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Biomedical subjects

B G White

Publications and source records attributed to B G White.

At least 19 recordsLinked to original sources
PubMed2005

Expression of alpha5 integrin (Itga5) is elevated in the rat myometrium during late pregnancy and labor: implications for development of a mechanical syncytium.

The underlying mechanisms controlling uterine contractions during labor are still poorly understood. Integrins are heterodimeric, transmembrane receptors composed of alpha and beta subunits that can be found in focal adhesions. Because these structures play an important role in the regulation of smooth muscle contractility and cell adhesion, we hypothesized that alpha5 integrin mRNA (Itga5) and protein (ITGA5) expression would be induced in the rat myometrium during late pregnancy and labor. Itga5 mRNA expression was significantly increased (P < 0.05) from Day 17 to labor, noticeably decreasing 1 day postpartum (PP). Immunoblot analysis illustrated a continual increase in ITGA5 levels during pregnancy, labor, and PP, with levels reaching significance at labor (P < 0.05). Analysis of ITGA5 expression by immunocytochemistry demonstrated that it is primarily localized to myometrial cell membranes in the longitudinal muscle layer of the myometrium from before pregnancy to Day 6, and in both the longitudinal and circular muscle layers from Day 15 to PP. Treatment of late-pregnant rats with progesterone blocked labor and resulted in sustained expression of Itga5 mRNA expression to Day 24. In addition, immunocytochemistry experiments showed ITGA5 was detectable at higher levels in cell membranes of both myometrial layers in progesterone-treated animals on Days 23 and 24, compared with vehicle controls. We propose that ITGA5, with its sole known partner, ITGB1, may be important in promoting cellular cohesion during late pregnancy. This process may aid the development of a mechanical syncytium for efficient force transduction during the sustained, coordinated, and powerful contractions of labor.

Animals↗
PubMed2005

Small heat shock protein 27 (Hsp27) expression is highly induced in rat myometrium during late pregnancy and labour.

The underlying mechanisms that regulate uterine contractions during labour are still poorly understood. A candidate regulatory protein is heat shock protein 27 (Hsp27). It belongs to the small heat shock protein family and can regulate actin cytoskeleton dynamics, act as a chaperone, and may regulate contractile protein activation. As a result, we hypothesized that Hsp27 expression would be highly induced during late pregnancy and labour. Hsp27 mRNA expression was significantly elevated (P <0.05) on days 17 to 22 of gestation. In addition, immunoblot analysis demonstrated that detection of total Hsp27 increased (P <0.05) between day 21 and 1 day post-partum (PP) inclusive. Since phosphorylation of Hsp27 has been reported to be a prerequisite for smooth muscle contraction, we examined the temporal and spatial expression of Ser-15 phosphorylated Hsp27. Immunoblot analysis showed that the detection of Ser-15 phosphorylated Hsp27 significantly increased (P <0.05) between days 19 and 23 (active labour) inclusive, in parallel with detection of total Hsp27. Immunocytochemical analysis of Ser-15 phosphorylated Hsp27 expression in situ demonstrated that phosphorylated Hsp27 in circular muscle became detectable in peri-nuclear and membrane regions on days 19 to 22, but was primarily restricted to the cytoplasm on days 23 to PP. In contrast, phosphorylated Hsp27 in longitudinal muscle was primarily detected in myocyte membranes on days 15 to 22, and then also became detectable in the cytoplasm of myocytes on days 23 and PP. Our results demonstrate that Hsp27 expression is highly upregulated during late pregnancy and labour and suggest that Hsp27 is a potential candidate contraction-associated protein.

Animals↗
PubMed2001

Cytokines and cytokine receptors in advanced heart failure: an analysis of the cytokine database from the Vesnarinone trial (VEST).

BACKGROUND: Previous reports have shown that elevated circulating levels of cytokines and/or cytokine receptors predict adverse outcomes in patients with heart failure. However, these studies were limited by small numbers of patients and/or they were performed in a single center. In addition, these studies did not have sufficient size to address the influence of age, race, sex, and cause of heart failure on the circulating levels of these inflammatory mediators in patients with heart failure. METHODS AND RESULTS: We analyzed circulating levels of cytokines (tumor necrosis factor [TNF] and interleukin-6) and their cognate receptors in 1200 consecutive patients who were enrolled in a multicenter clinical trial of patients with advanced heart failure. This analysis constitutes the largest analysis of cytokines and cytokine receptors to date. Analysis of the patients receiving placebo showed that increasing circulating levels of TNF, interleukin-6, and the soluble TNF receptors were associated with increased mortality. In men, there was a linear increase in circulating levels of TNF with advancing age. Women < or = 50 years of age had relatively low levels of TNF, but TNF levels were disproportionately higher in women >50 years of age. No differences existed in cytokines and/or cytokine receptors in whites versus nonwhites, and circulating levels of cytokines and cytokine receptors were significantly greater in patients with ischemic heart disease. CONCLUSIONS: Cytokines and cytokine receptors are independent predictors of mortality in patients with advanced heart failure. Moreover, circulating levels of cytokines are modified by age, sex, and cause of heart failure.

