The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease

GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period. Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007). This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.     

Wear of aluminum oxide antagonists by commercially available composites and compomers

PURPOSE: To investigate the wear of aluminum oxide antagonists by 19 light curing, commercially available composites and compomers. The influence of the filler particle size of the composites, the filler particle material and the filler particle morphology was determined. METHODS: Occlusal contact wear of the antagonists was simulated in a sliding wear test. Eight antagonists and specimens of each material were tested in a pin-on-block design with oscillating sliding of an aluminum oxide antagonist (Degussit antagonist, 5 mm diameter). After 50,000 cycles the contact area was evaluated using a dedicated software (UTHSCA image tool for windows V 2.0) under a light microscope. The size of the contact area was measured. RESULTS: Three types of boundaries of the contact area could be observed: (1) Sharp boundary, (2) No sharp boundary but easy to identify, and (3) No sharp boundary and difficult to identify. The method of Pearson was used to calculate the correlation coefficients. The coefficient of determination between the ranking of the measured contact area and the ranking of the maximum particle size was r2= 0.46 (P> 0.05). Composite materials with the same particle size were ranked by their filler content (wt. %).     

The effect of meniscus compression on the biomechanical properties of repaired meniscal lesions

Introduction The objective of the present study was to investigate the influence of meniscus compression, as it occurs with weight-bearing, on the biomechanical behavior of different repair types.Materials and methods Young human meniscal tissue specimens were fitted with a single Bionx Arrow, a Innovasive Meniscal Screw, or a vertical suture (Ethibond 2–0) according to standard clinical practice. Test specimens then underwent repetitive loading with 10 N under 1 N pretension up to a maximum of 1182 cycles and were finally loaded to failure. Half of the cases in each group were additionally subjected to synchronized intermittent compression during the test. The main variables investigated were the number of cycles survived and ultimate failure load. To reduce the complexity, investigations were limited to the peripheral repair site.Results The number of cycles survived was significantly affected by compression and the type of repair. Arrows and Screws survived 311 and 52 cycles, respectively, without compression, while 983 and 1182 cycles were survived with added compression. In the suture group, no premature failure occurred either with or without compression. Both compression and the type of repair had a significant effect on the ultimate failure load. It increased about twofold in the Arrow and Screw group, while the suture group was not affected.Conclusions Compression of the meniscus can substantially increase the pullout resistance of meniscal repair implants and thus seems not to be a factor negatively influencing the stability of the repair.     

Determination of the peptide binding motif and high-affinity ligands for HLA-DQ4 using synthetic peptide libraries

Juvenile idiopathic arthritis (JIA) is considered to be an autoimmune disease. Various human leukocyte antigen (HLA) associations for different subgroups of this heterogeneous disease have been found. For early-onset pauciarticular arthritis (now oligoarthritic JIA), a strong association with the HLA class II haplotype DQA1*0401/DQB1*0402 (DQ4) has been described. We determined the peptide-binding specificities of this HLA-DQ molecule by screening a synthetic acetylated nonapeptide amide library with one defined and eight random sequence positions. A characteristic binding motif could be deduced. By use of these data, we designed defined specific nonapeptides and identified high-affinity ligands binding to HLA-DQ4. The peptide binding motif of HLA-DQ4 is very similar to the motif of HLA-DQ7, also associated with oligoarthritic JIA. It is, however, different from binding motifs of neutral or protective HLA-DQ molecules. Our results further support the idea of differential peptide presentation in the pathogenesis of oligoarthritic JIA.     

Studies with low response proportions may be less biased than studies with high response proportions

The association between the response proportion in epidemiologic studies and nonresponse bias is complicated, because exposure prevalences and misclassification errors may vary by recruitment wave. In this paper, the authors illustrate the effect of varying degrees of wave-specific nondifferential exposure measurement error in a dichotomous exposure on the relative risk in a hypothetical cohort study of 5,000 participants, by recruitment wave. The field phase of the hypothetical cohort study consisted of five consecutive recruitment waves. The authors assigned response proportions to each wave (wave 1: 30%; wave 2: 10%; wave 3: 10%; wave 4: 30%; wave 5: 20%) and studied three different wave-specific patterns of true exposure prevalence: 1) the true exposure prevalence remains the same in all waves; 2) the true exposure prevalence increases by wave; and 3) the true exposure prevalence decreases by wave. The authors assumed three corresponding patterns of nondifferential misclassification error in exposure status across waves. If the nondifferential exposure misclassification increases by wave, the cumulative relative risk estimate is increasingly biased towards the null. This bias is intensified if the true exposure prevalence increases by wave. Studies with low response proportions may be less biased than studies with high response proportions if the nondifferential misclassification error in a dichotomous exposure increases by recruitment wave.     

