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Biomedical subjects

T M Morgan

Publications and source records attributed to T M Morgan.

At least 19 recordsLinked to original sources
PubMed1999

Migration kinetics and final destination of type 1 and type 2 CD8 effector cells predict protection against pulmonary virus infection.

The requirements for CD8 T cells to provide protection against a localized virus infection in models of adoptive immunotherapy are not well defined. Here we investigated the protective value of defined in vitro-generated hemagglutinin (HA) peptide-specific primary CD8 T cell effectors from the clone 4 T cell receptor transgenic mice, secreting type 1 or type 2 cytokines, against pulmonary infection with whole influenza virus. Cytotoxic T lymphocytes producing type 1 and type 2 cytokine (Tc1 and Tc2) populations were equally cytolytic, but Tc1 effectors and not Tc2 effectors reduced the pulmonary virus titer early during infection. Host recovery mediated by Tc1 effectors was found to be independent of interferon gamma production. Tc2 effectors entered the lung with delayed kinetics as compared with Tc1 effectors, and after lung entry Tc2 effector cells did not localize near the infected airway epithelium as did Tc1 effectors but were found within clusters of inflammatory cells distant from the epithelium. We also show that the expression of several chemokine receptors was selectively regulated in the Tc1 and Tc2 subsets. Thus, the protective value of a CD8 cell population against pulmonary influenza virus infection is strongly correlated with its ability to exert its effector potential at the site of virus infection.

Animals↗
PubMed1998

Enhanced skin permeation of sex hormones with novel topical spray vehicles.

The feasibility of using some novel topical spray vehicles for enhanced transdermal delivery of the sex hormones, testosterone (Tes), estradiol (E2), progesterone (Prog), and norethindrone acetate (NA) has been investigated. The new penetration enhancers, padimate O (PadO) and octyl salicylate (OSal) were used and compared with laurocapram (AZ) and oleic acid (OA). A finite dose (5 microL/cm2) of each vehicle was applied to either shed snake skin or swine skin in vitro, and the amount penetrated was measured with flow-through diffusion cells. Partitioning into swine skin was determined after an exposure time of 1 min. Rapid partitioning of Tes and PadO into swine skin occurred after 1 min with 70% and 60% of the applied dose, respectively, remaining in the skin after the unabsorbed dose was removed by rinsing with absolute ethanol. The cumulative amount at 24 h (Q24 h) of Tes penetrating across the snake skin was significantly enhanced (p < 0.05) up to 6-fold for OSal, 3-fold for OA and AZ, and 2-fold for PadO compared to control. Using PadO or AZ, the Q24 h ranged from three- to thirteen-fold over control (p < 0.05) for E2, Prog, and NA. Extrapolation of these data to predict what would happen in humans suggests that it should be possible to deliver clinically relevant amounts of sex hormones in this manner with once daily dosing.

4-Aminobenzoic Acid↗
PubMed1998

Enhanced transdermal delivery of sex hormones in swine with a novel topical aerosol.

This study investigated the enhanced transdermal delivery of testosterone (Tes) and estradiol (E2) in swine in vivo with novel metered-dose topical aerosols containing the penetration enhancer padimate O (PadO) and predicted the dose deliverable in humans from the calculated drug flux across the skin. Weanling swine were catheterized and castrated under general anaesthesia and used as a conscious hypogonadal model. Tes and E2 (with and without PadO) were applied once, and venous blood samples were taken over 24 h. Tes and E2 plasma levels were determined by radioimmunoassay. After daily topical dosing of Tes for 6 days, the plasma Tes levels were determined and the transdermal flux was calculated by correcting the pseudo steady-state plasma concentration versus time profile with the clearance of an iv dose within the same swine. After a single application of the E2 aerosol over 30 cm2, or the Tes aerosol over 180 cm2, the mean AUC0-24 h when PadO was included in the spray was 14.1- and 2.0-fold greater than control, respectively (p < 0.03). After the sixth application of the Tes spray with PadO, the mean flux (+/-SE, n = 4) across swine skin in vivo was 2.12 +/- 0.35 microg/cm2.h, which gave a predicted flux in humans of 0.95 microg/cm2.h. From these data the expected plasma levels of Tes in hypogonadal men would compare well with the normal diurnal Tes profile in healthy men. These novel topical aerosols are capable of enhanced transdermal delivery of sex hormones in vivo, and they have the potential to deliver clinically relevant doses to humans.

