Search PubMed⌕ Search

Biomedical subjects

L L Hall

Publications and source records attributed to L L Hall.

At least 37 records · Page 2Linked to original sources
PubMed1996

A brief staurosporine treatment of mitotic cells triggers premature exit from mitosis and polyploid cell formation.

At any point during the progression of many tumor types, cells can develop a hyperploid DNA content. Hyperploid tumors are significant more aggressive, with a higher growth rate and a poor patient prognosis. Yeast genetics have implicated three important genes involved in DNA ploidy changes: cdc2, cyclin b, and a specific inhibitor of the p34(cdc2)/cyclin B kinase, rum1. Mutations in these genes uncoupled the dependence mitosis on DNA replication in the fission yeast, Saccharomyces pombe. It was proposed that the inactivation of the mitotic kinase complex, p34(cdc2)/cyclin B, induces a G(1), state wherein the cells re-replicate their DNA without an intervening mitosis. We show in this report that treatment of only M phase-arrested mouse cells, with the protein kinase inhibitor staurosporine, induced polyploidy. Nocodazole-arrested metaphase FT210 cells were pulsed with 100 ng/ml of staurosporine for 1 h. This 1-h treatment results in the inhibition of the mitotic p34(cdc2) kinase. The inhibition of the mitotic kinases leads to a reduction in the histone H1 and H3 mitotic-associated phosphorylations, chromosome decondensation and nuclear membrane reformation. When released into normal growth medium, these cells are reset to a G(1)state, re-replicate their DNA without completing mitosis, and become octaploid.

Alkaloids↗
PubMed1996

Comparison of transdermal versus oral estradiol on endometrial receptivity.

OBJECTIVE: To compare the effects of oral micronized E2 with transdermal E2 on endometrial receptivity in women undergoing oocyte donation. DESIGN: Prospective, randomized, crossover trial. Serum E2 and P concentrations were measured on cycle days 14 and 22 (luteal day +8). Endometrial biopsies were obtained on day 22 and read in a blinded fashion for histology and beta-3-integrin expression. SETTING: University-based donor oocyte program. PATIENTS: Twenty-seven patients presenting for donor oocytes. MAIN OUTCOME MEASURES: Endometrial histology and beta-3-integrin expression. RESULTS: The endometrial glandular histology in women given oral micronized E2 was delayed by a mean of 1.6 days in comparison to that of women given transdermal E2. Seventy percent of women given oral E2 displayed a lag > or = 4 days whereas 29.6% given transdermal E2 displayed a similar lag. Serum E2 levels were 1,194 +/- 108.8 pg/mL (mean +/- SEM; conversion factor to SI unit, 3.671) in women on oral micronized E2 and 117.4 +/- 14.0 pg/mL in those on transdermal E2. CONCLUSION: The supraphysiologic serum E2 levels associated with oral micronized E2 may have a deleterious impact on endometrial receptivity. The development of more physiologic hormone replacement protocols may enhance endometrial receptivity and lead to improved clinical pregnancy rates.

Administration, Cutaneous↗
PubMed1995

Flare-up of endometriosis induced by gonadotropin-releasing hormone agonist leading to bowel obstruction.

OBJECTIVE: To report a case of intestinal obstruction that developed shortly after preoperative administration of a GnRH analogue (GnRH-a) that caused flare-up and rapid progression of enteric endometriosis. DESIGN: Case report. SETTING: University tertiary reproductive endocrinology practice. PATIENT: A 34-year-old nulligravid female with progressive severe symptomatic endometriosis. INTERVENTIONS: Planned preoperative administration of GnRH-a for 3 months followed by extirpative surgery and hormone replacement therapy. Instead, total abdominal hysterectomy, bilateral salpingoophorectomy, resection of the obstructed ileocecal junction, and side-to-side ileo-ascending enterocolostomy was performed. RESULTS: Preoperative GnRH-a administered in the midfollicular phase resulted in flare-up of preexisting ileocecal endometriosis that rapidly progressed, resulting in partial small bowel obstruction. CONCLUSION: Gonadotropin-releasing hormone agonist should be used with caution when there is known or suspected enteric endometriosis. Consideration should be given to blocking the agonistic effect of GnRH-a in this setting by the prior or concomitant use of progestins or danazol.

