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Biomedical subjects

J A Dodge

Publications and source records attributed to J A Dodge.

At least 37 records · Page 2Linked to original sources
PubMed1999

Survival estimates for adults with cystic fibrosis born in the United Kingdom between 1947 and 1967. The UK Cystic Fibrosis Survey Management Committee.

BACKGROUND: The UK has published observed cohort survival figures for subjects with cystic fibrosis born since 1968. Prior to 1968 cohorts cannot be established directly from routine data as cystic fibrosis was classified with a number of unrelated conditions in ICD7. Reported here are interrupted survival curves from 1978 for patients with cystic fibrosis born before 1968. METHODS: Life tables for the three year cohorts born between 1947 and 1967 were constructed by firstly estimating the numbers of patients with cystic fibrosis born in each cohort from live birth data and the disease incidence. The number of the estimated cohort that had survived to 1978 is known, which enables the proportion surviving to 1978 to be calculated. The survival of these cohorts after 1978 can be calculated in the usual way. RESULTS: The survival for each successive cohort was better than that of the previous one, but most of the improvements appear to have taken place up to the age of about 20 years. Only 3% of the 1947-49 cohort survived to 30 years of age compared with 21% for the 1965-67 cohort, and 3% of the 1953-55 cohort survived to 40 years of age. For the later cohorts the mortality rate for those aged between 26 and 30 years appears to be about 50 per 1000 per year. CONCLUSIONS: While the trend in the numbers surviving into later adulthood is upwards, the mortality rates for these ages does not appear to be improving. It is not possible to tell from these data whether the high mortality rates in adulthood will improve with better resourced adult clinics or with improved treatment during childhood.

Adult↗
PubMed1999

Exploring self-efficacy as a predictor of disease management.

Self-efficacy is posited in social cognitive theory as fundamental to behavior change. Few health behavior studies have examined self-efficacy prospectively, viewed it as part of a reciprocal behavioral process, or compared self-efficacy beliefs in the same population across different behaviors. This article first discusses self-efficacy in its theoretical context and reviews the available prospective studies. Second, it explores self-efficacy as a predictor of disease management behaviors in 570 older women with heart disease. Although the R2 statistics in each case were modest, the construct is shown to be a statistically significant (p<.05) predictor at both 4 and 12 months postbaseline of several disease management behaviors: using medicine as prescribed, getting adequate exercise, managing stress, and following a recommended diet. Building self-efficacy is likely a reasonable starting point for interventions aiming to enhance heart disease management behaviors of mature female patients.

Adaptation, Psychological↗
PubMed1999

The impact of a disease-management program on the symptom experience of older women with heart disease.

This study describes the symptom experience of 570 older women with heart disease and evaluates a disease-management program's impact on symptoms over time. Women were randomly assigned to either usual care or a 4-week program ("Women take PRIDE") designed to improve self-regulation skills by focusing on increasing physical activity. At 4 months follow-up, program women, compared to controls, reported fewer total symptoms (p = 0.01) and decreased symptom frequency (p = 0.02) and bothersomeness (p = 0.02). By 12 months, positive intervention effects emerged within the common cardiac and sleep and rest symptom categories. Program group women reported more improvements in symptoms likely to be affected by increasing physical activity at both follow-ups (p < 0.05).

Aged↗
PubMed1998

Paediatric and hereditary aspects of chronic pancreatitis.

Cystic fibrosis is by far the commonest cause of chronic pancreatitis in children, but pancreatitis itself is only rarely its presenting feature. In this paper an hypothesis for the development of the pancreatic lesions is presented. Impaired activation of pancreatic proteases in the small intestine is perceived as the pivotal problem that leads to continual feedback release of cholecystokinin, thus, in effect, causing a chronic hyperstimulation pancreatitis with intra-acinar activation of zymogens and, when bicarbonate secretion falls, precipitation of 'Reg' and other proteins in the duct system. This position contrasts with that in hereditary pancreatitis in which a mutation in the cationic trypsinogen gene leads to a form of trypsin that resists degradation by mesotrypsin and enzyme Y. A survey of the literature suggests that oxidant stress is a plausible contributor to pancreatic injury in both these diseases and in several other conditions linked with childhood pancreatitis.

