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Biomedical subjects

C Hall

Publications and source records attributed to C Hall.

At least 127 records · Page 7Linked to original sources
PubMed1997

Estimation of transplacental and nonplacental diphenhydramine clearances in the fetal lamb: the impact of fetal first-pass hepatic drug uptake.

Previous estimates of maternal and fetal placental and nonplacental clearances in pregnant sheep using a two-compartment open model have revealed higher values of fetal placental clearance (CLfm) compared to the maternal placental clearance (CLmf) for most drugs. This includes the antihistamine diphenhydramine (DPHM), which also has the highest weight-corrected fetal nonplacental clearance (CLfo) among the drugs studied. This study was designed to determine the reasons for this CLfm - CLmf difference and to identify the sites of high CLfo for DPHM. DPHM and a stable isotope-labeled analog, [2H(10)]DPHM, were simultaneously infused to steady state to the mother and fetus, respectively, in five pregnant sheep. CLmf, CLfm, CLmo and CLfo averaged 50.3 +/- 13.2, 214.4 +/- 30.8, 36.6 +/- 1.9 and 109.8 +/- 22.3 ml/min(-1)/kg(-1), respectively. By measuring diphenylmethoxyacetic acid and [2H(10)]diphenylmethoxyacetic acid levels in samples obtained from our previous study of fetal hepatic first-pass DPHM uptake, the hepatic first-pass extraction ratio of the drug from umbilical venous blood was estimated to be 0.44 +/- 0.05. This can account for virtually all of CLfo. Fetal hepatic first-pass uptake of maternally derived DPHM in the paired infusion study reduces the fetal/maternal plasma DPHM concentration ratio and results in significant underestimation of CLmf. When the CLmf estimate is corrected for this factor and for maternal-fetal DPHM plasma protein binding differences, its value approaches CLfm. Fetal hepatic first-pass uptake may also be a factor in the underestimation of CLmf for most of the other drugs. Conversely, a lower value of CLmf compared with CLfm provides evidence for significant fetal hepatic uptake of these compounds.

Animals↗
PubMed1996

Regulation of phosphorylation pathways by p21 GTPases. The p21 Ras-related Rho subfamily and its role in phosphorylation signalling pathways.

The oncogenic Ras p21 GTPases regulate phosphorylation pathways that underlie a wealth of activities, including growth and differentiation, in organisms ranging from yeast to human. In metazoa, growth factors trigger conversion of Ras from an inactive GDP-bound form to an active GTP-bound form. This activation of Ras leads to activation of Raf. Raf is one of the initial kinases in the cytoplasmic mitogen-activated protein kinase (MAPK) cascade, involving extracellular-signal-regulated kinases (ERK), which culminates in nuclear transcription. The Ras-related subfamily of Rho p21s, including Rho, Rac and Cdc42 are similarly active in their GTP-bound forms. These p21s mediate growth-factor-induced morphological changes involving actin-based cellular structures. For example, in mammalian fibroblasts, Rho mediates the formation of cytoskeletal stress fibres induced by lysophosphatidic acid, while Rac mediates the formation of membrane ruffles induced by platelet-derived growth factor, and Cdc42 mediates the formation of peripheral filopodia by bradykinin. In some cases, factor-induced Rac activation results in Rho activation, and factor-induced Cdc42 activation leads to Rac activation, as determined by specific morphological changes. Although separate Cdc42/Rac and Rac/Rho hierarchies exist, these might not extend into a linear form (i.e. Cdc42-->Rac-->Rho) since Cdc42 and Rho activities may be competitive or even antagonistic. Thus Cdc42-mediated formation of filopodia is accompanied by loss of stress fibres (whose formation is mediated by Rho). Recently, mammalian kinases that bind to the GTP-bound forms of Rho p21s have been isolated. These kinases include the p21-activated serine/threonine kinase (PAK), which is stimulated by binding to Cdc42 and Rac, and the Rho-binding serine/threonine kinase (ROK), which is not as strongly stimulated by binding. These kinases act as effectors for their p21 partners since they can directly affect the reorganization of the relevant actin-containing structures. ROK promotes the formation of Rho-induced actin-containing stress fibres and focal-adhesion complexes, to which the ends of the stress fibres attach. PAK stimulates the disassembly of stress fibres, which has been shown to accompany formation of Cdc42-induced peripheral-actin-containing structures, including filopodia, which with Rac-induced membrane ruffles play a role in cell movement. PAK also fosters loss of focal-adhesion complexes. Thus, there is cooperation between different Rho p21s as well as antagonism, with their associated kinases having a role in the integration of the reorganization of the actin cytoskeleton. The similarity of PAK to the Saccharomyces cerevisiae kinase Ste20p, which initiates the yeast mating/pheromone MAPK cascade, led to experiments showing that Cdc42 regulates Ste20p in this MAPK pathway. This similarity has also led to the demonstration that mammalian Cdc42 and Rac can signal to the nucleus through MAPK pathways. However, c-Jun N-terminal kinase (JNK, stress-activated protein kinase) rather than ERK, is involved. PAK have been implicated in the JNK pathway, but their exact roles are uncertain. Thus members of the Rho subfamily, and kinases that bind to these p21s are intimately involved in immediate morphological processes as well as long-term transcriptional events.