Adult↗
PubMed1995

Disposition of phenol in rat after oral, dermal, intravenous, and intratracheal administration.

The absorption and elimination of [14C]-phenol (63.5 nmol) after oral, dermal, intratracheal, or intravenous administration in rat was rapid and extensive. Urinary elimination of radioactivity predominated, with a range of 75-95% of the dose detected in urine by 72 h post-exposure. Washing the dermal site 72 h post-exposure removed 14% of the dose. Two per cent of the dose was detected in the skin. The urinary metabolites at 4 and 8 h after administration by the four routes included phenyl sulphate and lower amounts of phenyl glucuronide. Phenol was poorly retained in the body after administration by the four routes. Phenol remaining in the body was widely distributed, with accumulation primarily in the liver, lung, and kidney.

Administration, Cutaneous↗
PubMed1994

The kinetics of intravenously administered methyl mercury in man.

We describe a compartmental pharmacokinetic model for methyl mercury and its metabolite mercuric mercury in humans. A tracer dose of 203Hg-labeled methyl mercury was administered iv to seven healthy young adult male volunteers. Blood samples were obtained periodically and urine and feces were collected throughout the 70 days of the study. The blood contained predominantly methyl mercury, while the excreta contained principally inorganic mercury. The behavior of both methyl mercury and inorganic mercury in the body was modeled with the simplest compartmental model which fit the data. This five-compartment model shows that inorganic mercury accumulates in the body and at longer times is the predominant form of mercury present. The biological half-life of methyl mercury in the body is 44 days and 1.6% of the body burden is lost each day by both metabolism and excretion. This rate of loss is 60% greater than that currently accepted (1.0% per day). Thus, the risk associated with dietary methyl mercury may have been overestimated.

Adult↗
PubMed1994

Enteric coccidia of Cashmere goats in southwestern Montana, USA.

A survey of enteric coccidia was made in a Cashmere goat herd in Montana, USA. Eimerian oocysts were found in 97.2% of 616 fecal samples. Newly weaned wethers and does had higher oocyst counts than yearling wethers. Nine Eimeria species were identified, with Eimeria arloingi, Eimeria ninakohlyakimovae and Eimeria alijevi jointly comprising 88.3% of all oocysts recovered. These three species and Eimeria hirci were present in all specimens examined. Prevalence of the other species was as follows: Eimeria caprina, 88.2%; Eimeria jolchijevi, 70.6%; Eimeria christenseni, 32.4%; Eimeria caprovina, 29.4%; Eimeria apsheronica 26.5%.

Aging↗
PubMed1993

Toxicokinetics and structure-activity relationships of nine para-substituted phenols in rat embryos in vitro.

The purpose of this study was to examine the toxicokinetics of embryo uptake following exposure to a variety of chemically related phenols in rat embryo culture. The uptake of nine radiolabeled para-substituted phenols by day 10 (9-13 somite stage) rat embryos in vitro was determined from 1 to 42 hrs after being placed in culture media containing various phenols. Uptake was rapid, having a half-life of 3 hr or less, with 7 of the nine compounds having uptake half-times of less than one hour. The equilibrium concentration in the embryo ranged from 53 to 136% of the media concentration, indicating only a factor of 2 in maximum discrimination against the compound for any of the phenols studied. The fraction of radioactivity remaining unbound in the media decreased with increasing log P (octanol/water partition coefficient). The binding was calculated to be 50% for log P = 1.77 from the fitted regression equation and decreased by a factor of 5.9 for every decade increase in P. When hepatocytes were also present in the media the equilibrium concentration in the embryos was less than when hepatocytes were absent. With the limited data, four of the phenols appeared to have no (i.e., zero) equilibrium level when hepatocytes were present. Thus the metabolites produced by the hepatocytes appeared to have less affinity for the embryo than the parent phenol. Toxicodynamic information as given by the effective concentration of the phenol in the embryo to cause somite or tail teratological effects was best predicted by the measured unbound fraction.

