Comparison of effortful and noneffortful swallows in healthy middle-aged and older adults.

OBJECTIVE: To assess the effects of effortful swallowing, a common compensatory strategy for dysphagia, on the bolus and swallowing mechanism of middle-aged and older men and women. DESIGN: Case-controlled design in which subjects completed both the intervention technique and the control behavior. SETTING: A university hospital. PARTICIPANTS: Sixty-four healthy men and women between 45 and 93 years of age from the community. INTERVENTIONS: Participants swallowed 3-mL thin liquid boluses both normally and using the effortful swallow strategy. MAIN OUTCOMES MEASURES: The biomechanics and bolus flow patterns of swallows were analyzed from videofluoroscopic and simultaneous oral pressure data. RESULTS: Subjects at all ages generated significantly increased oral pressures at each sensor location using the effortful swallow (p = .0001), with the pressure increase greater for the middle-aged subjects compared with older subjects. Several durational measures were significantly longer with the effortful swallow including: hyoid maximum anterior excursion (p < .04), laryngeal vestibule closure (p < .0001), and duration of the upper esophageal sphincter opening (p =.0001). The hyoid bone moved further in the superior direction with the effortful swallow (p = .002). There was a trend of decreased oral residue with the effortful swallow (p = .06). CONCLUSION: Biomechanical and bolus flow aspects of swallowing changed when healthy individuals performed effortful swallows with 3-mL boluses.

Dietary restriction and glucose regulation in aging rhesus monkeys: a follow-up report at 8.5 yr.

In a longitudinal study of the effects of moderate (70%) dietary restriction (DR) on aging, plasma glucose and insulin concentrations were measured from semiannual, frequently sampled intravenous glucose tolerance tests (FSIGTT) in 30 adult male rhesus monkeys. FSIGTT data were analyzed with Bergman's minimal model, and analysis of covariance revealed that restricted (R) monkeys exhibited increased insulin sensitivity (S(I), P < 0.001) and plasma glucose disappearance rate (K(G), P = 0.015), and reduced fasting plasma insulin (I(b), P < 0.001) and insulin response to glucose (AIR(G), P = 0.023) compared with control (C; ad libitum-fed) monkeys. DR reduced the baseline fasting hyperinsulinemia of two R monkeys, whereas four C monkeys have maintained from baseline, or subsequently developed, fasting hyperinsulinemia; one has progressed to diabetes. Compared with only the normoinsulinemic C monkeys, R monkeys exhibited similarly improved FSIGTT and minimal-model parameters. Thus chronic DR not only has protected against the development of insulin resistance in aging rhesus monkeys, but has also improved glucoregulatory parameters compared with those of otherwise normoinsulinemic monkeys.

Effect of carvedilol on survival in severe chronic heart failure.

BACKGROUND: Beta-blocking agents reduce the risk of hospitalization and death in patients with mild-to-moderate heart failure, but little is known about their effects in severe heart failure. METHODS: We evaluated 2289 patients who had symptoms of heart failure at rest or on minimal exertion, who were clinically euvolemic, and who had an ejection fraction of less than 25 percent. In a double-blind fashion, we randomly assigned 1133 patients to placebo and 1156 patients to treatment with carvedilol for a mean period of 10.4 months, during which standard therapy for heart failure was continued. Patients who required intensive care, had marked fluid retention, or were receiving intravenous vasodilators or positive inotropic drugs were excluded. RESULTS: There were 190 deaths in the placebo group and 130 deaths in the carvedilol group. This difference reflected a 35 percent decrease in the risk of death with carvedilol (95 percent confidence interval, 19 to 48 percent; P=0.00013, unadjusted; P=0.0014, adjusted for interim analyses). A total of 507 patients died or were hospitalized in the placebo group, as compared with 425 in the carvedilol group. This difference reflected a 24 percent decrease in the combined risk of death or hospitalization with carvedilol (95 percent confidence interval, 13 to 33 percent; P<0.001). The favorable effects on both end points were seen consistently in all the subgroups we examined, including patients with a history of recent or recurrent cardiac decompensation. Fewer patients in the carvedilol group than in the placebo group withdrew because of adverse effects or for other reasons (P=0.02). CONCLUSIONS: The previously reported benefits of carvedilol with regard to morbidity and mortality in patients with mild-to-moderate heart failure were also apparent in the patients with severe heart failure who were evaluated in this trial.