Adult↗
PubMed2001

Effects of vesnarinone on peripheral circulating levels of cytokines and cytokine receptors in patients with heart failure: a report from the Vesnarinone Trial.

STUDY OBJECTIVES: Proinflammatory cytokines may contribute to disease progression in heart failure by virtue of the direct toxic effects that these molecules exert on the heart and the circulation. Accordingly, there is interest in developing therapeutic agents with anticytokine properties that might be used as adjunctive therapy to modulate proinflammatory cytokine levels in patients with heart failure. Previous experimental studies suggested that vesnarinone has potent anticytokine properties in vitro. Therefore, we examined the effects of vesnarinone on circulating levels of cytokines and cytokine receptors in a large-scale, multicenter, clinical trial of patients with moderate-to-advanced heart failure: the Vesnarinone Trial (VEST). METHODS: Circulating levels of tumor necrosis factor (TNF)-alpha, soluble TNF-receptor type 1, soluble TNF-receptor type 2, as well as interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R) were measured on plasma samples by enzyme-linked immunosorbent assay at baseline and at 24 weeks in patients who were receiving placebo (n = 352), 30 mg of vesnarinone (n = 367), and 60 mg of vesnarinone (n = 327). RESULTS: Treatment with 30 mg and 60 mg of vesnarinone had no effect on circulating levels of cytokines or cytokine receptors in patients with advanced heart failure over a 24-week period. CONCLUSIONS: In contrast to the potent anticytokine effects observed with vesnarinone in experimental studies in vitro, the results of this clinical study suggest that vesnarinone does not have any measurable anticytokine effects in vivo in patients with moderate-to-advanced heart failure.

Cardiotonic Agents↗
PubMed2000

Estrogen is associated with improved survival in aging women with congestive heart failure: analysis of the vesnarinone studies.

OBJECTIVES: This study sought to evaluate the effects of postmenopausal estrogen use on mortality in aging women with congestive heart failure (CHF). BACKGROUND: The age-related increase in CHF mortality in women may be related to a menopause-associated increased incidence of coronary artery disease. In addition to inhibiting coronary atherosclerosis, estrogen may also have protective effects on cardiac myocytes independent of the coronary vasculature. We hypothesized that estrogen use is associated with improved survival in elderly women with CHF. METHODS: Associations between survival, estrogen use and patient characteristics were assessed in 1,134 women who were at least 50 years of age, had CHF and left ventricular ejection fraction (EF) < or =30% and were enrolled in one of three clinical trials of vesnarinone. RESULTS: All-cause 12-month mortality was 15.0% among the 237 estrogen users versus 27.1% among the 897 estrogen nonusers (p = 0.004 for unadjusted comparison of survival). Similar results were observed for cardiac mortality. Regression analysis demonstrated that estrogen use was independently associated with improved survival (relative risk of mortality = 0.68, 95% confidence interval 0.48 to 0.96, p = 0.03). Advanced age, low EF, New York Heart Association class IV CHF, Caucasian race and abnormal serum creatinine, sodium, potassium and transaminase were independently associated with increased mortality. CONCLUSIONS: Estrogen use among older women with CHF is associated with decreased overall and cardiac mortality.

Aged↗
PubMed1999

Natural variability of circulating levels of cytokines and cytokine receptors in patients with heart failure: implications for clinical trials.