Animals↗
PubMed1992

Age-related percutaneous penetration of 2-sec-butyl-4,6-dinitrophenol (dinoseb) in rats.

[14C]Dinoseb was applied to previously clipped back skin of 33- and 82-day-old female Fischer 344 rats at a dosage range of 210-2680 nmol/cm2. Radioactivity in the treated skin, tissues, urine, and feces was determined at 1, 6, 24, 48, 72, and 120 hr following dermal application. In vitro dermal absorption of [14C]dinoseb was also measured in rats of the same age by static and flow-through methods. In vivo dermal absorption in both young and adults appeared biphasic with 55.6 and 82.7% of the recovered dose, respectively, penetrating in 72 hr. In vitro measurements of skin absorption at 72 hr with static cells showed higher values in young and lower values in the adult compared to in vivo dermal absorption values. In vitro flow-through measurements at 72 hr gave lower dermal absorption values for both young and adult rats, compared to in vivo values. Following in vivo application, adults excreted about 70% of the total recovered dose in urine, 16% in feces, and retained 7% in the body at 120 hr. HPLC analysis of urine collected at 24 hr from adults administered [14C]dinoseb showed extensive metabolism of parent. Excretion and retention results for young were about 80% of the adult values, which also was the young to adult ratio of dermal penetration. Blood had the highest concentration of dinoseb-derived radioactivity of the tissues examined. The kidney to blood ratio averaged 0.60 in young and 0.41 in adults, while the liver and carcass to blood ratio averaged 0.18 in young and 0.11 in adult. Dermal absorption in young rats was slightly less than that in adults, and the subsequent kinetics of retention and excretion appeared different. In vitro dermal penetration of dinoseb was usually lower than in vivo absorption.

2,4-Dinitrophenol↗
PubMed1992

Dermal penetration of [14C]captan in young and adult rats.

Age dependence in dermal absorption has been a major concern in risk assessment. Captan, a chloroalkyl thio heterocyclic fungicide, was selected for study of age dependence as representative of this class of pesticides. Dermal penetration of [14C]captan applied at 0.286 mumol/cm2 was determined in young (33-d-old) and adult (82-d-old) female Fischer 344 rats in vivo and by two in vitro methods. Dermal penetration in vivo at 72 h was about 9% of the recovered dose in both young and adult rats. The percentage penetration was found to increase as dosage (0.1, 0.5, 2.7 mumol/cm2) decreased. Two in vitro methods gave variable dermal penetration values compared with in vivo results. A static system yielded twofold higher dermal penetration values compared with in vivo results for both young and adult rats. A flow system yielded higher dermal penetration values in young rats and lower penetration values in adults compared with in vivo results. Concentration in body, kidney, and liver was less in young than in adult rats given the same absorbed dosage. A physiological pharmacokinetic model was developed having a dual compartment for the treated skin and appeared to describe dermal absorption and disposition well. From this model, tissue/blood ratios of captan-derived radioactivity for organs were found to range from 0.35 to 3.4, indicating no large uptake or binding preferences by any organ. This preliminary pharmacokinetic model summarizes the experimental findings and could provide impetus for more complex and realistic models.

Administration, Cutaneous↗
PubMed1992

Dermal absorption of chemicals: effect of application of chemicals as a solid, aqueous paste, suspension, or in volatile vehicle.