Animals↗
PubMed1996

Structure-activity relationship of 17 structural analogues of n-butyric acid upon c-myc expression.

Terminal differentiation of hematopoietic cells in vivo and in vitro is almost invariably accompanied by down-regulated expression of the c-myc proto-oncogene. Constitutive expression of c-myc in tumor cells inhibits terminal differentiation and maintains proliferation. In Burkitt's lymphoma, chromosomal translocations cause a deregulation of the c-myc gene through fusion of this locus with one of the immunoglobulin gene loci. However, the down-regulation of c-myc by n-butyric acid, a potent inducer of differentiation, is also observed in BL cells. Unlike other inducers of differentiation such as dimethylsulfoxide or hexamethylenebisacetamide, which down-regulate c-myc expression, albeit transiently, n-butyric acid causes a continuous, transcriptional shut-off. Because of the possible therapeutic implication of this finding, we have assayed structural analogues of n-butyric acid for their effect on c-myc expression in Burkitt's lymphoma cells. Of the analogues tested, 12 were active and 5 were inactive. Only unbranched fatty acids with 4 and 5 carbon atoms showed activity, a 4-carbon chain being optimal. 3-chloropropionic acid had maximal activity at a 3-fold lower concentration than n-butyric acid (1 mM versus 3 mM). The corresponding ester-analogues were equally effective. Those analogues found capable of down-regulating c-myc in Burkitt's lymphoma cells were similarly effective in their ability to induce terminal differentiation in murine erythroleukemia cells.

Animals↗
PubMed1996

Characterisation of the possible effect on birthweight following frequent prenatal ultrasound examinations.

The objective of this study was to evaluate and characterise by study of newborn biometry a possible effect on birthweight which we observed previously in a randomised controlled trial of multiple prenatal ultrasound examinations. A total of 2743 women with single pregnancies had been allocated at random to either a protocol of ultrasound imaging and continuous wave Doppler studies at 18, 24, 28, 34 and 38 weeks gestation (intensive group), or to a protocol of a single imaging examination at 18 weeks and further imaging scans only as clinically indicated (regular group). When compared with those in the regular group, and adjusted for other confounding variables, normally formed babies of term gestational age in the intensive group tended to be shorter when measured at birth (P = 0.123) and on day 2-3 of age (P = 0.068). There were statistically insignificant reductions in the circumferences of the chest, abdomen and mid-arm; and in the skinfold thicknesses of the triceps, parascapular and subscapular regions. Principal component analysis showed a trend for a reduction for the skeletal component (P = 0.085) but not for the soft tissue component (P = 0.332). Comparison of the neonatal biometry in the two groups is not conclusive, but the differential effects on the various growth parameters suggest that if multiple scans do indeed restrict fetal growth, the mechanism is more likely to be an effect on bone growth rather than a reduction in nutrient supply from the placenta.

Biometry↗
PubMed1996

[Pro-atrial natriuretic factor is predictive for the clinical status of patients with heart failure].

