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Biomedical subjects

K Fitzgerald

Publications and source records attributed to K Fitzgerald.

At least 37 records · Page 2Linked to original sources
PubMed1993

glp-1 can substitute for lin-12 in specifying cell fate decisions in Caenorhabditis elegans.

Members of the lin-12/Notch gene family encode receptors for intercellular signals and are found throughout the animal kingdom. In many animals, the presence of at least two lin-12/Notch genes raises the issue of the significance of this duplication and divergence. In Caenorhabditis elegans, two lin-12/Notch genes, lin-12 and glp-1, encode proteins that are 50% identical, with different numbers of epidermal growth factor-like motifs in their extracellular domains. Many of the cell fate decisions mediated by lin-12 and glp-1 are distinct. Here, we express glp-1 protein under the control of lin-12 regulatory sequences in animals lacking endogenous lin-12 activity and find that glp-1 can substitute for lin-12 in mediating cell fate decisions. These results imply that the lin-12 and glp-1 proteins are biochemically interchangeable, sharing common ligand and effector proteins, and that the discrete lin-12 and glp-1 mutant phenotypes result from differential gene expression. In addition, these results suggest that the duplicate lin-12/Notch genes found in vertebrates may also be biochemically interchangeable.

Animals↗
PubMed1992

Evidence for the involvement of a distinct form of cytochrome P450 3A in the oxidation of digitoxin by rat liver microsomes.

The preceding paper (B. Gemzik, D. Greenway, C. Nevins, and A. Parkinson (1992). Regulation of two electrophoretically distinct proteins recognized by antibody against rat liver cytochrome P450 3A1. J. Biochem. Toxicol., 7 (43-52).) described the regulation of two rat liver microsomal proteins (50- and 51-kDa) recognized by antibody against P450 3A1. It was also shown that changes in the levels of the 51-kDa 3A protein were usually paralleled by changes in the rate of testosterone 2 beta-, 6 beta-, and 15 beta-hydroxylation. The present study demonstrates that age- and sex-dependent changes in the 50-kDa protein were paralleled by changes in the rate of digitoxin oxidation to digitoxigenin bisdigitoxoside. Induction or suppression of the 50-kDa protein by treatment of rats with various xenobiotics were also paralleled by changes in the rate of digitoxin oxidation. These results suggest that, contrary to previous assumptions, the conversion of digitoxin to digitoxigenin bisdigitoxoside and the conversion of testosterone to 2 beta-, 6 beta-, and 15 beta-hydroxytestosterone are primarily catalyzed by different forms of P450 3A. Further evidence for this conclusion was obtained from studies in which the suicide inhibitor, chloramphenicol, was administered to mature female rats previously treated with pregnenolone-16 alpha-carbonitrile (PCN), which induces both the 50-kDa and the 51-kDa protein. Treatment of mature female rats with PCN alone caused a marked increase (16- to 18-fold) in the 6 beta-hydroxylation of testosterone and the rate of digitoxin oxidation. Treatment of PCN-induced rats with chloramphenicol caused a approximately 70% decrease in liver microsomal testosterone 6 beta-hydroxylation, but had no effect on the rate of conversion of digitoxin to digitoxigenin bisdigitoxoside. The oxidation of testosterone by purified 3A1 (a 51-kDa protein) was also inhibited by chloramphenicol in a time- and reduced nicotinamide adenine dinucleotide phosphate (NADPH)-dependent manner. In addition to testosterone and chloramphenicol, purified 3A1 also metabolized troleandomycin, but it was unable to convert digitoxin to digitoxigenin bisdigitoxoside. Testosterone inhibited the microsomal oxidation of digitoxin, but digitoxin did not inhibit testosterone oxidation. This suggests that testosterone is a substrate for the 3A enzyme that metabolizes digitoxin, but that this form of P450 3A does not contribute significantly to testosterone oxidation by rat liver microsomes.(ABSTRACT TRUNCATED AT 400 WORDS)

Aging↗
PubMed1992

Clinical considerations. Tube feeding in the elderly.

1. The major indication for tube feeding is the inability to ingest sufficient nutrients by mouth in the presence of a functioning gastrointestinal tract. 2. Diarrhea, a frequent complaint, may be due to a variety of factors, including medication side effects, bacterial contamination of formula, viral infection, low albumin, high osmolality of the formula, too rapid infusion rate, and fecal impaction. 3. Aspiration of the tube feeding resulting in pneumonia is a serious and potentially life-threatening complication seen more frequently in patients with altered mental status or the inability to protect their airway. 4. Key items in the nutritional assessment include body weight; weight loss; visceral protein estimation, eg, albumin; exercise tolerance; and muscle strength.