The purpose of this study was to investigate the dermal absorption of chemicals in different physical forms when applied to female F344 rats. Chemicals were applied either as a solid, aqueous paste, suspension, or dissolved in the volatile vehicle ethanol. The chemicals investigated were [14C]-2-sec-butyl-4,6-dinitrophenol (DNBP, 4.2 mumol), 2,4,5,2',4',5'-[14C]-hexachlorobiphenyl (HCB, 2.3 mumol), and 3,4,3',4'-[14C]-tetrachlorobiphenyl (TCB, 0.5 mumol). The chemicals were applied on the clipped mid-dorsal region of the rat over a 2.54-cm2 treatment area, which was then occluded. Urine and feces were collected and assayed for radioactivity. Twenty-four hours post-application, the treated skin was washed with a mixture (1:1) of soap and water, dried, and reoccluded. The animals were sacrificed at 120 h by exsanguination under ether anesthesia. Radioactivity in the blood, skin (treated and untreated), and carcass was assayed. Dermal absorption of DNBP-derived radioactivity was approximately 50% of the recovered dose after application in the four physical forms, and the major route of excretion was via the urine. Twelve percent of the absorbed dose of DNBP was retained in the body. Dermal penetration of HCB-derived radioactivity was 5-8% of the recovered dose after application in the four forms, and the major route of excretion was via the feces. Greater than 90% of the absorbed dose of HCB-derived radioactivity was retained in the body. Dermal penetration of TCB-derived radioactivity was 6-8% of the recovered dose in the four forms, and the major route of excretion was via the feces. Approximately 21% of the absorbed dose was retained in the body at 120 h. Absorption of each chemical applied either as solid, aqueous paste, or suspension was compared to the absorption of the same chemical in ethanol. Absorption of HCB applied as a solid was significantly higher (p less than or equal to .05) as compared to HCB applied in ethanol. There were no other significantly differences in the comparisons of absorption. The data indicate that the chemicals examined in this study can penetrate the skin as readily when applied either as a solid, aqueous paste, or suspension, as when applied in the volatile vehicle ethanol.

2,4-Dinitrophenol↗
PubMed1992

An evaluation of structure-penetration relationships in percutaneous absorption.

Prediction of chemical transport across skin is important both to the optimization of topical and transdermal drug delivery and to the assessment of risk following dermal exposure. To facilitate estimation of percutaneous absorption, a number of model in vitro experimental systems have been developed. However, the predictive applicability of the different approaches (with respect to human skin penetration), and the quantitative aspects of the structure-permeation behavior revealed, have not been critically evaluated. The objectives of this paper are to collect, from the literature, the more systematic investigations pertaining to chemical transport across the skin, to quantify the dependence of permeation on the lipophilicity of the penetrants studied, and to assess the relative utility of model systems for the prediction of percutaneous absorption. The categories of chemicals addressed in the survey include n-alkanols, para-substituted phenols, steroids and non-steroidal anti-inflammatory drugs. The experimental systems, used in the studies considered, involve, primarily, steady-state transport measurements across excised skin taken from either human cadavers or hairless mice. Favorable comparisons of these data to solute flux across simple organic liquid membranes are possible. Overall, general patterns of behavior emerge from the analysis such that qualitative predictions can be made. From a quantitative standpoint, though, it is clear that additional "structure-activity" work is necessary to provide appropriate equations that can relate penetration between different test systems and between different chemical classes.

Adult↗
PubMed1991

Percutaneous penetration of para-substituted phenols in vitro.

