Muscle mass and fat mass in relation to bone mineral density in very old men and women: the Framingham Heart Study

Aim of the study was investigate the cross-sectional relationship between body composition and bone mineral density (BMD) in very old men and women. The study sample consisted of 504 women and 285 men, aged 72-93 yr, participating in examination 22 (1992-1993) of the Framingham Heart Study. Total body BMD, regional BMD, and soft-tissue body composition was measured by dual-energy X-ray absorptiometry. Both muscle mass and percentage body fat were positively associated with total body BMD in women. After adjustment for age, physical activity, smoking status, estrogen use, and thiazide use, BMD increased with increasing tertile of muscle mass (p = 0.007) and with increasing tertile of percentage body fat (p = 0.0001) in women. In men muscle mass, not percentage body fat, was positively associated with BMD. After adjustment for potential confounders, BMD remained associated with muscle mass only (p = 0.02). These results were similar for leg BMD and arm BMD. The study suggests that the influence of muscle and fat mass on bone mineral density is different between very old men and women.     

Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study

OBJECTIVE: To examine whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women. METHODS: A total of 551 women ages 63-91 years (mean age 71) in the Framingham Study were followed up from biennial examination 18 (1983-1985) to examination 22 (1992-1993). Data on postmenopausal ERT were obtained every 2 years. Subjects were classified into 3 groups according to their estrogen use at biennial examination 18: never users (n = 349), past users (n = 162), and current users (n = 40). Women received anteroposterior weight-bearing knee radiographs at examinations 18 and 22. Using the Kellgren and Lawrence criteria, global radiographic knee OA was assessed, (grade range 0-4) and individual radiographic features, such as osteophytes and joint space narrowing, were scored from 0 to 3. Worsening was defined as either development of radiographic OA that was not present at baseline (incident OA) or progression of baseline radiographic OA by > or =1 Kellgren and Lawrence grade (progressive OA). Potential confounding factors included age, body mass index, weight change, smoking, knee injury, physical activity level, and bone mineral density at the femoral neck. RESULTS: During 8 years of followup, 17.4% of knee radiographic scores worsened by 1 grade and 5.8% by 2 or 3 grades among never users of ERT. Among current estrogen users, only 11.7% of knee radiographic scores worsened by 1 grade and none worsened by more than 1 grade. After adjusting for age and other potential confounding factors, the relative risk of incident radiographic knee OA in comparison with never users of estrogen was 0.8 (95% confidence interval [95% CI] 0.5-1.4) in past users and 0.4 (95% CI 0.1-3.0) in current users. Current use of estrogen also showed a trend toward decreased risk of progressive knee OA compared with never use (odds ratio [OR] 0.5, 95% CI 0.1-2.9). When both incident and progressive radiographic knee OA cases were combined, current ERT use had a 60% decreased risk compared with never use (OR 0.4, 95% CI 0.1-1.5). CONCLUSION: This is the first prospective cohort study to examine the effects of ERT on radiographic knee OA. The results indicate that current use of ERT had a moderate, but not statistically significant, protective effect against worsening of radiographic knee OA among elderly white women. These findings corroborate those of cross-sectional studies and point further to a potential benefit of female hormones in OA.     

Formation in the presence of C3 nephritic factor (C3NeF) of an alternative pathway C3 convertase containing uncleaved B

C3 nephritic factor (C3NeF) interacts with native C3 and B in the absence of D to generate a C3 convertase containing an uncleaved form of B. Dose response studies with C3NeF and B, respectively, revealed incremental C3 inactivation without loss of B. These findings are in agreement with the previous isolation from such reaction mixtures of a 10S complex containing haemolytically inactive C3 and active B and manifesting C3 convertase activity. Functional contamination of C3 with C3b was negated by demonstrating that pretreatment of C3 with C3bINA had no effect on its subsequent interaction with B and C3NeF to generate C3 convertase activity, while pretreatment of C3b eliminated its effective interaction with B and C3NeF. Relatively higher concentrations of C3bINA present during interaction of C3, B and C3NeF suppressed C3 inactivation, indicating its dependence on amplification by utilization of the initial C3b generated. Trace quantities of D were not found by functional analyses of C3, B and C3NeF and pretreatment of these proteins with a concentration of DFP sufficient to suppress D activity had no effect on their effective interaction. The introduction of D to mixtures of C3NeF, B, and C3 resulted in B clevage and more efficient expression of C3 convertase function as defined by a reduced requirement for C3NeF.     