This study was undertaken in order to evaluate the relationship between N-terminal proatrial natriuretic factor [1-98] and routinely available measures of clinical status. Odds ratio estimates demonstrated a much higher risk of presence of left ventricular dysfunction and dilatation, pulmonary hypertension, and New York Heart Association function class III or IV with increasing proANF values. Analysis is simple and can be of practical value as a supplement in the assessment of cardiac status in this heterogeneous population.

Adolescent↗
PubMed1996

Treatment of non-disseminated cancer of the lower rectum.

Apart from the occasional tumour which is suitable for local excision, most low rectal cancers are best treated by anterior resection with complete removal of the rectum; the construction of a coloanal reservoir should allow routine sphincter saving. This surgery may be carried out independently of adjuvant radiotherapy which, if given, should be administered before operation.

Humans↗
PubMed1996

Optimal delivery of perioperative chemotherapy: preliminary results of a randomized, prospective, comparative trial of preoperative and postoperative chemotherapy for invasive bladder carcinoma.

PURPOSE: We performed a planned interim analysis of a randomized trial comparing initial to postoperative chemotherapy for bladder cancer. The purpose of our analysis was to detect early evidence of survival differences, tolerance to therapy influenced by the sequence of treatment, predictive value of clinical state and influence of methotrexate, vinblastine, doxorubucin and cisplatin (M-VAC) on bladder resectability. MATERIALS AND METHODS: A total of 100 consecutive patients were randomized to receive 2 M-VAC courses before and 3 courses after surgery (group 1) or 5 adjuvant M-VAC courses following cystectomy (group 2). Survival, clinical response, clinical and pathological stage, and toxicity were evaluated in this second timed interim analysis. RESULTS: Of all patients 70% received at least 4 M-VAC courses. Overall survival at 31.7 months (range 1.8 to 87.7) was similar in groups 1 (60%) and 2 (63%), and independent of clinical stage. Preoperative clinical staging accurately identified patients at high risk for recurrence, while 37 of the 48 group 2 patients (77%) were considered at high risk by pathological staging (P3b, P4a, node-positive and unresectable disease). Comparison of pathological stage revealed that 14 of the 51 group 1 patients (28%) achieved stage P0 while only 1 of the 48 group 2 patients (2%) had P0 disease at surgery (p= 0.00043). Disease was unresectable in 3 group 1 (6%) and 8 group 2 patients (17%, p= 0.09). Tolerance to treatment was not significantly different in the 2 study arms. CONCLUSIONS: No survival advantage was noted between neoadjuvant and adjuvant M-VAC in our interim analysis. However, results suggest that M-VAC chemotherapy may be effective in increasing the resectability of localized bladder cancer and may contribute to organ preservation. Clinical stage was a reliable predictor of pathological findings at surgery. Future studies can use clinical staging to determine therapy before surgery for the select stages that we treated. Identification of the subset likely to achieve complete pathological remission will permit the selection of patients for organ preservation strategies.

Adult↗
PubMed1996

Delayed visual feedback while learning to track a moving target.

Two studies investigated the effects of delayed visual feedback on manual tracking. In Experiment 1, individuals practiced with visual feedback provided either immediately (0 delay) or with a 333-ms delay. During acquisition, the 0 delay group performed with less error than the 333-ms delay group. A retention test with 0 delay feedback was performed with the least error by the 0 delay group. A transfer test using a different 0 delay tracking pattern, was performed with the least error by the 333-ms delay group. In Experiment 2, individuals practiced at six different delays. Error increased as training feedback delay increased. For retention there were no differences between the delay groups during the 0 delay retention. At a 417-ms retention, test error decreased as training feedback delay increased. Results indicate that error during acquisition does not necessarily impair learning and that feedback delays can be beneficial for learning.

Analysis of Variance↗
PubMed1996

Serum N-terminal proatrial natriuretic factor in children with congenital heart disease.

