The relationship of self-rated vision and hearing to functional status and well-being among seniors 70 years and older

PURPOSE: To describe the relationship between self-reported visual and hearing impairment and an index of global functional status among seniors age 70 years or older. METHODS: A total of 7,320 United States community-dwelling persons aged 70 years or older participating in the 1993 Assets and Health Dynamics of the Oldest Old Survey (AHEAD) completed detailed questionnaires about their demographic, socioeconomic, and health status. Multivariate analyses of functional status (using a global index of functional status based on self-reported limitations in 11 activities) were conducted, controlling for demographic and socioeconomic status and common medical conditions, as well as independently for hearing and vision. RESULTS: Of the respondents, 27% rated their vision as fair or poor, whereas 25% rated their hearing as fair or poor. Controlling for demographic factors, socioeconomic status, medical conditions, and general health status, limitations in both vision and hearing correlated independently with worsened functional status. Controlling for income, wealth, and education did not greatly reduce the strength of the association between visual and hearing impairment and function. CONCLUSIONS: Visual and hearing impairment appear to have a significant relationship to overall functioning in the oldest old, regardless of income or wealth. By confirming these findings across income and household wealth groups, adjusted for medical conditions and general health status, in a nationally representative population of Americans age 70 years or older, this study provides a powerful added impetus to efforts for improving vision and hearing for all other Americans, including the oldest old.     

Prevention of naphthalene-1,2-dihydrodiol-induced lens protein modifications by structurally diverse aldose reductase inhibitors.

The effects of aldose reductase inhibitors on lens protein modifications induced by naphthalene-1,2-dihydrodiol were investigated in vitro to confirm the role of aldose reductase on naphthalene cataract formation. HPLC analysis of naphthalene-1, 2-dihydrodiol incubated with aldose reductase and NAD+indicated the formation of a metabolite peak corresponding to 1,2-naphthoquinone. Soluble proteins from rat lenses prepared by gel filtration of crude lens extracts through Sephadex PD-10, incubated with naphthalene-1, 2-dihydrodiol in the presence of NAD+displayed an absorbance ca 450 nm and their spectra were essentially identical to those of 1, 2-naphthoquinone-protein adducts. Similar spectra were also obtained from proteins isolated from the intact rat lens after in vitro incubation in medium containing naphthalene-1,2-dihydrodiol. The spectra obtained from lens proteins incubated with 1, 2-dihydroxynaphthalene were distinct from those of either naphthalene-1,2-dihydrodiol or 1,2-naphthoquinone. Aldose reductase inhibitors possessing either hydantoin or carboxylic acid groups prevented protein modification induced by naphthalene-1, 2-dihydrodiol but not protein modification induced by 1, 2-dihydroxynaphthalene or 1,2-naphthoquinone. Therefore, the metabolite formed from naphthalene-1,2-dihydrodiol by aldose reductase is 1,2-naphthoquinone. Lens proteins modified by naphthalene-1,2-dihydrodiol appear essentially identical to protein adducts formed with 1,2-naphthoquinone and their formation can be prevented by both hydantoin and carboxylic acid containing aldose reductase inhibitors.     

Synthesized TGF-beta s in RPE regulates cellular proliferation

Retinal pigment epithelial (RPE) cells transdifferentiate in culture, a transition which is accompanied by a shift in biological activity. The present study investigates whether transforming growth factor (TGF)-beta has the same effects on morphologically transformed RPE cells that it has on primary RPE cells. It also evaluates the autocrine and paracrine activities of TGF-beta s synthesized by RPE cells as well as the anti-TGF-beta effect of mannose-6-phosphate (M-6-P). RPE cells were subcultured at the sixth passage to induce morphological change. The effect of second passaged RPE-conditioned medium (CM) on DNA synthesis was evaluated by the incorporation of 3H-thymidine in rabbit subconjunctival fibroblasts (SCFs) and primary RPE cells. The presence of TGF-beta in RPE-CM was determined using immunoblotting analysis. And the inhibitory effect of M-6-P on cell proliferation mediated by RPE-CM was also analyzed using 3H-thymidine incorporation into DNA. TGF-beta 1, TGF-beta 2, and TGF-beta 3 inhibited the proliferation of the primary cultures of RPE cells in a dose-dependent manner, but the spindle-shaped sixth passaged RPE cells were not inhibited by these growth factors. The medium conditioned by RPE cells stimulated the proliferation of SCFs and inhibited the proliferation of primary RPE cells, in a manner similar to TGF-beta. When this medium was precipitated with either anti-TGF-beta 1, anti-TGF-beta 2, or anti-TGF-beta 3 antibodies, all three TGF-beta s, with an apparent molecular size of 25 kDa, were detected. Mannose-6-phosphate significantly blocked the effect of RPE-CM on cell proliferation. These findings indicate that RPE cells produce biologically functional TGF-beta s and that M-6-P can block the inhibitory effect of RPE-CM on cell proliferation.     