A phase I dose-ranging safety and pharmacokinetics study of a novel oral thromboxane synthase inhibitor, FCE 22, 178

A 100- to 3200-mg dose range of FCE 22,178 was studied in this phase I single-dose escalation safety/kinetics study. After oral administration, a rapid drug absorptive phase and a biexponential disposition profile were observed. Mean estimates of the terminal elimination half-life of FCE 22,178, over the doses studied, ranged from 7.6 to 14.4 hours. A disproportionate increase in both maximum peak plasma concentration (Cmax) and area under the curve (AUC0-infinity) was noticed for doses higher than 400 mg. Mean estimates of systemic clearance (CLs/F) over the 100- to 400-mg doses were 0.053 to 0.064 L/hour/kg, and were significantly higher for the three higher dose levels. This nonlinearity appears to be related to the changes in oral bioavailability. Estimates of distribution volume (Vd, lambda z/F) for FCE 22,178 increased from 0.75 L/kg at the 100-mg dose to 3.00 L/kg at the 3200-mg dose, and renal clearance (CLr) also increased with dose. Both observations may be related to an increase in free fraction of FCE 22,178 at higher doses. Urinary excretion of unchanged drug averaged < 10% for all dose levels. The urinary excretion of the glucuronide metabolite (M1) averaged 41 to 70% for doses up to 400 mg, but diminished to 13% at the 3200-mg dose. The disposition of M1 appeared to be formation-rate limited. In addition, the ratio of the formation to the disposition clearance for M1 was relatively stable and apparently dose independent. No drug-related adverse experiences were observed over the studied dose range after single doses at FCE 22,178.     

The 3'-terminal sequence of mitochondrial 13S ribosomal RNA

We have examined the 3'-terminal sequence of the "small" structural ribosomal RNA ("13S") of hamster cell mitochondria, using a procedure involving [3H]isoniazide labeling of samples subjected to sequential periodate oxidation and beta-elimination. The terminus was found to be PyUAUUAOH, which is similar, but not identical, to the corresponding terminus of eukaryotic cytoplasmic 18S rRNA.     

DNA recognition by the EcoK methyltransferase. The influence of DNA methylation and the cofactor S-adenosyl-L-methionine

The methyltransferase of the EcoK type I restriction/modification system is trimeric, M2S1, where the S subunit determines the sequence specificity of the enzyme. The methyltransferase has a strong preference for hemimethylated substrate DNA and, therefore, we have investigated the effect of the methylation state of DNA on binding by the enzyme, together with the effects on binding of the cofactor S-adenosyl-L-methionine. Our results indicate that the methyltransferase has two non-interacting S-adenosyl-L-methionine binding sites, each with a dissociation constant of 3.60 (+/- 0.42) microM determined by equilibrium dialysis, or 2.21 (+/- 0.29) microM determined by the displacement of a fluorescent probe. Ultraviolet light-induced crosslinking showed that S-adenosyl-L-methionine binds strongly only to the modification (M) subunits. Changes in the sedimentation velocity of the methyltransferase imply a protein conformational change due to S-adenosyl-L-methionine binding. Gel retardation results show that the binding of S-adenosyl-L-methionine to the methyltransferase enhances binding to both specific and non-specific DNAs, but the enhancement is greater for the specific DNA. Differences in binding affinities contribute to the recognition of the specific nucleotide sequence AAC(N)6GTGC by the methyltransferase in preference to a non-specific sequence. In contrast, although the complexes of unmodified and hemimethylated DNAs with the methyltransferase have different mobilities in non-denaturing gels, there appears to be no contribution of binding affinity to the distinction between these two substrates. Therefore, the preference for a hemimethylated substrate must be due to a difference in catalysis.     

Expression of polysialylated neural cell adhesion molecule by proliferating cells in the subependymal layer of the adult rat, in its rostral extension and in the olfactory bulb

The highly sialylated isoform of the neural cell adhesion molecule is thought to be expressed predominantly in the developing nervous system, where it is implicated in a variety of dynamic events linked to neural morphogenesis. It has become increasingly evident, however, that this "embryonic" neural cell adhesion molecule isoform continues to be expressed in certain adult neuronal systems, and in particular, in those that can undergo structural plasticity. In the present study, we performed light microscopic immunocytochemistry with an antibody specific for polysialylated neural cell adhesion molecule and confirmed our earlier observations [Bonfanti L. et al. (1992) Neuroscience 49, 419-436] showing polysialylated neural cell adhesion molecule-immunoreactive cells in the subependymal layer of the lateral ventricle of the adult rat, a region where cell proliferation continues into the postnatal period. In addition, we used an antibody raised against the proliferating cell nuclear antigen and found that proliferating cells continue to be visible in this area, even in the adult. Double immunolabeling showed that many of these newly generated cells displayed high polysialylated neural cell adhesion molecule immunoreactivity. Cells from a portion of the subependymal layer migrate to the olfactory bulb and contribute to the continual replacement of its granule neurons [Luskin M. B. (1993) Neuron 11, 173-189]. We found polysialylated neural cell adhesion molecule-immunoreactive cells all along the pathway purported to be followed by the newly generated cells to their final destination and in neurons corresponding to granular and periglomerular cells in the olfactory bulb. Our present observations thus support the contention that polysialylation is a feature of neurons capable of dynamic change and may contribute to the molecular mechanisms permitting cell proliferation and migration not only during development but also in the adult.