Age effects on the temporal evolution of isometric and swallowing pressure.

BACKGROUND: The tongue plays a key role in bolus propulsion through the oropharyngeal chamber. In this study, possible age effects on the magnitude and timing of lingual pressure generation were analyzed. METHODS: Oral pressure was measured during isometric and swallowing tasks for 10 elderly (mean age = 81 years) and 10 young (mean age = 51 years) subjects. Three trials each of the isometric task and swallows of three different boluses (3 ml semisolid, 3 ml liquid, and 10 ml liquid) were performed by each subject. The timing and magnitude of isometric and swallowing pressure generation along with the pattern of the swallowing pressure waveform were analyzed. RESULTS: Whereas maximum lingual isometric pressures decreased with age (p < .001). no significant age difference was found for swallowing pressure. Time taken to reach peak pressure also was reduced with age in both the isometric task and swallows of liquid boluses (p < .05), while no significant age effect was found for semisolid swallows. Finally, only elderly subjects showed a pattern of liquid swallowing pressure generation in which multiple lingual gestures were required to reach peak pressure (termed "pressure building"), a pattern demonstrated by both young and elderly groups for semisolids. CONCLUSIONS: Decreased lingual strength with age combined with unchanging swallowing pressure leads to a decreased "pressure reserve," perhaps leaving older individuals more at risk for dysphagia resulting from insults directly or indirectly to the swallowing system. Additionally, swallowing is generally "slowed" with age, apparently due to both central and peripheral factors, and this change may have an impact on bolus flow outcomes.

Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. EXCITE Trial Investigators. Evaluation of Oral Xemilofiban in Controlling Thrombotic Events.

BACKGROUND: When administered intravenously at the time of percutaneous coronary revascularization, glycoprotein IIb/IIIa receptor antagonists decrease the incidence of death and nonfatal myocardial infarction and the need for urgent revascularization. We hypothesized that long-term administration of oral glycoprotein IIb/IIIa antagonists, which block the aggregation of platelets, might stabilize intravascular plaque and prevent additional ischemic cardiac events. METHODS: We conducted a prospective, double-blind trial in which 7232 patients were randomly assigned to receive 20 mg of oral xemilofiban or placebo 30 to 90 minutes before undergoing percutaneous coronary revascularization, with maintenance doses of 10 or 20 mg of xemilofiban or placebo administered three times daily for up to 182 days. There were two primary composite end points: one was death, nonfatal myocardial infarction, or urgent revascularization at 182 days, and the other was death or nonfatal myocardial infarction at 182 days. RESULTS: Death, myocardial infarction, or urgent revascularization occurred within 182 days in 324 patients who received placebo (Kaplan-Meier cumulative event rate, 13.5 percent), 332 who received 10 mg of xemilofiban (13.9 percent, P=0.82 for the comparison with placebo), and 306 who received 20 mg of xemilofiban (12.7 percent, P=0.36 for the comparison with placebo). The incidence of death or myocardial infarction was also similar in all three groups. Clinically significant hemorrhagic complications and thrombocytopenia were infrequent. CONCLUSIONS: The administration of the glycoprotein IIb/IIIa antagonist xemilofiban before percutaneous coronary revascularization and for up to six months thereafter does not significantly reduce the incidence of important clinical end points.

Serum dehydroepiandrosterone sulfate concentrations across the life span of laboratory-housed rhesus monkeys.