YC-1 potentiates the antiplatelet effect of hydrogen peroxide via sensitization of soluble guanylate cyclase.

In the present study, we showed that 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole (YC-1), a nitric oxide (NO)-independent activator of soluble guanylate cyclase, could potentiate H2O2-induced inhibition of platelet aggregation and increase of platelet cGMP levels. The synergistic effect of YC-1 and H2O2 on platelet aggregation and increases of cGMP were almost completely prevented by catalase and a selective soluble guanylate cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), or partially attenuated by the hydroxyl radical scavenger mannitol. In contrast, superoxide dismutase failed to influence H2O2/YC-1-induced inhibition of aggregation. Furthermore, YC-1 could enhance the activation of soluble guanylate cyclase caused by FeSO4/H2O2 and, this effect was prevented markedly by mannitol. These results suggest that YC-1 may enhance the antiaggregatory effect of H2O2 via the sensitization of platelet soluble guanylate cyclase. In addition, this phenomenon is, at least in part, dependent on H2O2-derived hydroxyl radical.     

The inhibitory effect of ambroxol on hypochlorous acid-induced tissue damage and respiratory burst of phagocytic cells

Ambroxol (100 microM and 1 mM) and the thiols (all 1 mM), glutathione, tiopronin and cysteine, significantly attenuated the myeloperoxidase, H(2)O(2) and Cl(-) system-caused destruction of alpha(1)-antiproteinase and the HOCl-induced destruction of collagen, whereas they did not affect the elastase-induced destruction of collagen. Glutathione, tiopronin and cysteine almost completely decomposed both HOCl and H(2)O(2), while ambroxol up to 1 mM did not show a scavenging action on H(2)O(2). Ambroxol (1 to 100 microM) and 1 mM thiol compounds markedly inhibited the HOCl-induced alteration of elastase activity. Thiol compounds significantly attenuated the HOCl production caused by degraded immunoglobulin G-activated neutrophils. Ambroxol depressed superoxide and H(2)O(2) production induced by degraded immunoglobulin G-activated neutrophils and by lipopolysaccharide-activated alveolar macrophages in a dose-dependent manner. The results show that ambroxol may interfere with oxidative tissue damage and decrease proteolytic tissue destruction by attenuation of oxidative stress-induced inactivation of alpha(1)-antiproteinase through both decomposition of HOCl and inhibition of the respiratory burst in phagocytic cells.     

Discovery and structure-activity relationships of imidazole-containing tetrahydrobenzodiazepine inhibitors of farnesyltransferase

2,3,4,5-Tetrahydro-1-(imidazol-4-ylalkyl)-1,4-benzodiazepines were found to be potent inhibitors of farnesyltransferase (FT). A hydrophobic substituent at the 4-position of the benzodiazepine, linked via a hydrogen bond acceptor, was important to enzyme inhibitory activity. An aryl ring at position 7 or a hydrophobic group linked to the 8-position through an amide, carbamate, or urea linkage was also important for potent inhibition. 2,3,4, 5-Tetrahydro-1-(1H-imidazol-4-ylmethyl)-7-(4-pyridinyl)-4-[2-(t rifluo romethoxy)benzoyl]-1H-1,4-benzodiazepine (36), with an FT IC(50) value of 24 nM, produced 85% phenotypic reversion of Ras transformed NIH 3T3 cells at 1.25 microM and had an EC(50) of 160 nM for inhibition of anchorage-independent growth in soft agar of H-Ras transformed Rat-1 cells. Selected analogues demonstrated ip antitumor activity against an ip Rat-1 tumor in mice.     

Second-generation peptidomimetic inhibitors of protein farnesyltransferase demonstrating improved cellular potency and significant in vivo efficacy.