OBJECTIVES: The purpose of this study was to examine the variability in cytokines and cytokine receptors in patients with heart failure in comparison with a group of healthy control subjects who were free of cardiovascular disease. BACKGROUND: Despite increasing interest in cytokines as mediators of disease progression in heart failure and the recent interest in suppressing cytokines in clinical studies, the extent of variability in cytokines and cytokine receptors is largely unknown. This information is important for interpreting the results of studies in which changes in cytokine levels are measured in response to a specific form of therapy. METHODS: Circulating levels of tumor necrosis factor-alpha (TNF-alpha), and soluble TNF receptors (types 1 and 2), as well as interleukin (IL)-6 and IL-6 receptor were measured on a daily, weekly and monthly basis in heart failure patients (New York Heart Association class IIIa and IIIb; n = 10) and healthy volunteer subjects (n = 10). Measurements of cytokines and cytokine receptors were performed on plasma samples by enzyme-linked immunoassay. The daily, weekly and monthly degree of variability in cytokine and cytokine receptor levels was assessed by determining the coefficient of variation each point in time. RESULTS: The coefficient of variation for TNF-alpha and IL-6 levels increased over time in patients with heart failure; moreover, the coefficient of variation in heart failure subjects was significantly greater for IL-6 than for TNF-alpha. The coefficient of variation in cytokine receptor levels was minimal, and did not differ significantly between heart failure and control subjects. CONCLUSIONS: In patients with heart failure the degree of natural variability in circulating cytokine levels increases with time, and is greater for IL-6 than for TNF-alpha. Accordingly, the results of the present study suggest that the sample size needed to show a statistically significant change in the circulating level of a given cytokine will vary depending on the specific cytokine that is being measured, as well as the time period over which that cytokine is being assayed.

Adult↗
PubMed1999

Effect of inotrope withdrawal on morbidity and mortality in patients with chronic heart failure: results of the vesnarinone trial withdrawal substudy. Vest Withdrawal Substudy Group.

BACKGROUND: The use of inotropic agents in the therapy of patients with congestive heart failure (CHF) is controversial. One concern regarding inotropic therapy has been that drug withdrawal could be associated with a worsening of symptoms. METHODS AND RESULTS: We took advantage of the discontinuation of the recent trial of vesnarinone in the therapy of CHF to assess the effects of withdrawal of the inotropic agent, vesnarinone, in patients with chronic CHF who had been randomized to receive either placebo or 30 or 60 mg of vesnarinone. Contrary to our initial hypothesis, withdrawal of vesnarinone did not impact on either morbidity or mortality over a period of 6 months. CONCLUSION: Although these results suggest vesnarinone withdrawal is safe, the applicability of these results to other inotropic agents remains unclear.

Cardiotonic Agents↗
PubMed1998

A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators.

BACKGROUND: Vesnarinone, an inotropic drug, was shown in a short-term placebo-controlled trial to improve survival markedly in patients with severe heart failure when given at a dose of 60 mg per day, but there was a trend toward an adverse effect on survival when the dose was 120 mg per day. In a longer-term study, we evaluated the effects of daily doses of 60 mg or 30 mg of vesnarinone, as compared with placebo, on mortality and morbidity. METHODS: We enrolled 3833 patients who had symptoms of New York Heart Association class III or IV heart failure and a left ventricular ejection fraction of 30 percent or less despite optimal treatment. The mean follow-up was 286 days. RESULTS: There were significantly fewer deaths in the placebo group (242 deaths, or 18.9 percent) than in the 60-mg vesnarinone group (292 deaths, or 22.9 percent) and longer survival (P=0.02). The increase in mortality with vesnarinone was attributed to an increase in sudden death, presumed to be due to arrhythmia. The quality of life had improved significantly more in the 60-mg vesnarinone group than in the placebo group at 8 weeks (P<0.001) and 16 weeks (P=0.003) after randomization. Trends in mortality and in measures of the quality of life in the 30-mg vesnarinone group were similar to those in the 60-mg group but not significantly different from those in the placebo group. Agranulocytosis occurred in 1.2 percent of the patients given 60 mg of vesnarinone per day and 0.2 percent of those given 30 mg of vesnarinone. CONCLUSIONS: Vesnarinone is associated with a dose-dependent increase in mortality among patients with severe heart failure, an increase that is probably related to an increase in deaths due to arrhythmia. A short-term benefit in terms of the quality of life raises issues about the appropriate therapeutic goal in treating heart failure.

Aged↗
PubMed1995

A quarter-century of experience with career change education: an option for turning specialists into generalists.