Cross-sectional studies of humans have shown that dehydroepiandrosterone sulfate (DHEAS) peaks shortly after sexual maturation and declines thereafter, suggesting that the progressive reduction in DHEAS may play a role in the aging process and in the development of age-related morbidity. The present study examines changes in DHEAS concentrations across the life span of rhesus monkeys as part of the development of this primate model for studies of aging. Serum concentrations of DHEAS were measured in 792 laboratory-housed rhesus monkeys (Macaca mulatta) aged 0.5-36 years (527 females, 265 males). DHEAS concentrations in all monkeys were used to formulate an equation that describes two levels of decline of DHEAS with age. The most rapid decline occurs from infancy until approximately 5 years of age. The decline then occurs gradually with increasing age. There were no signs of an andrenarche just prior to sexual maturation, as is seen in humans or the great apes. This equation can be used to predict the expected mean serum DHEAS concentration and normal ranges of male or female rhesus monkeys at any age greater than 5 months.

Body fat distribution with long-term dietary restriction in adult male rhesus macaques.

Dietary restriction (DR) is the only intervention that has been shown to increase average and median life span in laboratory rodents. The effect of long-term, moderate DR on body composition and fat distribution was evaluated in male rhesus monkeys. Thirty animals (8-14 years of age)fed either 30% less than baseline intake (R, n = 15) or allowed to eat to satiety (C, n = 15), have been assessed semiannually using somatometrics and dual-energy alpha-ray absorptiometry (DXA)for 7.5 years. R subjects have reduced body weight (p <.0001), total body fat (p < .0001), and percentage body fat located in the abdominal region (p < .05). In addition, there has been a sustained reduction in plasma leptin concentrations (p <.001). These findings suggest reduced risk for common morbidities, such as insulin resistance, dyslipidemia, and type 2 diabetes mellitus, that are associated with advancing age and increased levels of bodyfat, especially in the visceral depot.

The effect of dietary restriction on body composition in adult male and female rhesus macaques.

Dietary restriction is the only intervention shown to increase maximal life span, and to retard the rate of aging in rodents. As part of a long-term randomized trial of the effects of a 20-30% dietary restriction (DR) on adult rhesus macaques, female (N = 30) and male (N = 16) monkeys were assessed at baseline and 6, 12 and 18 months, following randomization to control (C) or dietary restricted (R) groups, for body composition by dual-energy x-ray absorptiometry. At baseline, there were no significant differences between C and R groups in any body composition parameters measured. Males had significantly (p < 0.05) greater values at baseline than females for body weight (BW), body mass index (BMI), total body lean tissue mass (LTM), appendicular skeletal muscle mass (ASM), and total body bone mineral content (BMC). When analyzed longitudinally through 18 months of DR, C females had significantly increased BW, total body fat tissue mass (FTM), total body percent fat tissue mass (%FTM), LTM, ASM, BMC and abdominal fat tissue mass (AbFTM) relative to R animals. Male C animals had significantly increased BW, FTM, %FTM, BMC and AbFTM relative to R males. The primary effect of DR on body composition in these animals was on FTM.

Caloric restriction reduces fiber loss and mitochondrial abnormalities in aged rat muscle.

The influence of caloric restriction (CR) initiated at 17 months of age was investigated on selected age-associated measures in skeletal muscle. Tissue from young (3-4 months) ad libitum-fed, old (30-32 months) restricted (35% and 50% CR, designated CR35 and CR50, respectively), and old ad libitum-fed rats (29 months) was studied. CR preserved fiber number and fiber type composition in the vastus lateralis muscle of the CR50 rats. In the old rats from all groups, individual fibers were found with either no detectable cytochrome c oxidase activity (COX-), hyperreactivity for succinate dehydrogenase activity (SDH++; also known as ragged red fibers [RRF]), or both COX- and SDH++. Muscle from the CR50 rats contained significantly fewer COX- and SDH++ fibers than did the muscle from CR35 rats. CR50 rats also had significantly lower numbers of mtDNA deletion products in two (adductor longus and soleus) of the four muscles examined compared to CR35 rats. These data indicate that CR begun in late middle age can retard age-associated fiber loss and fiber type changes, as well as increases in the number of skeletal muscle fibers showing mitochondrial enzyme abnormalities. CR also decreased the accumulation of mtDNA deletions.