The percutaneous penetration of 11 para-substituted phenols has been measured across full-thickness hairless mouse skin in vitro. The phenols, which spanned more than a 1000-fold range in octanol/water partition coefficient (P), were applied (14C-radiolabeled) to the skin surface in a small volume of volatile organic solvent. Permeation kinetics were continuously monitored and were characterized by the maximum observed flux (Jmax). The linear correlation of log Jmax with log P was very poor. However, inclusion of molecular volume (MV) in a multiple regression analysis considerably improved the relationship between the measured transport parameter and the physicochemical descriptors. Furthermore, significant parabolic (log Jmax = -0.18 + 1.35.log P - 0.30.[log P]2) and bilinear (log Jmax = -0.17 + 1.08.log P - 1.95.[log(beta.10logP + 1)]) dependencies were obtained, suggesting a change in the rate-limiting transport step (for compounds of high log P) from diffusion across the stratum corneum (SC) to partitioning at the SC-viable epidermis interface. Addition of a term in MV (or molar refractivity) further improved the absolute correlations, but with marginal statistical significance. A wider range of molecular size is necessary to unequivocally define the role of permeant dimensions in percutaneous permeability for this group of compounds. The quadratic log Jmax correlation with log P was compared to the previously reported steady-state permeability coefficients (Kp) of a different set of phenol analogs through human epidermis. Despite the different methodologies, different compounds, and different skin membranes employed, the patterns of behavior in the two data sets were consistent, and suggest that the form of this correlation may be suitable description of phenol permeability under a range of experimental conditions.

Animals↗
PubMed1991

In vivo and in vitro structure-dosimetry-activity relationships of substituted phenols in developmental toxicity assays.

Structure-dosimetry-activity relationships (SDARs) of a series of substituted phenols were evaluated following exposure of gestation day 11 rats in vivo and in comparable stage embryos in vitro. In the in vivo study, 27 congeners were assayed and log P (a term used synomously with lipophilicity in this paper) and Hammett sigma values (a measure of the electronic withdrawing ability of the substituent) were shown to correlate with maternal toxicity; however, no relationships between these parameters and developmental effects were observed. In the in vitro system, 13 congeners were evaluated and molar refractivity and/or lipophilicity were shown to correlate with the ability of the phenols to induce embryonic growth retardation and structural defects in the absence of the hepatocytes. In contrast, when a metabolic activating system (primary hepatocytes) was present in the in vitro system, the potential to induce growth retardation was inversely related to lipophilicity, although the relationships were weaker than the positive relationship seen without the hepatocytes. The binding of the phenols to macromolecules in the culture medium was highly correlated with log P. Correcting the in vitro potency data for the variable amount of binding improved the predictiveness of the quantitative structure-activity relationships (QSARs). The potential to induce embryotoxicity in vitro was not well correlated with the potential to induce developmental toxicity in vivo: whereas the in vitro data demonstrates that the phenols are intrinsically embryotoxic, few of them actually produced significant developmental toxicity in the in vivo system, and there were few positive correlations between effects observed in the two systems.(ABSTRACT TRUNCATED AT 250 WORDS)

Abnormalities, Drug-Induced↗
PubMed1990

Partitioning of chemicals into human stratum corneum: implications for risk assessment following dermal exposure.

Assessment of the health hazard associated with chemical contamination of the skin is a complex problem of occupational and environmental relevance. A particularly important question is to what extent can the skin permeability of a given compound be predicted from simple experiments. The literature on percutaneous absorption identifies two key observations: (i) the stratum corneum (SC), the skin's outermost layer, is the major barrier to chemical transport, and (ii) there are qualitative correlations between penetrant permeability and various oil/water partition coefficients (PCs). To obtain more quantitative predictions of permeation, we have evaluated SC/water and SC/isopropyl myristate (IPM, a model lipophilic vehicle) PCs of (a) para-substituted phenols of diverse physicochemical properties (4-acetamido-, 4-cyano-, 4-iodo-, and 4-pentyloxyphenol), (b) polychlorinated biphenyls (54%), and (c) 1,1,1,-trichloro-2,2-bis(p-chlorophenyl)ethane. Partition coefficients were determined as a function of the following variables: length of equilibration, initial drug concentration in the vehicle, SC delipidization, and SC source and preparation technique. The data demonstrate that reproducible partitioning can be obtained using the biological tissue of greatest relevance, and that the pattern of behavior observed, for the two different vehicles studied, is compatible with physicochemical expectations. We suggest that the PC values measured may be useful predictors of in vitro and in vivo skin transport and valuable assets, therefore, in the evaluation of risk following dermal exposure.

Animals↗