Acute Disease↗
PubMed1998

Incidence of molecular forms of bile salt-stimulated lipase in preterm and term human milk.

Preterm and term human milk samples obtained at various times after delivery were analyzed for the presence of molecular forms of the human milk enzyme, bile salt-stimulated lipase (BSSL). Thirty-five percent of both the preterm and term milk samples contained two molecular forms of BSSL, of variable molecular mass. The remainder contained only one molecular species of either 115 kD (50%) or 120 kD (15%). The number of molecular forms present was not related to length of lactation, maternal age, gestation, or maternal blood group. The specific activity of BSSL purified from term milk was similar to that purified from preterm milk, and there was no difference in specific activity whether one or two molecular forms were present. This study demonstrates heterogeneity of both molecular mass and molecular forms. We conclude that preterm babies fed their own mother's milk are unlikely to be disadvantaged with respect to fat digestion as BSSL secreted in preterm milk appears to be very similar to that produced in term milk, although we cannot exclude other functional differences.

Adult↗
PubMed1998

Selective estrogen receptor modulators (SERMs).

Naturally occurring estrogens, such as 17 beta-estradiol and estrone, have traditionally been thought to play a central role in the development and maintenance of the female reproductive system and secondary sexual characteristics. In recent years, their beneficial effects on the skeleton, the cardiovascular system, and the central nervous system, as well as the cancer risks associated with long term exposure have also been recognized. The widespread use of "antiestrogens" such as tamoxifen for the prevention and treatment of breast cancer has revealed that such compounds, while functioning as estrogen antagonists in mammary tissue, actually mimic the effects of estrogen in other tissues. The search for more selective agents has led to the development of raloxifene, a Selective Estrogen Receptor Modulator, which functions as an estrogen antagonist in the breast and uterus and as an estrogen agonist in the skeleton and cardiovascular system. Recent progress in the development of SERMs is the subject of this review, with an emphasis on structure activity relationships and on their effects in non-traditional target tissues.

Animals↗
PubMed1997

Molecular determinants of tissue selectivity in estrogen receptor modulators.

Interaction of the estrogen receptor/ligand complex with a DNA estrogen response element is known to regulate gene transcription. In turn, specific conformations of the receptor-ligand complex have been postulated to influence unique subsets of estrogen-responsive genes resulting in differential modulation and, ultimately, tissue-selective outcomes. The estrogen receptor ligands raloxifene and tamoxifen have demonstrated such tissue-specific estrogen agonist/antagonist effects. Both agents antagonize the effects of estrogen on mammary tissue while mimicking the actions of estrogen on bone. However, tamoxifen induces significant stimulation of uterine tissue whereas raloxifene does not. We postulate that structural differences between raloxifene and tamoxifen may influence the conformations of their respective receptor/ligand complexes, thereby affecting which estrogen-responsive genes are modulated in various tissues. These structural differences are 4-fold: (A) the presence of phenolic hydroxyls, (B) different substituents on the basic amine, (C) incorporation of the stilbene moiety into a cyclic benzothiophene framework, and (D) the imposition of a carbonyl "hinge" between the basic amine-containing side chain and the olefin. A series of raloxifene analogs that separately exemplify each of these differences have been prepared and evaluated in a series of in vitro and in vivo assays. This strategy has resulted in the development of a pharmacophore model that attributes the differences in effects on the uterus between raloxifene and tamoxifen to a low-energy conformational preference imparting an orthogonal orientation of the basic side chain with respect to the stilbene plane. This three-dimensional array is dictated by a single carbon atom in the hinge region of raloxifene. These data indicate that differences in tissue selective actions among benzothiophene and triarylethylene estrogen receptor modulators can be ascribed to discrete ligand conformations.

Animals↗
PubMed1997

Evaluation of the major metabolites of raloxifene as modulators of tissue selectivity.