The Physician Refresher program, now 25 years old, at the Medical College of Pennsylvania offers training to clinically inactive physicians. The authors examined the characteristics of program participants to determine whether specialists who took the program to prepare for a change to a primary care career made the intended change. Application data from all registrants between 1982 and 1993 were compared with data on previously reported groups from 1968-1975 and 1976-1981. Specialist registrants' subsequent practice activities were documented from the AMA Medical Directory and the American Board of Medical Specialties Directory; a telephone survey elicited their reasons for making or not making the career change to primary care. During the last decade of the program women registrants constituted 36% of the total; international medical graduates (IMGs) 43%; and clinically inactive physicians 38%. Specialists outnumbered those in primary care by two to one. Although 65% of specialists planned to switch to primary care, ultimately only 27% of the total did so; many, especially the IMGs, were serving the disadvantaged. Those who did not switch cited a variety of disincentives, including individual educational needs not met by a general refresher course. If the medical profession accepts the need to devise programs that "retool" specialists to provide primary care, those programs should be specifically designed to address the individual needs of the specialists involved. Concomitantly, the incentives to make the switch need to be enhanced.

Adult↗
PubMed1988

A double-masked comparison of carteolol and timolol in ocular hypertension.

We performed a double-masked study in which 98 patients with ocular hypertension who had been previously treated with timolol received either timolol 0.25% or carteolol 1%, a beta-blocker with intrinsic sympathomimetic activity. The drugs were administered topically twice daily for one month after a one-week washout period. Intraocular pressure was measured at baseline and after one and four weeks of treatment. The appearance of the fundus, external eye, visual fields, tear secretion, blood pressure, and pulse were recorded. Adverse symptoms were elicited using a menu-type questionnaire and an overall judgment of therapy was recorded. Carteolol was as effective as timolol in reducing intraocular pressure. There were significantly fewer patients reporting adverse events overall (P = .019), and eye irritation specifically (P = .02), in the group treated with carteolol.

Administration, Topical↗
PubMed1985

Advances in the clinical development of antiepileptic drugs.

In this paper we describe advances in the clinical development of antiepileptic drugs as a function of the Antiepileptic Drug Development Program of the National Institute of Neurological and Communicative Disorders and Stroke. This program encompasses both the preclinical and clinical elements of drug development through the Anticonvulsant Screening Project, the Toxicology Project, and the support of controlled clinical trials of potential new drugs that emerge from these projects and promise to be more effective and less toxic than those currently available for the treatment of epilepsy.

Animals↗
PubMed1985

The Antiepileptic Drug Development Program: an example of government-industry collaboration.

By collaborating with the pharmaceutical industry in key areas of drug development, the ADD Program of the Epilepsy Branch, National Institute of Neurological and Communicative Disorders and Stroke, has responded to the need for more effective and less toxic antiepileptic drugs than those currently available. The program screens large numbers of compounds for anticonvulsant activity, conducts toxicology studies, and sponsors clinical trials of promising new drugs for the treatment of epilepsy. This collaboration with the pharmaceutical industry is providing a valuable model for a shared drug development program.

Anticonvulsants↗
PubMed1983

Clinical and EEG estimates of absence seizure frequency.

Absence seizure frequency was estimated in 20 patients (5 to 15 years old) before and after treatment with ethosuximide. Estimates were obtained from mothers' histories, observations by nurses, intensive observation by trained observers, physical and neurological examinations, routine EEG, and 12-hour telemetered EEG. Both before treatment (high seizure frequency) and after treatment (low frequency), telemetered EEG was the most reliable method of estimation, and intensive observation was the next best method. After treatment, the mothers' and nurses' estimates of seizure frequency were significantly less than the telemetered EEG estimates. The neurological examination and routine EEG were sufficient to diagnose absence attacks in all 20 patients and to determine if the attacks were completely controlled by therapy in all but two patients.

Adolescent↗
PubMed1981

Visual evoked potentials and eye dominance.

The amplitudes of pattern-reversal VEPs in 25 healthy volunteers were significantly higher from the dominant eye than the non-dominant eye in right eye dominant subjects. The difference was present over both hemispheres and over the midline. Handedness did not appear to influence the amplitude asymmetry. A similar trend was noted in left eye dominant subjects, but the difference was significantly only at O2. The mean latency of the P100 peak was significantly shorter with stimulation of the dominant eye. These amplitude and latency disparities between dominant and non-dominant eyes provide electrophysiological evidence of lateralization in the nervous system.

Analysis of Variance↗
PubMed1981

The hospital experience and seizure control.

We studied 30 patients who were admitted to the hospital because of intractable seizures. Twenty-three had fewer seizures during one or both of the first 2 hospital weeks than before admission, although medication was not changed. The role of environment in seizure control is difficult to measure, but hospital admission itself is a form of environmental manipulation. When seizure control is achieved in the hospital, the hospital experience itself must be considered in addition to other therapeutic interventions.

Anticonvulsants↗