Administration, Cutaneous↗
PubMed1998

Transdermal delivery of estradiol in postmenopausal women with a novel topical aerosol.

The objective of this study was to determine if a novel metered-dose topical aerosol (MDTA) formulation containing the new dermal penetration enhancer, padimate O, could enhance the transdermal delivery of estradiol to an extent that would result in clinically relevant plasma concentrations. The estradiol MDTA (with padimate O) was applied once daily at 0800 h to postmenopausal women for 9 days, and plasma estradiol and estrone was measured daily (24 h postapplication) by radioimmunoassay. The topical dose was administered as three 1 mg doses of estradiol, each applied as a single spray over 10 cm2 which were placed adjacent to each other on the subject's ventral forearm. None of the subjects tested showed any sign of skin irritation at the application site over the entire study period using the Draize irritation score. In four postmenopausal women (age 54-63 years, weight 67-93 kg) the mean estradiol level 24 h postapplication over the 9 day study period was 53 pg/mL. This result was significantly greater (p < 0.001) than the baseline value of 13 pg/mL. The mean estradiol/estrone ratio also rose significantly (p < 0.04) from a baseline value of 0.2 up to 0.8. We conclude that this novel MDTA formulation significantly enhances the transdermal delivery of estradiol to allow a clinically relevant dose of estradiol to be delivered in postmenopausal women with once daily dosing.

4-Aminobenzoic Acid↗
PubMed1998

Activity Counseling Trial (ACT): rationale, design, and methods. Activity Counseling Trial Research Group.

The Activity Counseling Trial (ACT) is a multicenter, randomized controlled trial to evaluate the effectiveness of interventions to promote physical activity in the primary health care setting. ACT has recruited, evaluated, and randomized 874 men and women 35-75 yr of age who are patients of primary care physicians. Participants were assigned to one of three educational interventions that differ in amount of interpersonal contact and resources required: standard care control, staff-assisted intervention, or staff-counseling intervention. The study is designed to provide 90% power in both men and women to detect a 1.1 kcal.kg-1.day-1 difference in total daily energy expenditure between any two treatment groups, and over 90% power to detect a 7% increase in maximal oxygen uptake, the two primary outcomes. Primary analyses will compare study groups on mean outcome measures at 24 months post-randomization, be adjusted for the baseline value of the outcome measure and for multiple comparisons, and be conducted separately for men and women. Secondary outcomes include comparisons between interventions at 24 months of factors related to cardiovascular disease (blood lipids/lipoproteins, blood pressure, body composition, plasma insulin, fibrinogen, dietary intake, smoking, heart rate variability), psychosocial effect, and cost-effectiveness, and at 6 months for primary outcome measures. ACT is the first large-scale behavioral intervention study of physical activity counseling in a clinical setting, includes a generalizable sample of adult men and women and of clinical setting, and examines long-term (24 months) effects. ACT has the potential to make substantial contributions to the understanding of how to promote physical activity in the primary health care setting.

Adult↗
PubMed1997

Thymic stromal organization is regulated by the specificity of T cell receptor/major histocompatibility complex interactions.

The thymic architecture is normally compartmentalized into a central medulla surrounded by a peripheral cortical region. We investigated how compartmentalization of the thymic stroma is regulated using T cell receptor (TCR)-transgenic mouse models. Our studies show that the signals generated by TCR/peptide/major histocompatibility complex interactions regulate thymic stromal cell compartmentalization. In TCR-transgenic mice, normal stromal cell compartmentalization occurs when the transgenic TCR is expressed on a background that does not result in skewing toward either positive or negative selection. In models representing strong positive selection, the thymic stromal elements do not fully organize into a central medulla. Instead, small medullary foci are dispersed throughout the thymus with some regions residing directly under the capsule. The highest degree of disorganization in medullary epithelial regions is observed in TCR-transgenic mice that exhibit negative selection. Although the medullary foci lack central organization, the expression in these regions of CD80, CD86 and CD40, as well as the clustering of dendritic cells, is similar to that observed in medullae of wild-type mice. Thus, the organization of the medulla appears to occur in two stages: (1) small medullary epithelial regions that are dispersed in fetal thymi expand and associate with antigen-presenting cells, and (2) the expanded medullary foci organize into a central medullary compartment. Our data suggest a model in which this second stage of stromal cell organization is increasingly inhibited as the normal balance of TCR-mediated signals is skewed by higher-avidity interactions between thymocytes and antigen-presenting cells.

