Recently, we demonstrated the nearly ubiquitous presence of brain-reactive autoantibodies in human sera. The significance of these observations to AD pathology is unknown. Here, we show that IgG-immunopositive neurons are abundant in brain regions exhibiting AD pathology, including intraneuronal amyloid-β(42) (Aβ(42)) and amyloid plaques, and confirm by western analysis that brain-reactive autoantibodies are nearly ubiquitous in human serum. To investigate a possible interrelationship between neuronal antibody binding and Aβ pathology, we tested the effects of human serum autoantibodies on the intraneuronal deposition of soluble Aβ(42) peptide in adult mouse neurons in vitro (organotypic brain slice cultures). Binding of human autoantibodies to mouse neurons dramatically increased the rate and extent of intraneuronal Aβ(42) accumulation in the mouse cerebral cortex and hippocampus. Additionally, individual sera exhibited variable potency related to their capacity to enhance intraneuronal Aβ(42) peptide accumulation and immunolabel neurons in AD brain sections. Replacement of human sera with antibodies targeting abundant neuronal surface proteins resulted in a comparable enhancement of Aβ(42) accumulation in mouse neurons. Overall, results suggest that brain-reactive autoantibodies are ubiquitous in the blood and that a defective BBB allows these antibodies to access the brain interstitium, bind to neuronal surfaces and enhance intraneuronal deposition of Aβ(42) in AD brains. Thus, in the context of BBB compromise, brain-reactive autoantibodies may be an important risk factor for the initiation and/or progression of AD as well as other neurodegenerative diseases.     

Cytoprotective activity of a trans-chalcone against hydrogen peroxide induced toxicity in hepatocellular carcinoma (HepG2) cells

Dietary flavonoids have attracted attention as chemopreventive agents. Chalcones are abundantly present in nature starting from ferns to higher plants. Chemically 1,3-diphenyl-2-propen-1-ones, these are often cytotoxic in vitro. The cellular defense system (including glutathione, glutathione-related enzymes, and antioxidant and redox enzymes) plays a crucial role in cell survival and growth in aerobic organisms. In the present study, we aimed to evaluate the modulatory effect of trans-chalcone on protection from oxidative stress caused by hydrogen peroxide (H2O2) in hepatocellular carcinoma (HepG2) cells. Cell growth was evaluated by the 3-(4,5-dimethyl thiazol-2- yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Sub-toxic concentrations of compound (20 uM) increased cell survival and a decreased lipid peroxidation. The drug also decreased the H2O2 induction of glutathione related enzymes. Our results support the efficacy of trans-chalcone in offering protection against oxidative stress.     

Topical antiglaucoma medications and lacrimal drainage system obstruction

PURPOSE: To evaluate the effect of topical antiglaucoma medications on the lacrimal drainage system. METHODS: In a prospective controlled blind observational case series, 627 eyes of 384 patients (219 males, 165 females) were screened. Data recording (demographics and history taking), allocation in case (on topical antiglaucoma medications) and control (no glaucoma) groups, and examinations (eye examination and dye disappearance test) were performed by a senior ophthalmology resident. Exclusion criteria were epiphora prior to onset of treatment with topical antiglaucoma medication (only for case group), history of long-term use of topical medications (other than antiglaucoma medications in the case group), and previous ocular and periocular disorders. Diagnostic probing and irrigation of the lacrimal drainage system were performed by an oculoplastic surgeon masked to a patient's status as case or control. RESULTS: After exclusion, there were 130 eyes from 98 patients and 280 eyes from 178 patients in the case and control groups, respectively. Case and control groups were matched. There was significantly more lacrimal drainage system obstruction in the case group (26 of 130, 20%) than in the control group (24 of 280, 8.57%) (p = 0.002). Upper lacrimal drainage system obstruction was significantly more in the case group (p = 0.018). Increasing age was associated with significantly more obstruction in the control group only (p = 0.029). Statistically significant obstruction was found in the patients taking timolol + dorzolamide (p = 0.021) and timolol + dorzolamide + pilocarpine (p = 0.017) with a duration of 2 weeks to 156 months. CONCLUSION: Patients taking a combination of topical antiglaucoma medications showed significantly increased risk of developing lacrimal drainage system obstruction. Both total and upper obstruction was significantly more frequent in patients on topical antiglaucoma medications.     