Plasma antioxidants and lipid oxidation after submaximal resistance exercise in men

Summary.Background: An increased generation of reactive oxygen species occurs during exercise.The aim of the study: We investigated whether changes in plasma antioxidants and lipid oxidation products after submaximal resistance exercise are detectable, and whether training status has any effect on changes.Methods: Seven resistance trained (RT, 31.3 ± 10.2 yrs) and ten non-resistance trained male subjects (NRT, 28.2 ± 3.9 yrs) performed a submaximal resistance exercise circuit (10 different exercises, 75% of 1-repetition maximum, 18.6 ± 1.1 minutes). Blood samples were taken before and immediately after exercise. Plasma antioxidants (AO), lipid oxidation products malondialdehyde (MDA) and conjugated dienes (CD) were measured using HPLC and/or photometric detection. Groups were compared using the Mann-Whitney U test, the exercise effect was tested using the Wilcoxon signed ranks test. P < 0.05 was regarded as significant.Results: -Tocopherol, -tocopherol, -carotene, lycopene, ascorbic acid,MDA and CD concentrations did not differ between groups at rest. There was a similar increase of fat soluble plasma AO in both groups after exercise, but not ascorbic acid. MDA increased also in both groups after exercise, but CD increased only in NRT.Conclusion: There is no difference in plasma AO and lipid oxidation products in RT and NRT at rest. After short time resistance exercise there is a mobilization of fat soluble AO. Despite mobilization of AO, oxidative stress occurs during submaximal resistance exercise, which is indicated by increased MDA and CD concentrations. As exercise induced an increase of CD only in NRT, it seems that regular resistance training partly prevents lipid peroxidation during exercise.     

Multiple familial trichoepithelioma caused by mutations in the cylindromatosis tumor suppressor gene

The recessive oncogene cylindromatosis (CYLD) mapping on 16q12-q13 is generally implicated in familial cylindromatosis, whereas a gene region for multiple familial trichoepithelioma has been assigned to 9p21. Markers from both chromosome intervals were subjected to linkage analysis in a large family with multiple hereditary trichoepithelioma (TE) from Algeria. Linkage to 9p21 was excluded, whereas CYLD remained as a candidate. Mutation analysis identified a single bp germ-line deletion expected to result in truncation or absence of the encoded protein, which segregated with the multiple TE phenotype. In individual tumors, loss of heterozygosity at 16q or a somatic point mutation in the CYLD gene was detected. Hence, mutations of the tumor suppressor gene CYLD at 16q12-q13 may give rise to familial TE indistinguishable from the phenotype assigned to 9p21.     

Secondhand smoke exposure in adulthood and risk of lung cancer among never smokers: a pooled analysis of two large studies

The interpretation of the evidence linking exposure to secondhand smoke with lung cancer is constrained by the imprecision of risk estimates. The objective of the study was to obtain precise and valid estimates of the risk of lung cancer in never smokers following exposure to secondhand smoke, including adjustment for potential confounders and exposure misclassification. Pooled analysis of data from 2 previously reported large case-control studies was used. Subjects included 1263 never smoking lung cancer patients and 2740 population and hospital controls recruited during 1985-1994 from 5 metropolitan areas in the United States, 11 areas in Germany, Italy, Sweden, United Kingdom, France, Spain and Portugal. Odds ratios (ORs) of lung cancer were calculated for ever exposure and duration of exposure to secondhand smoke from spouse, workplace and social sources. The OR for ever exposure to spousal smoking was 1.18 (95% CI = 1.01-1.37) and for long-term exposure was 1.23 (95% CI = 1.01-1.51). After exclusion of proxy interviews, the OR for ever exposure from the workplace was 1.16 (95% CI = 0.99-1.36) and for long-term exposure was 1.27 (95% CI = 1.03-1.57). Similar results were obtained for exposure from social settings and for exposure from combined sources. A dose-response relationship was present with increasing duration of exposure to secondhand smoke for all 3 sources, with an OR of 1.32 (95% CI = 1.10-1.79) for the long-term exposure from all sources. There was no evidence of confounding by employment in high-risk occupations, education or low vegetable intake. Sensitivity analysis for the effects of misclassification (both positive and negative) indicated that the observed risks are likely to underestimate the true risk. Clear dose-response relationships consistent with a causal association were observed between exposure to secondhand smoke from spousal, workplace and social sources and the development of lung cancer among never smokers.