Aged↗
PubMed1991

Serotonin mimics tail shock in producing transient inhibition in the siphon withdrawal reflex of Aplysia.

Tail shock-induced modulation of the siphon withdrawal reflex of Aplysia has recently been shown to have a transient inhibitory component, as well as a facilitatory component. This transient behavioral inhibition is also seen in a reduced preparation in which a cellular reflection of the inhibitory process, tail shock-induced inhibition of complex EPSPs in siphon motor neurons, is observed. The biogenic amine serotonin (5-HT) is known to play a role in the facilitatory aspects of sensitization in Aplysia. The aim of this article was to examine whether 5-HT might also contribute to the inhibitory effects of tail shock in the siphon withdrawal reflex. To examine this question, we carried out two kinds of experiments. First, in the isolated abdominal ganglion, we recorded intracellularly from siphon motor neurons and examined the effects of 5-HT on (1) complex (polysynaptic) EPSPs, produced by siphon nerve stimulation, and, simultaneously, (2) monosynaptic EPSPs from siphon sensory neurons. We found that, paralleling the effects of tail shock in the reduced preparation, 5-HT produced transient inhibition of the complex EPSP; the monosynaptic EPSP was facilitated by 5-HT. Second, we examined the behavioral effects of 5-HT on siphon withdrawal in a reduced preparation. We found that 5-HT again paralleled tail shock by producing transient inhibition of the siphon withdrawal reflex. Our results suggest that, in addition to its well-established facilitatory role in reflex modulation in Aplysia, 5-HT might play an important inhibitory role, as well.

Animals↗
PubMed1990

Multiple forms of non-associative plasticity in Aplysia: a behavioural, cellular and pharmacological analysis.

A complete understanding of the cellular mechanisms underlying the formation of associations between stimuli, as occurs during classical conditioning, requires an understanding of the non-associative effects of the individual stimuli. The siphon withdrawal reflex of Aplysia exhibits both non-associative and associative learning when a tactile stimulus to the siphon serves as a conditioned stimulus, and tail shock serves as an unconditioned stimulus. In this chapter we describe experiments which examine the non-associative effects of tail shock at three different levels of analysis. At a behavioural level we found that the magnitude, and even the sign of reflex modulation induced by tail shock depended critically on three parameters: (i) the state of the reflex (habituated or non-habituated); (ii) the strength of the tail shock, and (iii) the time of testing after tail shock. Specifically, when non-habituated responses produced by water jet stimuli to the siphon were examined, tail shock produced transient inhibition 90 s later; facilitation of non-habituated responses (sensitization) only emerged after a considerable delay of 20-30 min. When habituated responses were examined, tail shock produced immediate facilitation (dishabituation); the amount of facilitation was inversely related to the strength of tail shock, with stronger shock producing no dishabituation. At a cellular level it was found that the complex excitatory postsynaptic potential (EPSP) in siphon motor neurons produced by water jet stimuli to the siphon provides a reliable cellular correlate of several of the non-associative effects of tail shock that we observe behaviourally. When non-decremented complex EPSPS were examined, strong tail shock produced transient inhibition at a test 90 s after shock.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1990

Reconstitution of testosterone oxidation by purified rat cytochrome P450p (IIIA1).

