Lung disease mortality in the United States: the National Longitudinal Mortality Study.

SETTING: The National Longitudinal Mortality Study (NLMS) offers the advantage of assessing mortality in a representative population of the United States. OBJECTIVE: To evaluate health disparities associated with lung cancer and chronic obstructive pulmonary disease (COPD) mortality in the United States and whether these associations are similar between these outcomes. DESIGN: The NLMS is a prospective study. Data from NLMS cohort years 1985, 1992, 1993, 1995 and 1996 were included, representing nearly 1.5 million person-years. Lung cancer and COPD mortality relative risks (RRs) from Cox regression analysis, including residential characteristics, marital status, education, health insurance and family income, were evaluated. RESULTS: By 1998, 1273 lung cancer deaths and 772 COPD deaths occurred. Lung cancer mortality rates were approximately two times higher than COPD mortality rates among race and ethnic groups. Cox regression analysis revealed that low education (RR = 1.77, significant, P = 0.01) and low family income (RR = 1.50, significant, P = 0.01) are associated with lung cancer and COPD mortality, controlling for age, race/ethnicity, sex and smoking status. CONCLUSIONS: COPD and lung cancer mortality have similar associations with health disparity indicators in the NLMS data, with some differences in the magnitude of the effect.

Biochemical modulation of 5-bromo-2'-deoxyuridine and 5-iodo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analogues 5-bromo-2'-deoxyuridine (Brd-Urd) and 5-iodo-2'-deoxyuridine (IdUrd) compete with thymidine for incorporation into the DNA of replicating cells. This incorporation results in radiosensitizing effects which are directly related to the degree of analogue substitution. In vitro and in vivo evidence suggests that preadministration or coadministration of the thymidylate synthetase inhibitors fluorouracil and 5-fluoro-2'-deoxyuridine (FdUrd) can modulate analogue incorporation into DNA. We have evaluated in the rabbit VX2 tumor model the effects of thymidylate synthetase inhibitor (fluorouracil or FdUrd) coadministration (as 24-hour, intravenous infusions) on the incorporation of BrdUrd or IdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa) and intrahepatic VX2 tumor. Tissues were harvested and processed for gas chromatography-mass spectrometry analysis of the thymine, 5-bromouracil, and 5-iodouracil contents in hydrolyzed DNA. Coadministration of FdUrd resulted in statistically significant (P less than .01) enhancement of IdUrd incorporation into the DNA of intrahepatic VX2 tumor and normal (bone marrow and duodenal mucosa) rabbit tissues. Coadministered fluorouracil, on the other hand, significantly enhanced IdUrd incorporation only into DNA of intrahepatic VX2 tumor. Statistically significant enhancement of BrdUrd incorporation was achieved only with FdUrd coadministration and then only into the DNA of intrahepatic VX2 tumor. The percent of thymine replaced by analogue (I) is related to the steady-state arterial plasma drug concentration (C) by the Michaelis-Menten equation: I = I(MAX.) C/(C50 + C). The primary effect of FdUrd coadministration on BrdUrd incorporation into VX2 tumor DNA was a reduction of the C50 parameter (plasma BrdUrd concentration eliciting I = I(MAX)/2) from 8.17 microM to 1.78 microM. On the other hand, the I(MAX) parameter (I as C approaches infinity) was only slightly affected (29.7% to 25.2%). Thus, the degree to which the modulator enhanced analogue incorporation varied inversely with the analogue's steady-state plasma concentration. These results, which describe potential tissue specificity of modulator efficacy and characterize the effects of thymidylate synthetase inhibitor modulation on thymidine analogue incorporation pharmacodynamics, should provide guidance as to dose scheduling of BrdUrd and IdUrd in clinical trials for improved tumor specificity of uptake.

Tissue-specific pharmacodynamics of 5-bromo-2'-deoxyuridine incorporation into DNA in VX2 tumor-bearing rabbits.

