Nutritional approaches to modulate oxidative stress in Alzheimer's disease.

Alzheimer's disease (AD) brain is characterized by amyloid ß-peptide (Aß) deposits, neurofibrillary tangles, synapse loss, and extensive oxidative stress. Aß-induced oxidative stress is indexed by protein oxidation, lipid peroxidation, free radical formation, DNA oxidation and neuronal cell death. Oxidative stress is combated by antioxidants. Antioxidants and nutrition have long been considered as an approach to slow down AD progression. In this review, we focus on antioxidants that have been shown to protect against Aß-induced oxidative stress, particularly vitamin E, ferulic acid, various polyphenols, including quercetin and resveratrol, α-lipoic acid, N-acetyl-L-cysteine (NAC), curcumin, epigallocatechin gallate (EGCG), and γ-glutamylcysteine ethyl ester (GCEE). Brain-accessible antioxidants with both radical scavenging properties and ability to induce protective genes are hypothesized to be helpful in treatment for AD.

[Anterior interbody-fusion of the lumbar spine (author's transl)]. / Ventrale Segmentspondylodese (Interbody-fusion) der Lendenwirbelsäule.

Anterior interbody spine fusion was performed by the extraperitoneal technique in 55 patients. Their diagnoses included instability of the spine in spondylolisthesis and degenerative disk disease, failed posterior fusion, progressive slip in spondylolisthesis, and in 4 patients tumour destruction of lumbar vertebral bodies. The follow-up of 47 patients after 0,5 to 7 years (average 2,8 years) revealed that the clinical result was successful in 37 patients (78%) and unsuccessful in 10 patients (22%). 34 patients (72%) had a solid union, whereas pseudoarthrosis had developed in 8 patients (17%). Technique and complications of the anterior approach to the lumbar part of the spine are described and indications are discussed.

Should improvement in rheumatoid arthritis clinical trials be defined as fifty percent or seventy percent improvement in core set measures, rather than twenty percent?

OBJECTIVE: To determine whether improvement of more than 20% in core set parameters should be required before patients are characterized as improved in rheumatoid arthritis (RA) clinical trials. METHODS: Data from 6 RA trials were reanalyzed to evaluate the discriminant validity (ability to differentiate active treatment from control) of 4 proposed definitions of improvement: the current American College of Rheumatology (ACR) definition (a 20% threshold for core set parameters [ACR 201), a 50% threshold (ACR 50), a 70% threshold (ACR 70), and an ordinal definition in which a patient could be classified in any of 3 categories (unimproved, ACR 20, or ACR 50). To evaluate the discriminant validity of these 4 definitions of improvement, we characterized each patient in each trial as improved or not, based on each definition, and computed a chi-square value differentiating the active treatment group from the control group, with the corresponding P value. RESULTS: With an increase in the threshold for improvement, the percentage of placebo-treated patients who were classified as experiencing response dropped dramatically in all trials, as did the percentage of patients receiving active therapy (second-line drug, combination therapy, tumor necrosis factor p75-Fc fusion protein) who were classified as experiencing response. Generally, the drop in active treatment response rates was greater than the drop in placebo response rates, leaving the difference between the 2 groups less at the higher thresholds. Therefore, chi-square values fell as the threshold for response was raised. The ordinal definition of improvement yielded chi-square values similar to those obtained using ACR 20 alone. CONCLUSION: Adopting a definition of efficacy in RA trials that requires 50% or 70% improvement in core set parameters would likely compromise statistical power and make it more difficult to distinguish between 2 treatments with different efficacy. ACR 20 should continue to be the primary measure of efficacy in RA trials, with higher thresholds for improvement being determined and reported as secondary efficacy measures.

[Acquired immunodeficiency syndrome with chronic granulomatous inflammation. Clinically definable special form of the variable immunodeficiency syndrome]. / Erworbenes Antikörpermangelsyndrom mit chronisch-granulomatöser Entzündung. Klinisch abgrenzbare Sonderform des variablen Immundefektsyndroms.