Cytochrome P450p (IIIA1) has been purified from rat liver microsomes by several investigators, but in all cases the purified protein, in contrast to other P450 enzymes, has not been catalytically active when reconstituted with NADPH-cytochrome P450 reductase and dilauroylphosphatidylcholine. We now report the successful reconstitution of testosterone oxidation by cytochrome P450p, which was purified from liver microsomes from troleandomycin-treated rats. The rate of testosterone oxidation was greatest when purified cytochrome P450p (50 pmol/ml) was reconstituted with a fivefold molar excess of NADPH-cytochrome P450 reductase, an equimolar amount of cytochrome b5, 200 micrograms/ml of a chloroform/methanol extract of microsomal lipid (which could not be substituted with dilauroylphosphatidylcholine), and the nonionic detergent, Emulgen 911 (50 micrograms/ml). Testosterone oxidation by cytochrome P450p was optimal at 200 mM potassium phosphate, pH 7.25. In addition to their final concentration, the order of addition of these components was found to influence the catalytic activity of cytochrome P450p. Under these experimental conditions, purified cytochrome P450p converted testosterone to four major and four minor metabolites at an overall rate of 18 nmol/nmol P450p/min (which is comparable to the rate of testosterone oxidation catalyzed by other purified forms of rat liver cytochrome P450). The four major metabolites were 6 beta-hydroxytestosterone (51%), 2 beta-hydroxytestosterone (18%), 15 beta-hydroxytestosterone (11%) and 6-dehydrotestosterone (10%). The four minor metabolites were 18-hydroxytestosterone (3%), 1 beta-hydroxytestosterone (3%), 16 beta-hydroxytestosterone (2%), and androstenedione (2%). With the exception of 16 beta-hydroxytestosterone and androstenedione, the conversion of testosterone to each of these metabolites was inhibited greater than 85% when liver microsomes from various sources were incubated with rabbit polyclonal antibody against cytochrome P450p. This antibody, which recognized two electrophoretically distinct proteins in liver microsomes from troleandomycin-treated rats, did not inhibit testosterone oxidation by cytochromes P450a, P450b, P450h, or P450m. The catalytic turnover of microsomal cytochrome P450p was estimated from the increase in testosterone oxidation and the apparent increase in cytochrome P450 concentration following treatment of liver microsomes from troleandomycin- or erythromycin-induced rats with potassium ferricyanide (which dissociates the cytochrome P450p-inducer complex). Based on this estimate, the catalytic turnover values for purified, reconstituted cytochrome P450p were 4.2 to 4.6 times greater than the rate catalyzed by microsomal cytochrome P450p.

Animals↗
PubMed1989

Effects of sex, thyro-parathyroidectomy, and light regime on levels and circadian rhythms of wheel-running in rats.

Intact and thyro-parathyroidectomized (TPX) Sprague-Dawley rats of both sexes were observed for 24 days under a 12:12 light:dark cycle (Entrainment), followed by 20 days in constant dim red light (Free-Run). Circadian periods and levels of wheel-running activity were examined. Intact females and TPX males were significantly more active and had significantly shorter free-running circadian periods than intact males, and the effects of TPX in females were different from those in males. Circadian periods in TPX females were slightly, but not significantly, shorter than in intact females, and activity levels in TPX females were nonsignificantly depressed relative to intact females. It was also found that day versus night activity levels differed more in TPX animals than in intact animals, especially during entrainment, suggesting that TPXs may be more sensitive to some effects of light. A number of possible explanations for the effects of TPX are considered, including changes in thyroid and calcitonin levels, interactions with gonadal hormones, and possible developmental effects of thyroid hormones on the circadian system. It is also possible that rhythm changes are secondary to alterations in activity levels. Human manic depressives reportedly have an unusually high incidence of thyroid, parathyroid, and calcium regulation abnormalities, display shortened circadian sleep-wake rhythms and abnormal levels of activity, and may also be hypersensitive to some effects of light; in addition, depression predominates in women, whereas mania predominates in men. The present results suggest that thyroid dysfunction could be partially responsible for the some of these abnormalities, and for sex differences in the manifestations of these disorders.

Animals↗
PubMed1985

A new partition thin-layer chromatographic method for steroid separations.

TLC plates with a 25 mu thick polyamide stationary phase were modified for the separation of neutral steroids by impregnation with propylene glycol. A mixture of tritiated 5 alpha-androstan-3 alpha,17 beta-diol, testosterone, 17 beta-hydroxy-5 alpha-androstan-3-one and 4-androstene-3,17-dione was applied to the plate and developed in a toluene mobile phase to a height of 13.6 cm. This resulted in complete resolution of the 4 compounds as detected by a gas flow scanner or imaging analyzer. Cutting and elution of peak areas with methanol resulted in quantitative recovery of all four steroids. The thinness of the layer also permitted a 3-5% counting efficiency on scanning, resulting in good quantitation of recovery without liquid scintillation counting. The high sorptive capacity of the polyamide layer also enabled extracts of normal human serum to be defatted on the TLC plate by development with pure hexane prior to the toluene step. The new method thus offers several advantages over existing methods for steroid separations and should be adaptable to separations of other relatively non-polar compounds.

Chromatography, Thin Layer↗
PubMed1984

Development of a computerized vascular registry for large-scale use.