Energy expenditure of adult male rhesus monkeys during the first 30 mo of dietary restriction.

Energy expenditure, activity, and body composition were measured in 30 adult male rhesus monkeys used in a study having the long-term goal of determining the effects of moderate dietary restriction (DR) on aging. All animals were fed a defined diet, with the restricted animals maintained at approximately 70% of the caloric intakes of the controls. After 12 mo of DR, body fat mass of restricted monkeys was 33% less than that of controls (P = 0.004), whereas lean body mass differences were not present until after 24 mo. At the 24- and 30-mo assessments, nighttime energy expenditure was significantly reduced (P < 0.01) in the restricted compared with control monkeys after adjustment for lean body mass differences, whereas morning, afternoon, and total energy expenditure were not significantly different (P > 0.05). No significant differences (P > 0.05) in activity were noticed between treatment groups at any time point. DR resulted in a prolonged decrease in resting energy expenditure, which could contribute to the possible life-extending action of this treatment.

Influence of fat intake and caloric restriction on bone in aging male rats.

Caloric and fat intake may have important skeletal consequences. To evaluate this possibility, skeletal effects of adult-onset caloric restriction (CR) at differing fat intakes were assessed in male Lobund-Wistar rats. At age 17 months, two groups of animals received an anti-obesity diet, restricted approximately 35% from individual ad libitum baseline calorie consumption, and two groups received a diet approximately 50% restricted. Dietary fat concentrations were 5, 15, 15, and 25% by weight, respectively. At ages 20, 24, 28, 30, and 32 months, ex vivo femoral bone densitometry and serum biochemical analyses were performed. Body weight (BW) decreased with time on CR in each group (p < .005), declining faster at the more severe restriction (p = .001). Femoral bone mineral contents (BMC) were also reduced. After adjusting for bone area and BW differences among groups, the only significant difference was a reduction in distal femur BMC in the 25% fat group subjected to more severe CR (p = .02). No differences were observed in serum parathyroid hormone, calcium, phosphorus, or creatinine. Femoral bone loss occurred with CR. This was entirely accounted for by reduction in BW. Higher dietary fat content did not affect BW in CR animals, but did result in lower distal femur BMC.

The effect of advancing age on bone mineral content of female rhesus monkeys.

Dual-energy X-ray absorptiometry (DXA) can be used to assess bone mass in nonhuman primates; however, the changes in bone mineral across the lifespan have not been well described. The purpose of this cross-sectional study was to evaluate the effect of maturation and subsequent aging on bone mineral content (BMC) and bone size (two dimensional bone area) in female rhesus monkeys at sites analogous to those commonly evaluated in humans. Total body (n = 178) and lumbar spine (n = 167) DXA scans were performed on female rhesus monkeys aged 2.8 to 34.6 years. Radius scans (n = 86) were performed on monkeys aged 9.7 to 34.6 years. Measurement precision was comparable to that reported for humans. At all sites, BMC was highly correlated with bone area (p = 0.0001), which was positively correlated with both body weight (p < or = 0.002) and age (p < or = 0.08). Total body and lumbar spine BMC and bone area increased with maturation (p < 0.0001) until age 11 and then remained stable with further advancing age. There was little change in total body and lumbar spine area-adjusted BMC across the lifespan. At the radial sites, there were no significant changes in BMC or bone area with age, but the area-adjusted BMC and the weight- and area-adjusted BMC declined in older animals (p < 0.05). In conclusion, the female rhesus monkey does not attain peak bone mass until age 11. Significant bone loss at later ages was observed only at radial sites.