Animals↗
PubMed1996

Functional outcomes of acute medical illness and hospitalization in older persons.

BACKGROUND: Short-stay hospitalization in older patients is frequently associated with a loss of function, which can lead to a need for postdischarge assistance and longer-term institutionalization. Because little is known about this adverse outcome of hospitalization, this study was conducted to (1) determine the discharge and 3-month postdischarge functional outcomes for a large cohort of older persons hospitalized for medical illness, (2) determine the extent to which patients were able to recover to preadmission levels of functioning after hospital discharge, and (3) identify the patient factors associated with an increased risk of developing disability associated with acute illness and hospitalization. METHODS: A total of 1279 community-dwelling patients, aged 70 years and older, hospitalized for acute medical illness were enrolled in this multicenter, prospective cohort study. Functional measurements obtained at discharge (Activities of Daily Living) and at 3 months after discharge (Activities of Daily Living and Instrumental Activities of Daily Living) were compared with a preadmission baseline level of functioning to document loss and recovery of functioning. RESULTS: At discharge, 59% of the study population reported no change, 10% improved, and 31% declined in Activities of Daily Living when compared with the preadmission baseline. At the 3-month follow-up, 51% of the original study population, for whom postdischarge data were available (n=1206), were found to have died (11%) or to report new Activities of Daily Living and/or Instrumental Activities of Daily Living disabilities (40%) when compared with the preadmission baseline. Among survivors, 19% reported a new Activities of Daily Living and 40% reported a new Instrumental Activities of Daily Living disability at follow-up. The 3-month outcomes were the result of the loss of function during the index hospitalization, the failure of many patients to recover after discharge, and the development of new postdischarge disabilities. Patients at greatest risk of adverse functional outcomes at follow-up were older, had preadmission Instrumental Activities of Daily Living disabilities and lower mental status scores on admission, and had been rehospitalized. CONCLUSION: This study documents a high incidence of functional decline after hospitalization for acute medial illness. Although there are several potential explanations for these findings, this study suggests a need to reexamine current inpatient and postdischarge practices that might influence the functioning of older patients.

Activities of Daily Living↗
PubMed1996

Soybean isoflavones improve cardiovascular risk factors without affecting the reproductive system of peripubertal rhesus monkeys.

Although the beneficial effects of dietary soybean protein compared with animal proteins on plasma lipids, lipoproteins and atherosclerosis have been known for about 50 years, it has been uncertain whether these effects are due to its amino acid concentrations or other components in soybeans. To assess the effect of soybean protein's alcohol-extractable components (including the isoflavonic phytoestrogens genistein and daidzein) on plasma lipid and lipoprotein concentrations and to establish its lack of effect on the reproductive system, we fed 27 peripubertal male and female rhesus monkeys moderately atherogenic diets in which the source of dietary protein was a soy isolate (20% by weight), either containing phytoestrogens (also termed isoflavones) or with the phytoestrogens removed by alcohol extraction. The study was a crossover design with each period lasting for 6 mo. The phytoestrogen-intact soy protein (compared with the alcohol-extracted soy protein) had favorable effects on plasma lipid and lipoprotein concentrations, specifically by significantly reducing LDL+VLDL cholesterol concentrations in both males and females (approximately 30-40% lower), significantly increasing high density lipoprotein cholesterol (HDLC) concentrations for females (approximately 15% higher) and significantly lowering total plasma cholesterol (TPC):HDLC ratios (approximately 20% lower for males and 50% lower for females). The phytoestrogens had no adverse effects on the reproductive systems of either the males or females, as evaluated by reproductive hormone concentrations and organ weights at necropsy. Thus, the isoflavones in soy protein improve cardiovascular disease risk factors without apparent deleterious effects on the reproductive system of peripubertal rhesus monkeys.

Aging↗
PubMed1996

Statistical considerations in the use and analysis of single-subject designs.