Five cases (3 men, 2 women) of late-onset variable immunodeficiency syndrome (CVID), characterized by similar clinical and immunological findings as well as histological demonstration of chronic granulomatous infection, are reported. All patients had frequent attacks of respiratory infections with recurrent bronchitis and pneumonia. In addition to predominating basally localized streaky-nodular lung changes all patients had hepatosplenomegaly and granulomatous infections of other organs. Immunologically, marked hypogammaglobulinaemia of all Ig classes, lymphopenia, and absence of terminal B-cell maturation were predominant. In-vitro tests under pokeweed-mitogen failed to demonstrate terminal plasma-cell differentiation of B-lymphocytes and thus Ig synthesis. Without pokeweed-mitogen there were largely nonsecretory B-blasts with abnormal granulated cytoplasmic Ig formation. Skin testing with Multitest application revealed almost complete anergy, both in the Arthus (24 h) and the late reactions (48 and 72 h). Nonetheless, T-cell reaction in-vitro was much less affected than B-cell function. "Natural killing" and antibody-dependent cytotoxicity were normal or slightly increased.

ACR and EULAR improvement criteria have comparable validity in rheumatoid arthritis trials. American College of Rheumatology European League of Associations for Rheumatology.

We compared the validity of the American College of Rheumatology (ACR) and the European League of Associations for Rheumatology (EULAR) definitions of response in rheumatoid arthritis (RA) clinical trials. US: ACR and EULAR improvement criteria were calculated in 7 large randomized RA clinical trials. The discriminant validity of the response criteria between treatment groups was studied using the Mantel-Haenszel chi-squared value. To compare both sets of criteria the chi-squared ratio was determined for each trial. Europe: In 2 large randomized RA clinical trials, ACR and EULAR criteria were calculated, once with extensive and once with 28 joint counts. The classification of patients with these 4 criteria were compared with each other using cross tables. We further studied the difference in response between treatment groups per trial, the association of response with patient and investigator assessment of improvement, and the association of response with radiological progression. US: The chi-squared ratio for most trials was close to 1. There was no clear pattern suggesting that the discriminant validity of the ACR criteria was stronger than the discriminant validity of the EULAR definition of response or vice versa. Europe: Conflicting results between ACR and EULAR were present in only 3% of patients in both trials. The discriminant validity of all 4 criteria (ACR and EULAR with reduced and extensive joint counts) was comparable. All criteria were related with the overall assessment of improvement by both investigator and patient. The association with radiographic progression was comparable for EULAR and ACR improvement criteria. There is a high level of agreement between ACR and EULAR improvement classification, and their validity is equivalent. The discriminating potential of the criteria between treatment groups is comparable, as is the association with patient's and investigator's overall assessment and with radiographic progression.

Etanercept therapy in rheumatoid arthritis. A randomized, controlled trial.

BACKGROUND: In a phase II study, etanercept (recombinant human tumor necrosis factor receptor [p75]:Fc fusion protein) safely produced rapid, dose-dependent improvement in rheumatoid arthritis over 3 months. OBJECTIVE: To confirm the benefit of etanercept therapy of longer duration and simplified dosing in patients with rheumatoid arthritis. DESIGN: Randomized, double-blind, placebo-controlled trial with blinded joint assessors. SETTING: 13 North American centers. PATIENTS: 234 patients with active rheumatoid arthritis who had an inadequate response to disease-modifying antirheumatic drugs. INTERVENTION: Twice-weekly subcutaneous injections of etanercept, 10 or 25 mg, or placebo for 6 months. MEASUREMENTS: The primary end points were 20% and 50% improvement in disease activity according to American College of Rheumatology (ACR) responses at 3 and 6 months. Other end points were 70% ACR responses at 3 and 6 months and other measures of disease activity at 3 and 6 months. RESULTS: Etanercept significantly reduced disease activity in a dose-related fashion. At 3 months, 62% of the patients receiving 25 mg of etanercept and 23% of the placebo recipients achieved 20% ACR response (P < 0.001). At 6 months, 59% of the 25-mg group and 11% of the placebo group achieved a 20% ACR response (P < 0.001); 40% and 5%, respectively, achieved a 50% ACR response (P < 0.01). The respective mean percentage reduction in the number of tender and swollen joints at 6 months was 56% and 47% in the 25-mg group and 6% and -7% in the placebo group (P < 0.05). Significantly more etanercept recipients achieved a 70% ACR response, minimal disease status (0 to 5 affected joints), and improved quality of life. Etanercept was well tolerated, with no dose-limiting toxic effects. CONCLUSIONS: Etanercept can safely provide rapid, significant, and sustained benefit in patients with active rheumatoid arthritis.