Reduced immune responses in rhesus monkeys subjected to dietary restriction.

Dietary restriction (DR) has emerged as a major paradigm in experimental gerontology. The effects of DR on rodents are numerous and include reduced rates of immunologic aging, delayed morbidity, and increases in longevity. The effects of DR on primate species remain largely unknown. We began a randomized trial of long-term, adult-onset DR in rhesus monkeys (Macaca mulatta) in 1989. This report describes some early differences in immunologic function after two to four years of DR. Peripheral blood mononuclear cells were studied for mitogen-induced proliferation, natural killer (NK) cell lysis, and expression of cell surface antigens. Antibody response to influenza vaccine and the number of peripheral blood lymphocytes were also measured. Unexpectedly, concanavalin A and pokeweed mitogen response measures were reduced in restricted monkeys compared to controls (p < or = .01). NK activity and antibody responses were also reduced (p < .05). Neither cell surface antigens nor peripheral blood lymphocyte counts appear affected by DR thus far.

Age and sex differences in body size and composition during rhesus monkey adulthood.

Body size and composition were measured in forty-one adult Rhesus monkeys (Macaca mulatta) in order to characterize changes that occur during later life for both genders. Data were obtained by traditional somatometric techniques and by dual-energy X-ray absorptiometry. Representative monkeys were chosen within six categories defined by age (Young Adult, 6-9 year-old; Middle Aged, 15-19 year-old; Older Adult, 26-30 year-old), and sex. Body weight and most external measures of body size were greater during middle age and later life than in young adulthood, as were body fat content and lean body mass. Females tended to have a higher percentage body fat than males in all age categories. Lean tissue mass was markedly greater in the two younger groups for both sexes, compared to older adults. Bone mineral content and density were higher in the males than the females, but differences in bone mineralization among age groups did not achieve statistical significance. Such data derived from adult nonhuman primates are useful for defining fundamental biological changes with age in these species, and have value as a comparative model for studies of human aging and age-related morbidity.

Thermal application reduces the duration of stage transition in dysphagia after stroke.

The present study had two purposes. The first was to provide variability data on objectively measured durational parameters of swallowing as accomplished by dysphagic patients secondary to stroke. The second was to examine the short-term effects of thermal application on these same durational measures. The study employed a cross-over design with each dysphagic stroke subject swallowing 10 times in both untreated and treated conditions. Two findings emerged: (1) swallowing durations in the 22 dysphagic stroke subjects were highly variable within and across subjects and have distributions that were nonnormal with nonhomogeneous variances; (2) thermal application reduced duration of stage transition (DST) and total swallow duration (TSD). Implications of these findings are discussed.

A penetration-aspiration scale.

The development and use of an 8-point, equal-appearing interval scale to describe penetration and aspiration events are described. Scores are determined primarily by the depth to which material passes in the airway and by whether or not material entering the airway is expelled. Intra- and interjudge reliability have been established. Clinical and scientific uses of the scale are discussed.

Age effects on lingual pressure generation as a risk factor for dysphagia.

BACKGROUND: Tongue activity plays a crucial role in both oral and pharyngeal phases of swallowing. In this study, maximum lingual isometric and swallowing pressures were quantified in two groups of healthy men to investigate possible age effects on performance. Magnetic resonance images of the brain were also obtained to examine the relationship between age-related anatomical changes and swallowing function. METHODS: Pressures were recorded at three lingual sites (tip, blade, and dorsum) during a maximal isometric task and during saliva swallows. Task order was randomized, and subjects performed three trails per placement site. Additionally, t2-weighted MRIs were obtained on 9 of the 10 young subjects (mean age = 25 years) and all 15 older subjects (mean age = 75 years). RESULTS: Maximal isometric pressures were significantly greater for younger subjects at the tongue blade site (p = .002), whereas peak swallowing pressures remained similar across both age groups. Within-subject comparisons of maximum isometric to swallowing pressures, a measure of reserve capacity, revealed reduced difference scores at the tongue blade in the older group (p = .02). Older subjects exhibited significantly more cerebral atrophy (p = .001) and greater incidence of periventricular white matter lesions (p = .0001) than did younger subjects. CONCLUSIONS: While swallowing pressures remain similar across the life span, overall pressure reserve declines with age. The implications are: (a) older people may be working harder to produce adequate swallowing pressures, and (b) age-related illness may put geriatric patients at higher risk for dysphagia, thus further complicating recovery.