An objective and simple method of establishing and grading heart failure in children is needed. The N-terminal of the atrial natriuretic factor prohormone, called proANF, is stable in vitro, relatively easy to measure and has been demonstrated as a clinically useful marker of heart failure in adults. We measured proANF in 62 children with congenital heart disease and in 62 age-matched controls, in order to examine the relationship of proANF to different clinical and haemodynamic parameters. Echo Doppler cardiography was performed in all children, and 29 also underwent cardiac catheterization. The children were classified for volume and pressure load in each cardiac chamber, for shunt size and for signs of heart failure. In paediatric patients without cardiac or renal disease, median proANF was 384 pmol.l(-1). In children with congenital heart disease, median proANF was 904 (200-5320) pmol.l(-1) (P < 0.001). The three groups with the highest proANF levels were children with documented high atrial pressure (median proANF 1885 pmol.l(-1)), a large left to right shunt (median proANF 1565 pmol.l-(1)) and moderate or severe heart failure (median proANF 1305 pmol.l(-1)). Furthermore, the proANF level correlated negatively with age and glomerular filtration rate. We conclude that elevation of the proANF level is related to atrial pressures, heart failure and a high pulmonary to systemic flow ratio. These findings make proANF a potential new diagnostic tool in heart disease in children.

Adolescent↗
PubMed1996

Reversible ovulatory failure associated with the development of luteinized unruptured follicles in women with inflammatory arthritis taking non-steroidal anti-inflammatory drugs.

The case histories of three young women with ankylosing spondylitis, rheumatoid arthritis and a seronegative inflammatory polyarthritis undergoing investigations for infertility are presented. In each, non-steroidal anti-inflammatory drug (NSAID) therapy was associated with the recurrent development of luteinized unruptured ovarian follicles and normal ovulation following drug withdrawal. It is suggested that NSAID therapy may be an important and frequently overlooked cause of anovulation and infertility.

Adult↗
PubMed1996

Hemodynamics and tissue blood flow after porcine surfactant replacement in surfactant-depleted newborn piglets.

In 22 newborn piglets we studied the effect of hypovolemia or hypoxemia on hemodynamics and regional blood flow after instillation of porcine surfactant. Surfactant deficiency was obtained by repeated lung lavage, and blood flow measurements were carried out using radioactive microspheres. Three groups of piglets were studied, controls (n = 8), hypovolemia (n = 7), and hypoxemia (n = 7). Three to five minutes after instillation of surfactant, mean arterial blood pressure decreased significantly in all three groups with a mean decrease (+/- SD) of 31(+/- 12), 33(+/- 9), and 29(+/- 9) mm Hg, respectively (p < 0.01 in all three groups). Systemic vascular resistance decreased significantly in all three groups immediately after surfactant instillation (p < 0.01) and returned to presurfactant level after 60 min. Blood flow did not change after surfactant instillation in any of the three groups, in neither skin, muscle, pancreas, brain, nor retina. In liver, kidney, intestine, and choroidea there was a decrease in blood flow immediately after instillation with return to presur-factant levels within 60 min. Hypoxemia or hypovolemia before surfactant instillation did not increase the hemodynamic instability. The decrease in mean arterial blood pressure was caused by a vasodilation and not by a reduced cardiac output.

Animals↗
PubMed1996

A comparison of Culture-Free Self-Esteem Scale means from different child and adolescent groups.

The Culture-Free Self-Esteem Inventory (CFSEI-2) was administered to 7 groups of children: 84 White Catholic school students from a New Orleans suburb, 78 White rural public school students from Virginia, 62 Hispanic Migrant student from Florida, 90 Aboriginal and White students from an isolated Canadian community, 199 African American students attending an inner city school, 60 Hispanic and White international students from Venezuela, and 61 Innuit students from isolated community in Labrador. The four elder groups also wrote three words to describe themselves (the Adjective Generation Technique [AGT]). Significant differences in responding between groups were found on all CFSEI-2 scales and for AGT favorability means. Although several possible reasons for these results are discussed, we conclude that the CFSEI-2 is not culture-free. Recommendations are: change the title of the test to avoid misrepresentation, limit test usage to elementary school children, develop an adolescent version with age appropriate language, and construct local norms before using the CFSEI-2 to make decisions about a child's self-esteem. To determine relevance of scores, a team of professionals and lay persons should review items from this or any test given to children who may be different from the normative or standardization group.

Adolescent↗