On the basis of the experiences of the Upstate New York Vascular Society and the Society for Clinical Vascular Surgery (total membership 526), a computerized vascular registry has been developed to collate and handle data from this multitude. After several developments a standard encoding vehicle has been arrived at, and data are entered on light-sensitive cards and processed electronically. This system has been in place for 2 years and has already revealed several trends about the practice of vascular surgery on a large-scale and/or community basis. Of importance among these are the differences in vascular surgical reconstructive success compared with the published individual reports as well as an examination of the trends in vascular surgical practice and the standards of proficiency required. The problems of inertia, resentment, and inaccurate data entry have also been addressed, and steps have been taken to overcome these as well as to ensure security of individual data. It is expected that use of such systems will eventually provide us with a much clearer picture of the overall practice and standards in vascular surgery that apply throughout the nation.

Computers↗
PubMed1976

Circadian organization of the estrous cycle of the golden hamster.

In constant dim illumination the hamster estrous cycle free-runs with a period that is a quadruple multiple of the concurrently recorded rhythm of wheel-running activity; both activity and estrous cycles are generated by biological clocks. Maintenance of stable phase angle differences between heat onset and running onset before and after treatment with deuterium oxide suggests that a common circadian system generates periodicities in estrus and activity. An organization of the estrous cycle is proposed in which the stimulus for the ovulatory surge of luteinizing hormone is generated by a circadian system that includes the suprachiasmatic nuclei of the hypothalamus. Various possible interactions of estradiol and photoperiod with the neurogenic stimulus for the luteinizing hormone surge are described and implications of different types of circadian organization of the estrous cycle for theories of sexual differentiation are considered.

Animals↗
PubMedDate not supplied

Impact of emergency admissions on elective surgical workload.

BACKGROUND: Day case surgery is the most cost-effective approach for all minor, most intermediate and some major surgery. AIMS: To examine the effect of the current 'escalation' policy of opening the surgical day ward to A&E admissions at the expense of planned surgery. PATIENTS AND METHODS: A retrospective study was carried out on all elective general surgical operations planned for January through March 2003. The number of cases cancelled and the reasons for cancellation were documented. RESULTS: The total number of patients booked for surgery was 836, 66.6% of which were day cases (557 patients). Overall 338 patients accounting for 40.4% of all planned cases were cancelled. Day case cancellations accounted for 68.9% of all cancellations (233 patients). Bed unavailability was the main reason due to the overflow of A&E admissions, accounting for 92% of cancelled patients and 73.8% of day ward cancellations. CONCLUSIONS: The cancellation of surgery creates untold hardship for patients who plan their working and family lives around the proposed operation date. Most are cancelled at less than 24 hours notice. The cost implications to the community are immense but have not been calculated. The separation of emergency and planned surgery is essential through adequate observation ward access.

Ambulatory Surgical Procedures↗
PubMedDate not supplied

Abnormal vitamin levels in patients receiving home total parenteral nutrition.

The administration of multivitamins to patients receiving home parenteral nutrition (HPN) was decreased from once daily to three times weekly during the parenteral multivitamin shortage in 1997. Blood vitamin levels were measured to examine whether the decrement in the infused vitamins affected the levels. Six patients with normal renal and liver function, receiving HPN for 6 months to 10 years, were studied 6 months after the institution of 10 mL of multivitamins thrice weekly. Two patients with renal insufficiency who required hemodialysis and HPN were also studied. Multivitamin administration was eliminated in one patient and was reduced to once weekly when elevated pyridoxine levels were found in association with possible neurotoxicity. Five of the six patients with normal renal function had low serum ascorbic acid levels. Serum riboflavin levels were found to be low in one patient, serum pyridoxine was low in one, serum retinoids were low in three, and serum niacin was low in one. There were no clinically obvious untoward effects caused by the vitamin deficiencies. Each of the dialysis patients had elevated serum pyridoxine levels and had some neurologic disturbance (peripheral neuropathy, involuntary movements). The serum pyridoxine levels fell to normal in each after the cessation or decrease of the multivitamin preparation. Ascorbic acid levels were low in one patient and fell into abnormally low levels in the other when the parenteral multivitamins were reduced, but they corrected with the separate administration of intravenous vitamin C. In conclusion, the reduced administration of multivitamins in 1997 resulted in diminished ascorbic acid levels in seven of eight patients receiving total parenteral nutrition. Less often, low levels of retinoids, niacin, pyridoxine, and riboflavin were seen. Patients with chronic renal failure receiving HPN with multivitamins may develop elevated pyridoxine levels, which might result in neurologic sequelae.

Adult↗