Raloxifene (LY139481 HCl) is a selective estrogen receptor modulator (SERM) which blocks the effects of estrogen on some tissues, such as the breast and uterus, while mimicking estrogen in other tissues, such as bone. To study the origins of this unique pharmacology, we have prepared the major metabolites of raloxifene as chemical probes for examining the estrogen receptor function in vitro and in vivo. In human breast cancer cell (MCF-7) related assays, these glucuronide conjugates show little affinity for the estrogen receptor and are more than two orders of magnitude less potent at inhibiting cell proliferation than raloxifene. In non-traditional estrogen target tissue, such as bone, these metabolites are less effective than the parent at inhibiting cytokine-stimulated bone resorbing activity in rat osteoclasts or producing transforming growth factor beta-3 (TGF-beta3). In animal models, tissue distribution studies with radiolabelled metabolite indicate that conversion to raloxifene occurs readily in a variety of tissues including the liver, lung, spleen, kidney, bone and uterus. Differential conversion of metabolite in target organs, such as bone and the uterus, is not observed indicating that the origin of raloxifene's pharmacology does not result from tissue-selective deconjugation of metabolite to parent.

Adenocarcinoma↗
PubMed1997

Incidence, population, and survival of cystic fibrosis in the UK, 1968-95. UK Cystic Fibrosis Survey Management Committee.

The UK Cystic Fibrosis Survey holds data on all people resident in the UK who were diagnosed as having cystic fibrosis and born either since 1968 or before 1968 and alive in 1977. Thus, incidence may be reported from 1968 and prevalence from 1977. The previous estimates are updated to the end of 1995 from data held in the database on 23 August 1996. The incidence is now calculated as one in 2415 live births. The 1992 mid-year population was 6500 people with 65% aged under 16 years. Births outnumber deaths by 160 per year, which suggests a population of 7750 by the year 2000, with all the increase being in the adult age range. The survival of successive cohorts continues to be better than earlier cohorts, the linear descent of the curves is still evident. The infant mortality rate for cystic fibrosis is now under 20 per thousand per year and early childhood mortality is under five per thousand per year. The crude mortality rate for 1995 was 21 per thousand per year, but the standardised mortality ratio was about 3300.

Adolescent↗
PubMed1997

Height and weight in cystic fibrosis: a cross sectional study. UK Cystic Fibrosis Survey Management Committee.

Cross sectional data reporting the height, weight, and body mass index of UK patients with cystic fibrosis are presented. During the first decade of life height and weight in patients with cystic fibrosis are maintained at about 0.5 SD below those of the general population, which reflects an improvement over earlier published observations. Postpubertal stature and weight maintenance in the cystic fibrosis population still show substantial deficits which may be related to treatment.

Adolescent↗
PubMed1997

Confidential inquiry into families with two siblings with cystic fibrosis.

OBJECTIVE: To audit the care that had been provided to couples before the birth of a child with cystic fibrosis where a sibling had been previously diagnosed. DESIGN: Retrospective review of case notes. SAMPLE: Families where at least one affected child had been born between 1 January 1991 and 30 June 1995 and the diagnosis in the first child was made before the second affected pregnancy reached 20 weeks. The combination of information on these families with data from the prenatal diagnosis register allowed the reconstruction of a cohort of pregnancies in women with a previous affected child. MAIN RESULTS: Forty six eligible families with a second affected child were identified. Details from the paediatrician who had diagnosed the first affected child were obtained in 43 cases: all 43 couples were offered genetic counselling, but where provided by a paediatrician this was difficult to assess as no couple was sent a summary letter. Details were obtained from the obstetrician in the subsequent affected pregnancy in 42 cases: prenatal diagnosis was not offered in 10 (24%), offered and declined in 24 (57%), offered and accepted but termination declined in eight (19%). In the overall cohort of at risk pregnancies, the estimated rate of prenatal diagnosis offer was 97%, prenatal diagnosis uptake 86%, false negative prenatal diagnosis rate 0%, and uptake of termination 95%. CONCLUSIONS: (1) Parental choice was an important determinant of second affected births. (2) Despite widespread availability, prenatal diagnosis was not offered in an estimated 3% of at risk pregnancies. (3) There were shortcomings in counselling documentation, in particular failure to send a summary letter to counselled couples.

Abortion, Legal↗
PubMed1997

Randomised controlled trial of an aggressive nutritional regimen in sick very low birthweight infants.