The thymidine analog 5-bromo-2'-deoxyuridine (BrdUrd) is felt to exert its cytotoxic effects primarily through incorporation into DNA. We have evaluated the incorporation of BrdUrd into the DNA of relevant normal tissues (bone marrow, gut mucosa, and liver) and tumor in rabbits with the VX2 tumor growing intrahepatically. Using constant i.v. infusions, steady state plasma drug concentrations ranging from 0.4 to 65.4 microM were maintained for 24 h and tissues were harvested and processed so that a sensitive gas chromatography/mass spectrometry (GC/MS) method could be used to analyze the thymine and 5-bromouracil content of hydrolyzed DNA. In all tissues, DNA incorporation showed saturating effects as plasma BrdUrd concentration was increased and, BrdUrd incorporation as a function of plasma concentration could be fitted to a Langmuir-like equation generating tissue-specific pharmacodynamic parameters: Imax for percentage thymine replacement at infinite plasma BrdUrd concentrations, and C50 for the arterial BrdUrd concentration generating incorporation that is Imax/2. At all plasma concentrations of BrdUrd the incorporation into DNA of bone marrow was greater than that observed in VX2 tumor. However, BrdUrd labeling index (with a BrdUrd monoclonal antibody) was greater in tumor than bone marrow. Thus, pharmacodynamic differences in incorporation do not result solely from cytokinetic differences between tissues. This model may prove useful in evaluating the pharmacodynamics of incorporation in studies using hepatic arterial infusion and biochemical modulation to improve selectivity.

Arrhythmias induced by device antitachycardia therapy due to diagnostic nonspecificity.

New technology has produced automatic cardioverter-defibrillators capable of delivering antitachycardia pacing, as well as low and high energy shocks and backup bradycardia pacing. These expanded treatment options have led to a wider range of clinical applications for such devices, including the treatment of ventricular tachycardias with longer cycle lengths, which may overlap the cycle lengths of some supraventricular arrhythmias. The diagnostic capability of these devices, although improved, has not advanced sufficiently to ensure reliable discrimination between all supraventricular and ventricular arrhythmias. Two cases are presented in which device-mediated pacing therapy, triggered by supraventricular arrhythmias, induced ventricular tachycardia requiring additional therapeutic intervention. This report illustrates the therapeutic versatility and some of the potential pitfalls, of the recently developed devices and reviews the status of automatic arrhythmia identification technology.

Triggered activity as a cause of bigeminy.

Standard microelectrode techniques were used to study bigeminal rhythms occurring during otherwise stable triggered activity in ouabain-toxic canine Purkinje fibers. The basis for the bigeminy appeared to be an alternans phenomenon in the delayed afterdepolarizations that induced the triggered activity, as well as in the maximal diastolic potential. The occurrence of bigeminy, previously thought to result from reentry, from single delayed afterdepolarizations coupled to a triggered action potential or from parasystole, can also be considered a manifestation of sustained triggered activity.

Mortality in the uninsured compared with that in persons with public and private health insurance.

OBJECTIVE: To compare mortality in persons with employer-provided health insurance, Medicare, Medicaid, military health benefits, other private health insurance, and no health insurance, before and after adjustment for income and employment status. DESIGN: Cohort study using national survey data containing information on social, economic, and demographic factors and health insurance, with deaths identified through matching to the National Death Index resulting in a mortality follow-up period of 5 years. SETTING: Noninstitutionalized population of the United States. PARTICIPANTS: Approximately 150,000 respondents to national surveys conducted by the US Bureau of the Census (Current Population Surveys), aged 25 to 64 years. RESULTS: After adjustment for age and income, persons with Medicare and Medicaid had the highest mortality in comparison with those with employer-provided insurance, with relative risks generally greater than 2. With adjustment for age and income, persons without insurance had higher mortality than those with employer-provided insurance, with relative risks of 1.2 for white men and 1.5 for white women. These relationships held after adjustment for employment status, with the working uninsured showing mortality between 1.2 and 1.3 times higher than that of the working insured. Mortality was higher in those with lower incomes after adjustment for insurance status. Those with annual income of $10,000 or less per year had mortality about two times that of persons with incomes greater than $25,000 per year. CONCLUSION: Mortality was lowest in employed persons with employer-provided health insurance. The higher mortality in those with public insurance or with no insurance reflects an indeterminate mix of selection on existing health status and access to medical care.

Quality of death rates by race and Hispanic origin: a summary of current research, 1999.

OBJECTIVES: This report provides a summary of current knowledge and research on the quality and reliability of death rates by race and Hispanic origin in official mortality statistics of the United States produced by the National Center for Health Statistics (NCHS). It also provides a quantitative assessment of bias in death rates by race and Hispanic origin. It identifies areas for targeted research. METHODS: Death rates are based on information on deaths (numerators of the rates) from death certificates filed in the states and compiled into a national database by NCHS, and on population data (denominators) from the Census Bureau. Selected studies of race/Hispanic-origin misclassification and under coverage are summarized on deaths and population. Estimates are made of the separate and the joint bias on death rates by race and Hispanic origin from the two sources. Simplifying assumptions are made about the stability of the biases over time and among age groups. Original results are presented using an expanded and updated database from the National Longitudinal Mortality Study. RESULTS: While biases in the numerator and denominator tend to offset each other somewhat, death rates for all groups show net effects of race misclassification and under coverage. For the white population and the black population, published death rates are overstated in official publications by an estimated 1.0 percent and 5.0 percent, respectively, resulting principally from undercounts of these population groups in the census. Death rates for the other minority groups are understated in official publications approximately as follows: American Indians, 21 percent; Asian or Pacific Islanders, 11 percent; and Hispanics, 2 percent. These estimates do not take into account differential misreporting of age among the race/ethnic groups.