High levels of mitochondrial DNA deletions in skeletal muscle of old rhesus monkeys.

Mitochondrial DNA (mtDNA) deletions increase in abundance with age in many tissues, however, their calculated low levels (usually < 0.1%) in samples from tissue homogenates containing thousands of cells argue against physiologic significance. Through the analysis of defined numbers of cells (skeletal muscle fibers) from rhesus monkeys, we report that the calculated abundance of specific mtDNA deletions is dependent upon the number of fibers analyzed: as the number of fibers decreases, the calculated deletion abundance increases. Also, most mtDNA deletions appear to occur in a mosaic pattern, varying from cell to cell in size, number and abundance. These data support the hypothesis that mtDNA deletions can focally accumulate to high levels contributing to declines in mass and function of aging skeletal muscle.

Dietary restriction attenuates age-related increases in rat skeletal muscle antioxidant enzyme activities.

Dietary restriction (DR) retards aging in rodents, but its mechanism of action remains unclear. Free radicals have been hypothesized to be involved in aging and in DR's actions. We investigated the influences of age and DR on the antioxidant enzymes catalase (CAT), glutathione peroxidase (GPX), and superoxide dismutase (SOD) in skeletal muscle from 11-, 26- and 34-mo-old (BN x Fischer 344) F1 rats fed either ad libitum (AL) or subjected to a 30% DR from 14 weeks of age. The mass of the upper hindlimb muscles recoverable in 34-mo-old AL rats was only 52% that of 11-mo-old AL rats, whereas rats on DR showed a stable, intermediate value at both ages. CAT and GPX activities increased progressively and markedly in muscle of AL animals with aging. The increase in CAT activity was partially attenuated by DR, while that of GPX was entirely prevented. These effects of aging and DR were more profound in 12,000 x g pellets than in cytosolic fractions. SOD activities were more variable and not clearly influenced by age or DR. These data agree with prior reports of an age-related increase in skeletal muscle antioxidant enzyme activities. Further, DR attenuates this alteration and does so most profoundly in the 12,000 x g pellet, the fraction which is enriched in mitochondria.

Effects of recombinant human interleukin-6 administration on bone in rhesus monkeys.

The role of interleukin-6 in the bone microenvironment is controversial. We studied the effect of recombinant human interleukin-6 (rhIL-6) administration on bone metabolism in 10 adult female rhesus monkeys (age 12-27 years). Monkeys received rhIL-6 (15 micrograms/kg/day) daily by subcutaneous injection for 28 days. Serum alkaline phosphatase, osteocalcin, and 24 h urinary calcium excretion were determined before, during (at weeks 2 and 4), and after (at week 6) treatment. Transilial biopsies (right and left) were obtained before treatment was initiated and just after the final (28th) dose at week 4. The serum alkaline phosphatase significantly increased at 2 and 4 weeks of rhIL-6 administration. Osteocalcin and urinary calcium excretion significantly decreased at week 2. Upon treatment with rhIL-6 significant reductions in OS/BS and Ob.S/BS were observed without changes in other static histomorphometry parameters. The reductions in urinary calcium excretion, serum osteocalcin, and the static bone parameters are consistent with an IL-6 induced reduction in bone formation or turnover. Whether this pharmacologic effect is relevant at the physiologic level remains to be determined.