AIMS: To improve energy intake in sick very low birthweight (VLBW) infants; to decrease growth problems, lessen pulmonary morbidity, shorten hospital stay, and avoid possible feeding related morbidity. Morbidity in VLBW infants thought to be associated with parenteral and enteral feeding includes bronchopulmonary dysplasia, necrotising enterocolitis, septicaemia, cholestasis and osteopenia of prematurity. METHODS: A prospective randomised controlled trial (RCT) comparing two types of nutritional intervention was performed involving 125 sick VLBW infants in the setting of a regional neonatal intensive care unit. Babies were randomly allocated to either an aggressive nutritional regimen (group A) or a control group (group B). Babies in group B received a conservative nutritional regimen while group A received a package of more aggressive parenteral and enteral nutrition. Statistical analysis was done using Student's t test, the Mann-Whitney U test, the chi 2 test and logistic regression. RESULTS: There was an excess of sicker babies in group A, as measured by initial disease severity (P < 0.01), but mean total energy intakes were significantly higher (P < 0.001) in group A at days 3 to 42 while receiving total or partial parenteral nutrition. Survival and the incidences of bronchopulmonary dysplasia, septicaemia, cholestasis, osteopenia and necrotising enterocolitis were similar in both groups. Growth in early life and at discharge from hospital was significantly better in babies in group A. There were no decreases in pulmonary morbidity or hospital stay. CONCLUSION: Nutritional intake in sick VLBW infants can be improved without increasing the risk of adverse clinical or metabolic sequelae. Improved nutritional intake resulted in better growth, both in discharge, but did not decrease pulmonary morbidity or shorten hospital stay.

Bacterial Infections↗
PubMed1996

Studies on the mechanism of phosphatidylinositol 3-kinase inhibition by wortmannin and related analogs.

Wortmannin, a fungal metabolite, was identified as a potent inhibitor (IC50 = 4.2 nM) of phosphatidylinositol 3-kinase (PI 3-kinase). Due to the importance of PI 3-kinase in several intracellular signaling pathways, structure-activities studies on wortmannin analogs were performed in an effort to understand the structural requirements necessary for PI 3-kinase inhibition. Since wortmannin is an irreversible inhibitor of PI 3-kinase, it was postulated that covalent attachment at the electrophilic C-21 site was a possible mode of action for PI 3-kinase inhibition. We have prepared various wortmannin analogs which address the possibility of this mechanism. Of particular interest are compounds which affect the C-21 position of wortaminnin either sterically or electronically. Our results support the conclusion that nucleophilic addition by the kinase onto the C-21 position of wortmannin is required for inhibition of PI 3-kinase by wortmannin analogs. Additionally, we have prepared several D-ring analogs of wortmannin, and their activities are reported herein. We conclude that the wortmannin D ring is an important recognition site since modifications have such a dramatic effect on inhibitor potency. Finally, the identification of 17beta-hydroxywortmannin represents the first reported subnanomolar inhibitor of PI 3-kinase. These studies, along with in vivo antitumor experiments, suggest that the mechanism of PI 3-kinase inhibition correlates to the associated toxicity observed with wortmannin-based inhibitors of PI 3-kinase.

Androstadienes↗
PubMed1996

Environmental estrogens: effects on cholesterol lowering and bone in the ovariectomized rat.

Representative non-steroidal estrogens, from common environmental sources such as plants, pesticides, surfactants, plastics, and animal health products, demonstrated an ability to lower serum cholesterol and prevent bone loss. Specifically, select environmental estrogens (coumestrol, genistein, methoxychlor, bisphenol A, and zeranol) effectively lowered total serum cholesterol in an estrogen-dependent animal model, the ovariectomized rat. Of these entities, coumestrol, methoxychlor, and zeranol prevented ovariectomy-induced bone loss. In an in vitro environment, these compounds competed with 17beta-estradiol for estrogen receptor binding and stimulated cell proliferation in a human breast cancer cell line (MCF-7). In addition to their well-documented effects on reproductive tissue, various environmental estrogens can dramatically affect non-reproductive parameters such as cholesterol lowering and bone metabolism.

Adenocarcinoma↗