Cholecystokinin and anxiety: promises and pitfalls.

In the past 5 years, considerable interest has been expressed in the possible involvement of cholecystokinin (CCK) receptor mechanisms in anxiety disorders. Stemming from early clinical observations in the 1960s and electrophysiological findings some twenty years later, this interest now encompasses research on the behavioral effects of CCK receptor agonists and antagonists at both clinical and preclinical levels. The results to date have been encouraging enough to prompt a number of pharmaceutical companies to "fast track" the development of CCK receptor antagonists as antipanic agents. The present review critically assesses research findings in this area and concludes that the field is rife with inconsistency, the date are subject to a variety of methodological and interpretative pitfalls, and, unfortunately, the promise of therapeutic advance through CCK receptor antagonists may be illusory.

The shape of the relationship between income and mortality in the United States. Evidence from the National Longitudinal Mortality Study.

A follow-up study based on a large national sample was used to examine differences in the well-established inverse gradient between income and mortality at different income levels. The study showed the income-mortality gradient to be much smaller at high income levels than at low to moderate income levels in the working age (25 to 64 years) and elderly (over 65 years) populations for men and women both before and after adjustment for other socioeconomic variables. In addition, a much larger gradient existed for working age women at extreme poverty levels than for those women at low to moderate income levels. The income-mortality gradient was much smaller in the elderly than in the working age population. The study also examined the ability of several different mathematic functions of income to delineate the relationship between income and mortality. The study suggested that the health benefits associated with increased income diminish as income increases.

Marital status and mortality: the national longitudinal mortality study.

PURPOSE: To examine the effect of marital status (married, widowed, divorced/separated, and never-married) on mortality in a cohort of 281,460 men and women, ages 45 years and older, of black and white races, who were part of the National Longitudinal Mortality Study (NLMS). METHODS: Major findings are based on assessments of estimated relative risk (RR) from Cox proportional hazards models. Duration of bereavement for the widowed is also estimated using the Cox model. RESULTS: For persons aged 45-64, each of the non-married groups generally showed statistically significant increased risk compared to their married counterparts (RR for white males, 1.24-1.39; white females, 1.46-1.49; black males, 1.27-1.57; and black females, 1. 10-1.36). Older age groups tended to have smaller RRs than their younger counterparts. Elevated risk for non-married females was comparable to that of non-married males. For cardiovascular disease mortality, widowed and never-married white males ages 45-64 showed statistically significant increased RRs of 1.25 and 1.32, respectively, whereas each non-married group of white females showed statistically significant increased RRs from 1.50 to 1.60. RRs for causes other than cardiovascular diseases or cancers were high (for white males ages 45-64: widowed, 1.85; divorced/separated, 2.15; and never-married, 1.48). The importance of labor force status in determining the elevated risk of non-married males compared to non-married females by race is shown. CONCLUSIONS: Each of the non-married categories show elevated RR of death compared to married persons, and these effects continue to be strong after adjustment for other socioeconomic factors.

The effect of combined therapy with ranitidine and pirenzepine in the treatment of reflux oesophagitis.

The combination of a histamine H2-receptor antagonist and a muscarinic receptor antagonist has been reported to result in greater suppression of intragastric acidity than either agent alone. The present randomized, double-blind, multicentre trial compared the effects of the oral combination of 150 mg ranitidine b.d. plus 50 mg pirenzepine b.d. with 150 mg ranitidine b.d. plus placebo pirenzepine b.d. in the treatment of patients with reflux oesophagitis. All 157 patients had symptoms of gastro-oesophageal reflux with endoscopically confirmed oesophageal erosions (Savary and Miller grades I-III). After four weeks of treatment, healing rates were 32/75 (43%) in the combined treatment group and 34/76 (45%) in the group receiving ranitidine alone. After eight weeks, the cumulative healing rates had increased to 48/72 (67%) and 51/75 (68%), respectively. More patients receiving ranitidine plus pirenzepine had complete relief of day- and night-time heartburn after four weeks compared with those receiving ranitidine alone (day: 59% vs. 38%, P = 0.02; night: 69% vs. 52%, P = 0.04). After eight weeks, symptom relief was comparable in both groups. Clinical adverse effects were reported by nine patients receiving ranitidine and by 19 patients receiving the combination. It is concluded that combining ranitidine with pirenzepine does not aid the healing of reflux oesophagitis but does improve symptom relief at four weeks.