Childhood onset in familial prion disease with a novel mutation in the PRNP gene

BACKGROUND: Up to 15% of cases of prion diseases are due to the autosomal dominant inheritance of coding PRNP mutations. OBJECTIVE: To describe the unique clinical and genetic findings in a family of East Indian origin with autosomal dominant inheritance of a novel PRNP mutation. DESIGN: Detailed neurological examination and sequencing analysis of the MAPT and PRNP genes. SETTING: Toronto Western Hospital, Toronto, Ontario. PATIENTS: Five available members of a family of East Indian origin with a rapidly progressive neurodegenerative disorder characterized by dementia, motor decline, and ataxia. RESULTS: We identified a novel Pro105Thr mutation in the PRNP gene in all of the 3 clinically affected family members but not in their unaffected relatives or normal controls. Although 5 of 6 affected family members had a relatively homogeneous phenotype and age at onset (range, 33-41 years), 1 of the 6 patients developed the disease at age 13 years. CONCLUSIONS: A novel mutation in the PRNP gene was identified in all of the available, clinically affected members of this family with a rapidly progressive neurodegenerative disease. To our knowledge, the propositus represents the youngest individual with inherited prion disease described to date.     

Disparities between rural and urban areas for osteoporosis management in the province of Quebec following the Canadian 2002 guidelines publication

Rationale, aims and objectives Clinical guidelines have been seen as a tool for improving management of osteoporosis in order to prevent fragility fractures. However, the impact of guidelines on clinical management of osteoporosis has not been measured. We examined medical investigation and treatment before and after the 2002 Canadian guidelines publication and examined if practice changes were different between rural and urban areas. Methods We conducted a retrospective population‐based observational study using secondary data analysis. Two studied populations were selected; one before, the other after the publication of Canadian practice guidelines. The studied populations consisted of all individuals 65 years or older from Quebec (Canada) for whom a physician claimed a consultation or have been hospitalized for fragility fracture between the two predefined periods. Results There was no significant difference in the rate of bone mineral density testing for women before and after guidelines publication. For men a statistically significant increase was observed but remained very low. A significant increase in bisphosphonates prescribing, but no increased in the reporting of a diagnosis of osteoporosis were observed. A significant reduction of hormonal replacement therapy was seen during the year following guidelines publication. The strongest significant increases were mostly seen in urban regions compared to rural areas. Conclusions Very small changes were observed for diagnostic recognition by physicians, diagnostic testing and some recommended drugs prescribing following guidelines publication. This suggests low guidelines impact on medical practice for osteoporosis in patients suffering fragility fractures.     

The First 100 Consecutive,Robot-assisted,Intracorporeal Ileal Conduits: Evolution of Technique and 90-day Outcomes

Background

Robot-assisted radical cystectomy (RARC) has evolved over the last few years to become an acceptable alternative option to open radical cystectomy. Most series of RARC used an open approach to urinary diversion. Even though robot-assisted intracorporeal urinary diversion (RICUD) is the natural extension of RARC, few centers have reported their experiences with RICUD in general, and in particular, of robot-assisted intracorporeal ileal conduits (RICIC).

Objective

To report our experience with RICIC using the Marionette technique.

Design, setting, and participants

The first 100 consecutive patients who underwent RARC and RICIC, and had ≥3 mo of postoperative follow-up were included in this study. Patients were divided into four groups of 25 patients each to study the evolution of our surgical technique.

Intervention

RICIC.

Outcome measurements and statistical analysis

Intraoperative, pathologic, and 90-d postoperative outcomes for the four groups and the overall cohort were compared using the Fisher exact test (categorical variables) and the Kruskal-Wallis test (continuous variables). Continuous variables were reported as median (range) and categorical variables were specified as frequency (percentage).

Results and limitations

Overall operative and specific diversion times were 352 and 123 min, respectively. Estimated blood loss was 300 ml, lymph node yield was 24, and positive surgical margin rate was 4%. Length of hospital stay increased from 7 d for group 1 to 9 d for group 4. The overall 90-d complication rate was 81%; 19% of complications were high grade. Infections were the most common complications, representing 31% of all complications. There were no statistically significant intergroup differences except in diversion time, intraoperative transfusions, and length of stay.

Conclusions

RICIC diversion is safe, feasible, and reproducible. Larger series with longer follow-up are needed to validate the procedure and define its place in the minimally invasive urologic armamentarium. Quality of life studies need to be conducted to compare benefits of intracorporeal urinary diversion.