The synthesis and evaluation of analogues of previously reported farnesyltransferase inhibitors, pyridyl benzyl ether 3 and pyridylbenzylamine 4, are described. Substitution of 3 at the 5-position of the core aryl ring resulted in inhibitors of equal or less potency against the enzyme and decreased efficacy in a cellular assay against Ras processing by the enzyme. Substitution of 4 at the benzyl nitrogen yielded 26, which showed improved efficacy and potency and yet presented a poor pharmacokinetic profile. Further modification afforded 30, which demonstrated a dramatically improved pharmacokinetic profile. Compounds 26 and 29 demonstrated significant in vivo efficacy in nude mice inoculated with MiaPaCa-2, a human pancreatic tumor-derived cell line.     

Helicobacter pylori clearance and serum gastrin and pepsinogen I concentrations in omeprazole treatment of duodenal ulcer patients

Objective: To determine which demographic factors may influence serum gastrin and pepsinogen I (PGI) levels in duodenal ulcer patients undergoing omeprazole treatment. Methods: We conducted an outpatient-based prospective study in the Veterans General Hospital, Taipei, to investigate the pharmacological effects on patients with duodenal ulcers receiving omeprazole treatment for 4 weeks. Sixty-eight patients (61 males/7 females, aged 25–73 years) with endoscopically confirmed duodenal ulcer were included. Gastrin and pepsinogen I levels were measured before and after treatment. Demographic factors including age, sex, smoking, ulcer healing and antral Helicobacter pylori colonization/clearance were analyzed, in order to measure their probable influences on serum gastrin and pepsinogen I levels. Results: Ulcer healing was seen in 92.6% of patients while 48 (70.6%) antral clearances were seen in 66 H. pylori colonized patients at the end of trial. Omeprazole monotherapy led to a marked elevation of serum gastrin (85.8 pg · ml⁻¹, SD 32.0 pg · ml⁻¹ vs 133.9 pg · ml⁻¹, SD 71.6 pg · ml⁻¹, P < 0.01), and pepsinogen I (111.0 ng · ml⁻¹, SD 36.7 ng · ml⁻¹ vs 253.6 ng · ml⁻¹, SD 64.8 ng · ml⁻¹, P < 0.01) levels when measured on day 29. Only patients showing antral H. pylori clearance exhibited an influence on the magnitude of pepsinogen I elevation following omeprazole monotherapy (143.9%, SD 67.3% vs 78.6%, SD 51.2%, P < 0.01). Moreover, the sensitivity and specificity of serum pepsinogen I variations were plotted on a receiving operating characteristic (ROC) curve. The 140% increased pepsinogen I level yielded a maximum accuracy of 80% specificity or 50% sensitivity to predict antral H. pylori clearance. Conclusion: Antral H. pylori clearance is at least partially responsible for the omeprzaole-induced hyperpepsinogenemia I. The magnitude of hyperpepsinogenemia I probably provides a non-invasive alternative for predicting H. pylori clearance. Received: 22 August 1996 / Accepted in revised form: 1 October 1998     

Neuroprotective mechanism of glial cell line-derived neurotrophic factor on dopamine neurons: role of antioxidation.

Recombinant human GDNF was infused into the rat striatum either acutely or subchronically. Its effects and its interactions with MPP+ on antioxidant enzyme activities were examined. Results indicated that acute GDNF infusion significantly increased glutathione peroxidase, superoxide dismutase and catalase activities. Subchronic GDNF treatment decreased the DA level and enhanced DA turnover. Pre-treatment with GDNF markedly protected DA neurons against MPP+-induced toxicity. These results suggest that GDNF protects DA neurons through its activation of the antioxidant enzyme systems.     

Effects of estrogen on autotomy in normal and ovariectomized rats.

Gonadal hormones may modulate analgesia responses induced by acute stress in humans and rats. To evaluate the effects of gonadal hormones in modifying neuropathic pain, we measured autotomy changes following sciatic nerve resection in ovariectomized rats and in the presence of estrogen replacement. Two groups of female rats were subjected to ovariectomy and sham surgery. Each group was then divided into two subgroups receiving subcutaneously sesame oil with or without estradiol benzoate (5 microg/day/rat). All rats then underwent sciatic nerve resection in one hindlimb. Degree of self-mutilation was measured daily for 8 weeks. Estradiol treatment resulted in significantly lower autotomy scores in ovariectomized rats (3.6 +/- 0.6 vs. 5.5 +/- 0.3, p < 0.01) and in sham-operated rats (3.4 +/- 0.7 vs. 5.1 +/- 0.4, p < 0.05). The results of this study indicate that estrogen can modify the autotomy behavior, an indicator of neuropathic pain, in rats after nerve injury.