Single-subject designs measure one individual's responses to some experimental manipulation. Statistical methods exist for validly estimating the effect of an intervention on a specific individual by using data from a single-subject design. However, without strong assumptions regarding how an intervention on one individual relates to its effects on others, the results from a single-subject design provide little useful information on the general utility of the intervention. Examination of a single subject cannot verify these assumptions. Correct analysis of data from such designs allows for the possibility of correlation among the observations and the modeling of any changes over time not related to an intervention effect. When data from single-subject designs are collected, the role of assumptions in both the analysis and the generality of conclusions must be frankly acknowledged. Research often develops in stages and the single-subject design can be useful in early stages for hypothesis generation.

Data Interpretation, Statistical↗
PubMed1995

Long-term (5-year) changes in HDL cholesterol in cardiac rehabilitation patients. Do sex differences exist?

BACKGROUND: It is unknown whether the benefits of a cardiac rehabilitation program on HDL cholesterol (HDL-C) are equally achieved in men and women. To study this, we compared changes in HDL-C and other lipids in a large group of men and women participating in a cardiac rehabilitation program for up to 5 years. METHODS AND RESULTS: We compared changes in HDL-C and other fasting lipids in 553 men and 166 women participating in a cardiac rehabilitation program at baseline and then annually for up to 5 years. Patients exercised 3 days a week at 70% to 85% of their maximum heart rate predetermined by a symptom-limited treadmill test. Aerobic capacity was estimated in metabolic equivalents (METs), and percent body fat was determined by skin-fold measurements. Baseline HDL-C, LDL cholesterol (LDL-C), and total cholesterol were significantly higher in women, whereas the ratio of total cholesterol to HDL-C was lower. Although both men and women showed an increase in HDL-C after 1 year (10% and 7%, respectively), only the women's level continued to increase over 5 years (20% versus 5% for men, P = .03). The sex difference in change in HDL-C remained after adjustment for age and smoking. A nonsignificant trend toward a greater change in HDL-C in women existed after adjustment for baseline percent body fat and estimated METs. The change in the ratio of total cholesterol to HDL-C was also more favorable in women, with a 38% decrease over 5 years compared with a 14% decrease in men (P = .01). Total cholesterol decreased by 20% in women and 8% in men (P = .001), whereas LDL-C dropped by 34% in women and 15% in men (P = .0001). There was no sex difference in change in triglycerides. CONCLUSIONS: Women with heart disease who participate in a cardiac rehabilitation program may achieve greater lipid benefits over longer periods of time than previously demonstrated in men.

Aged↗
PubMed1995

Lessons learned from a prospective meta-analysis.

OBJECTIVE: To describe the unique aspects of and the lessons learned in planning and conducting a pooled analysis of multiple trials evaluating interventions to reduce functional decline in hospitalized older persons. Specific examples from the Hospital Outcomes Project for the Elderly (HOPE) meta-analysis are discussed. DESIGN: A prospective meta-analysis (PMA) that compiled and pooled data from concurrently conducted clinical trials testing related but distinct interventions. SETTING: The Data Coordinating Center for the prospective meta-analysis coordinated the collection and analysis of common outcome data from five university-affiliated hospitals and one community hospital conducting the clinical trials. PARTICIPANTS: Acutely ill hospitalized elderly participants at least 65 to 75 years old. INTERVENTIONS: Treatments being evaluated included exercise, physical therapy, a multidisciplinary geriatric care unit, a multidisciplinary in-hospital intervention with post-discharge care, a nursing-based geriatric care program, and a program to improve detection and evaluation of delirious patients. CONCLUSION: The prospective meta-analysis provides selected advantages over independently conducted clinical trials and retrospective meta-analyses. It does, however, pose special design and operational challenges that must be addressed well before initiation of the individual trials. Specific issues of concern include: maintaining scientific integrity of both the individual trials and the PMA; reaching consensus on PMA goals, what data to collect, how and when to collect them and how to maintain uniformly high quality data across all sites; defining the role of the Data Coordinating Center in a multicenter project that utilizes different trials and protocols; and establishing policies concerning analyses of the pooled data, publication of pooled analyses, and ownership of the pooled database.

Aged↗
PubMed1995

Dominant social status and contraceptive hormone treatment inhibit atherogenesis in premenopausal monkeys.