Acute treatment of reflux oesophagitis: a multicentre trial to compare 150 mg ranitidine b.d. with 300 mg ranitidine q.d.s.

H2-receptor antagonists administered in conventional dosage regimens fail to heal a significant proportion of patients with moderate or severe reflux oesophagitis. We have compared the effects of a higher dose of ranitidine (300 mg q.d.s.) with the currently recommended dosage regimen (150 mg b.d.) in 138 patients suffering from reflux oesophagitis. After 4 weeks of treatment 29% of patients who received 150 mg ranitidine b.d., and 63% of patients who received 300 mg ranitidine q.d.s. had complete endoscopic healing of their lesions (P less than 0.0001). After 8 weeks these proportions had increased to 54% and 75%, respectively (P less than 0.01). After 4 weeks of treatment, compete symptomatic relief had been achieved in 46% of patients who received 150 mg ranitidine b.d. and in 67% of patients who received 300 mg ranitidine q.d.s. (P less than 0.05). After 8 weeks these proportions were 64% and 84%, respectively (P less than 0.05). Both dosage schedules were well-tolerated. We conclude that more rapid symptom relief and healing in reflux oesophagitis can be achieved with 300 mg ranitidine q.d.s. than with 150 mg ranitidine b.d.

Acute treatment of reflux oesophagitis: a multicentre study to compare 150 mg ranitidine twice daily with 300 mg ranitidine at bedtime.

A randomized, double-blind, clinical trial was undertaken to compare 150 mg ranitidine b.d. with 300 mg ranitidine nocte in the treatment of reflux oesophagitis. Endoscopy data were evaluable for 336 patients after 8 weeks of treatment. At this time 75% of patients who received 150 mg ranitidine b.d., and 73% of those who received 300 mg nocte, had healed or showed endoscopic improvement to grade I oesophagitis. At 12 weeks these rates had increased to 89 and 88%, respectively. Oesophageal biopsies from 258 patients at 8 weeks showed histological improvement in 44 and 47% of those treated with 150 mg ranitidine b.d. and 300 mg ranitidine nocte, respectively. After 12 weeks histological improvement was apparent in 57 and 54% of biopsies from each group, respectively. Symptom severity and frequency was reduced to a similar extent by both treatments. Adverse events were reported by 15 patients. A 300-mg bedtime dose of ranitidine was found to be a well-tolerated, effective alternative to twice daily treatment in reflux oesophagitis.

Ethological analysis of cholecystokinin (CCKA and CCKB) receptor ligands in the elevated plus-maze test of anxiety in mice.

The literature on the effects of CCK receptor manipulations in animal models of anxiety is rife with inconsistency, and the data subject to a variety of methodological and interpretative difficulties. In the present paper, the effects of a range of CCK receptor ligands on anxiety in male mice have been assessed using an ethological version of the elevated plus-maze test. Compounds selected for study were the agonists, CCK-4 and CCK-8s (12.5-100 micrograms/kg), and the antagonists, devazepide, L-365, 260 and PD 135158 (1.0 microgram/kg-1.0 mg/kg). CCK-4 failed to produce any significant behavioural effects over the dose range tested, while treatment with the sulphated octapeptide, CCK-8s, induced signs of behavioural inhibition at 100 microgram/kg without altering anxiety-related indices. Furthermore, in contrast to the clear anxiolytic profile of diazepam (1 mg/kg), and despite the comprehensive behavioural profiles yielded by ethological analysis, all three CCK receptor antagonists studied (devazepide, L-365, 260 and PD 135158) were found to be without significant effect under present test conditions. Together, present findings provide little support for the involvement of CCK receptor mechanisms in anxiety and, in particular, the form of anxiety evoked in mice by exposure to a plus-maze.

Resistance of experientially-induced changes in murine plus-maze behaviour to altered retest conditions.

Prior exposure to the elevated plus-maze results in profound behavioural alterations in rats and mice, with 24 h retest profiles indicative of fear sensitization. The present study was designed to examine the influence of retest cues on this phenomenon in male DBA/2 mice. Results confirmed the potent influence of prior maze experience on subsequent behavioural patterns, and showed that this was not affected by manipulations of extra-maze cues (90 degrees re-orientation of the maze or use of a different laboratory) on Trial 2. Data are discussed in relation to experientially-induced shifts in behavioural strategy and the apparent involvement of simple proximal cues (probably thigmotactic) in this enduring and adaptive form of spatial learning.