The stress of social subordination is associated with exacerbation of coronary artery atherosclerosis in premenopausal cynomolgus monkeys, possibly as a result of the ovarian dysfunction that reliably accompanies subordinate social status. The primary objective of the current study was to determine whether treatment with an oral contraceptive (OC) provides relative protection from development of atherosclerotic plaques, especially among animals made vulnerable to atherosclerosis by social subordination. In the present study, 193 adult female monkeys (Macaca fascicularis) were placed in social groups of 5 or 6 animals each. Half of the animals were then fed an atherogenic diet to which had been added a triphasic OC, while the remainder received only the atherogenic diet. At the end of 26 months, atherosclerosis was measured in an iliac artery biopsy taken from each monkey. The results demonstrated that among untreated animals subordinate individuals developed significantly more atherosclerosis than did their dominant counterparts (P < .01); however, OC treatment inhibited atherosclerosis in subordinate animals (P < .05) and eliminated the difference between dominant and subordinate animals that was observed in the untreated condition. Subordinate social status and OC treatment were both associated with reduced plasma concentrations of HDL cholesterol (P < .01 for both), and subordinate monkeys also had elevations in LDL cholesterol plus VLDL cholesterol (P < .01). Nonetheless, the interaction between social status and OC treatment remained significant even after covariance adjustment for variation in plasma lipids. Taken together, these results suggest that social subordination worsens, whereas OC treatment inhibits, atherosclerosis, and that these effects are independent of concomitant variability in plasma lipids.

Animals↗
PubMed1995

Regression of atherosclerosis in female monkeys.

The objective of this study was to determine the structural and functional changes that occur in the artery wall in response to plasma lipid lowering and hormone replacement in surgically postmenopausal monkeys with established coronary artery atherosclerosis. Eighty-eight surgically postmenopausal cynomolgus monkeys were fed an atherogenic diet for 24 months and were then allocated into 4 groups: group 1 (n = 20), a baseline necropsy group; group 2 (n = 25), a lipid-lowering diet only; group 3 (n = 22), lipid lowering plus conjugated equine estrogen treatment equivalent to 0.625 mg/d for a woman; and group 4 (n = 21), lipid lowering plus conjugated equine estrogen and medroxyprogesterone acetate treatment (equivalent to 2.5 mg/d for a woman). Treatment was for 30 months. Histomorphometric analysis of perfusion-fixed coronary arteries revealed that plaque size did not change significantly in any of the groups compared with group 1 (P > .20). Plasma lipid lowering permitted coronary artery remodeling to occur (coronary artery and lumen size doubled compared with group 1) (P < .05); however, hormone therapy did not augment remodeling. Quantitative angiographic analysis of coronary artery reactivity revealed that lipid lowering improved dilator responses to acetylcholine by 22 +/- 4% (P = .01) but not to nitroglycerin (P = .23). Hormone replacement did not further affect vascular reactivity to the agonists tested (P > .4), but addition of medroxyprogesterone acetate diminished the beneficial effects of conjugated estrogens on coronary flow reserve (P = .03). In summary, the major arterial sequelae of lipid lowering in female monkeys were artery and lumen enlargement and improved reactivity of large epicardial coronary arteries. Addition of hormone replacement to the dietary modification did not further augment these improvements, except for the dilator capacity of the coronary microcirculation.

Acetylcholine↗
PubMed1994

Remodeling of coronary arteries in human and nonhuman primates.

OBJECTIVE: To compare coronary artery remodeling (compensatory enlargement) in human and nonhuman primates. DESIGN: Coronary artery data were analyzed retrospectively for 416 nonhuman primates and 100 men and women. SETTING: The monkeys had been in experiments involving diet-induced coronary artery atherosclerosis. The human hearts were obtained from the North Carolina Baptist Hospital, Winston-Salem, and age greater than 25 years was the only criterion. PATIENTS AND OTHER PARTICIPANTS: The left anterior descending coronary arteries from 100 humans, 328 cynomolgus monkeys, and 88 male rhesus monkeys were used. INTERVENTIONS: None; this was a cross-sectional observational study. MAIN OUTCOME MEASURES: Coronary artery size, lumen area, and plaque size. In the humans, we also examined demographic characteristics (ethnicity, sex, and history of hypertension) and pathologic criteria (eccentricity or concentricity of plaque area). RESULTS: On average, lumen size remained unaffected by plaque size. Lumen size was variable and could not be predicted by traditional risk factors for coronary heart disease. However, lack of compensation (decreased lumen size as plaques enlarged) and history of coronary heart disease were significantly correlated. CONCLUSIONS: The similarity of remodeling in human and nonhuman primates suggests that the process has general biologic significance. Lack of remodelling may be a major determinant of whether a person with coronary artery atherosclerosis develops its complications.

Animals↗
PubMed1994

Evaluation of effects of unmodified niacin on fasting and postprandial plasma lipids in normolipidemic men with hypoalphalipoproteinemia.

PURPOSE: The aim of this study was to define the effects of unmodified niacin on basal lipids and lipoproteins and on the plasma triglyceride response to a fatty meal--postprandial or alimentary lipemia--in individuals with low levels of high-density lipoprotein cholesterol (HDL-C) and normal fasting cholesterol and triglyceride concentrations (normolipidemic hypoalphalipoproteinemia, isolated low HDL-C). PATIENTS AND METHODS: Twenty-eight normolipidemic men (total plasma cholesterol concentration [TC] < 230 mg/dL [< 6 mmol/L], plasma triglyceride [Tg] < 250 mg/dL [2.75 mmol/L]) with low plasma concentrations of HDL-C were randomly assigned to increasing doses of crystalline niacin (up to 3,000 mg/d) or no drug for 12 weeks, then crossed over to the alternate regimen. Outcome measures included changes in plasma lipoproteins and alimentary lipemia. RESULTS: Fifteen participants completed the study. Mean baseline HDL-C +/- SD was 31.7 +/- 6.2 mg/dL (0.82 +/- 0.16 mmol/L). Mean baseline TC, plasma concentration of low-density lipoprotein cholesterol (LDL-C), and Tg were 192 +/- 29.4 mg/dL (4.97 +/- 0.76 mmol/L), 123 +/- 27 mg/dL (3.17 +/- 0.69 mmol/L), and 197 +/- 75 mg/dL (2.17 +/- 0.83 mmol/L), respectively. Unmodified niacin treatment resulted in significant (P < 0.001) reductions of 14% in TC (to 165 mg/dL, 4.26 mmol/L), 40% in Tg (to 119 mg/dL, 1.31 mmol/L), and 18% in LDL-C (to 101 mg/dL, 2.60 mmol/L) and significant increases of 30% in HDL-C (to 42 mg/dL, 1.07 mmol/L), 100% in HDL2 cholesterol (from 5 mg/dL to 9 mg/dL, 0.12 mmol/L to 0.24 mmol/L), and 21% in HDL3 cholesterol (from 27 mg/dL to 33 mg/dL, 0.70 mmol/L to 0.85 mmol/L). Unmodified niacin treatment reduced alimentary lipemia by 45% (P < 0.02). CONCLUSIONS: Crystalline niacin effectively raises HDL-C, lowers LDL-C, and reduces alimentary lipemia in patients with isolated low HDL-C. However, many patients have difficulty tolerating the drug, and supervision may be required to sustain patient compliance and avoid toxicity.

Dietary Fats↗
PubMed1994

Clinical application of polymerase chain reaction amplification to diagnosis of herpes virus infection.

Amplification of viral DNA offers a potentially sensitive and specific method for identifying herpes viruses in pathologic specimens. The purpose of this study is to assess the value of polymerase chain reaction amplification of DNA as a diagnostic test for herpes virus in pathologic specimens. The purpose of this study is to assess for herpes virus infections. We examined 79 paraffin-embedded tissue samples from 43 patients and 55 viral culture samples from 45 patients. Herpes virus DNA in the specimens was amplified by polymerase chain reaction. Using paraffin-embedded tissue on which a diagnosis of herpes virus was made by morphologic criteria, 11 of 19 patients had herpes virus DNA identified by PCR; herpes virus DNA was not identified in any of 35 negative control specimens. Herpes virus DNA was also identified by polymerase chain reaction in all of the positive herpes virus culture specimens. Of 29 culture negative specimens, herpes virus DNA was identified in six. We conclude that polymerase chain reaction is useful to establish or confirm the presence of a herpes virus infection in paraffin-embedded tissue samples and that it is more sensitive than viral culture.

DNA, Viral↗