Estrogen treatment increases the oral component of apomorphine-induced stereotypy.

Twelve weeks after surgery, sham operated intact and ovariectomized (OVX) female rats were treated for 3 days with either estradiol benzoate (50 micrograms/kg per day) or the oil vehicle. They were then tested for apomorphine-induced stereotypy 24 or 72 h after the last steroid injection. The data was collected and analysed in terms of both stereotypy ratings and individual behavioural responses. Estradiol, in those animals tested 72 h after estrogen, increased the frequency of oral behaviour in intact and in OVX groups. One possible explanation for the results is that estradiol may exert an anti-dopaminergic effect in the nigrostriatal system.

Effects of stereoisomers of estradiol on food intake, body weight and hoarding behavior in female rats.

The effects of 17-alpha and 17-beta estradiol on food intake, body weight and hoarding behavior in ovariectomised rats were investigated. For five days, ten animals received subcutaneous injections of both isomers (10 micrograms/kg/day) in a counterbalanced design. Hoarding tests were conducted on the last three days of each 5-day injection period. 17-Alpha estradiol significantly reduced food intake but was without effect on body weight. 17-Beta estradiol reduced food intake significantly more than the alpha form and also significantly reduced body weight. These differential effects suggest that stereoisomers of estradiol may be acting on separate regulatory systems. The treatments did not change hoarding activity compared to pre-treatment levels.

Effects of ritanserin and 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in the murine elevated plus-maze test of anxiety: an ethopharmacological study.

The 5-HT(2A/2c) receptor antagonist, ritanserin, has produced highly variable results in animal models of anxiety. The present study addressed the effects of this compound (0.5-5.0 mg/kg) and those of the 5-HT(2A/2C) receptor agonist, 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (0.25-1.0 mg/kg), in an ethological version of the murine elevated plus-maze paradigm. In marked contrast to the potent effects produced by other compounds (anxiolytic and anxiogenic) under identical test conditions, results show that, over the dose ranges tested, neither compound significantly altered behavioural profiles. Findings are discussed in relation to the question of receptor affinities and the need for studies on compounds with more selective profiles of action.

A comparison of the relationships of education and income with mortality: the National Longitudinal Mortality Study.

A sample of over 400,000 men and women, ages 25-64, from the National Longitudinal Mortality Study (NLMS), a cohort study representative of the noninstitutionalized US population, was followed for mortality between the years of 1979 and 1989 in order to compare and contrast the functional forms of the relationships of education and income with mortality. Results from the study suggest that functional forms for both variables are nonlinear. Education is described significantly better by a trichotomy (represented by less than a high school diploma, a high school diploma or greater but no college diploma, or a college diploma or greater) than by a simple linear function for both men (p < 0.0001 for lack of fit) and women (p = 0.006 for lack of fit). For describing the association between income and mortality, a two-sloped function, where the decrease in mortality associated with a US$1000 increase in income is much greater at incomes below US$22,500 than at incomes above US$22,500, fits significantly better than a linear function for both men (p < 0.0001 for lack of fit) and women (p = 0.0005 for lack of fit). The different shapes for the two functional forms imply that differences in mortality may primarily be a function of income at the low end of the socioeconomic continuum, but primarily a function of education at the high end.

Factor analysis of spatiotemporal and ethological measures in the murine elevated plus-maze test of anxiety.

Recent research employing the elevated plus-maze to assess anxiety in rodents has incorporated a variety of behavioral elements in addition to the standard parameters of entries onto and time spent in the aversive open arms. In the present study, we have used a large database comprising the behavioral profiles of 90 undrugged mice to examine the relationship between the standard spatiotemporal measures and a range of specific behaviors related to the defensive repertoire of the mouse. A factor analysis applied to the standard measures revealed two factors related to anxiety and locomotor activity. The simple addition of center time (an infrequently recorded measure) to the analysis yielded a third factor, most probably related to decision making. A large-scale factor analysis applied to all measures further confirmed the existence of factors related to anxiety, locomotor activity, and decision making, and revealed three further factors thought to represent risk assessment, vertical activity, and exploratory behavior. Thus, the inclusion of ethological measures not only confirmed prior knowledge based on a very limited range of measures, but also demonstrated the existence of additional behavioral dimensions. The potential applications of this knowledge are discussed.