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Biomedical subjects

H Tucker

Publications and source records attributed to H Tucker.

At least 19 recordsLinked to original sources
PubMed2001

Community hospitals for the new millennium.

There is a lack of basic information regarding the numbers of and facilities offered by community hospitals. This survey identified 471 community hospitals in the United Kingdom containing 18,579 beds with 20% of general practitioners having admitting rights. The majority of hospitals provide a comprehensive range of rehabilitation services and consultant outpatient clinics. Community hospitals are potentially an important resource in providing intermediate care in the community.

Health Services Accessibility↗
PubMed2000

How can the incidence of negative specimens resulting from large loop excision of the cervical transformation zone (LLETZ) be reduced? An analysis of negative LLETZ specimens and development of a predictive model.

OBJECTIVE: To analyse biopsies of large loop excision of the transformation zone of the cervix; to identify factors associated with negative histology; and to develop predictive models in order to reduce the number of negative loop excisions. DESIGN: Retrospective analysis of patient notes and audit database. SETTING: Colposcopy clinic of a large district general hospital in North Staffordshire. POPULATION: Four hundred and fifty-two women who underwent a large loop excision of the transformation zone (LLETZ) procedure for suspected cervical intraepithelial neoplasia. METHODS: Women who underwent a LLETZ procedure were placed in two different groups, one positive for cervical intra epithelial neoplasia and the other negative for cervical intra epithelial neoplasia. Information was obtained on a number of clinical and colposcopic variables. Analysis was undertaken to determine if there were any differences between the two groups. These factors were then identified and three predictive models generated. Receiver-operator characteristic curves were used to assess and test these models. MAIN OUTCOMES MEASURES: To identify factors associated with negative histology on a LLETZ specimen. To predict how to reduce the number of negative LLETZ specimens. RESULTS: Four hundred and fifty-two women underwent a LLETZ procedure, 88 were negative (19%) and 364 were positive (81%). In women who were treated at their first visit, 56/316 (18%) had negative histology. There were significant associations between negative histology in the LLETZ and negative or low grade cytological atypia, negative colposcopic findings and years of age > 50 in both bivariate analysis and stepwise logistic regression. In the predictive models, the sensitivity ranged between 72% and 80%, the specificity 59%-72%, and the area under the receiver-operator characteristic was 0.75-0.77. If we had used the predictor models and managed women with negative or low grade cervical atypia and negative colposcopy findings conservatively, we would have reduced the negative biopsy rate from 19% to 14%, but five cases of high grade disease and 25 cases of low grade disease would have been missed. If we had also included women aged > 50 years in this model, the negative biopsy rate would have dropped from 19% to 15%, with only one case of high grade disease and 11 cases of low grade disease missed. All these women would require continued cytological and colposcopic surveillance. Importantly, no cases of invasion would have been missed. CONCLUSION: Using a predictive model can reduce the number of negative LLETZ specimens, but at the expense of continued cytological and colposcopic surveillance and cannot be recommended in normal practice. This raises the question whether current standards for negative histology in LLETZ specimens are set unrealistically high.

Adolescent↗
PubMed2000

A comparison of the side effects of prilocaine with felypressin and lignocaine with adrenaline in large loop excision of the transformation zone of the cervix: results of a randomised trial.

OBJECTIVE: To test the hypothesis that prilocaine with felypressin causes fewer side effects than lignocaine with adrenaline when performing large loop excision of the transformation zone of the cervix. DESIGN: Randomised trial. SETTING: Colposcopy clinic in a large district general hospital. PARTICIPANTS: Two hundred consecutive women undergoing large loop excision of the transformation zone of the cervix. METHODS: Two different local anaesthetic combinations (prilocaine with felypressin and lignocaine with adrenaline) were compared in women undergoing large loop excision of the transformation zone. Prospective collection of clinical and treatment data was undertaken with scoring using an ordinal scale of pain experienced by the women during the procedure. Peri-operative blood loss and any side effects were also recorded. MAIN OUTCOME MEASURES: Side effects associated with the local anaesthetic agents. RESULTS: Lignocaine with adrenaline resulted in less blood loss (P = 0.006) but was more likely to cause side effects, such as feeling faint (P = 0.017) and shaking (P < 0.001). CONCLUSION: Prilocaine with felypressin causes fewer side effects than lignocaine with adrenaline and is therefore the preferred local anaesthetic combination for large loop excision of the transformation zone.

Adult↗
PubMed1998

Flow cytometric assessment of three different methods for the measurement of in vitro apoptosis.

Chlorambucil-induced apoptosis was assessed by three different flow cytometric methods in B-cell chronic lymphocytic leukaemia (B-CLL) cells cultured in vitro and the results were compared with those derived from the morphological assessment of the same samples. Spontaneous apoptosis was consistently observed in the control cultures in the absence of drug but this accounted for less than 12% of all cells in every case. The methods under investigation were the Annexin V labelling assay, the terminal deoxynucleotidyl transferase (TdT) end-labelling assay and the labelling of a 38 kDa mitochondrial membrane protein (7A6 antigen) which is exposed on cells undergoing apoptotic cell death (Apo2.7 assay). The Annexin V assay consistently stained a higher percentage of cells and with a greater separation between the positive and negative cell populations. We conclude that the phosphatidyl serine translocation to the outer leaflet of the cell membrane following an apoptotic signal, as labelled by Annexin V, probably occurs before the development of the DNA strand breaks or the exposure of 7A6 antigen in those cells triggered to die by apoptosis.

Annexin A5↗
PubMed1998

Do routine antibiotics after loop diathermy excision reduce morbidity?

OBJECTIVE: To evaluate whether routinely giving an antibiotic after loop diathermy excision of the cervical transformation zone reduced post-operative vaginal loss. DESIGN: Prospective, randomised, double-blind placebo controlled parallel study. PARTICIPANTS: Five hundred women undergoing loop diathermy excision in a colposcopy clinic. INTERVENTION: Administration of either ofloxacin 400 mg (2x200 mg) once daily for 5 days or an identical placebo. MAIN OUTCOME MEASURE: Vaginal loss, assessed using a pictorial chart. RESULTS: No significant difference in post-operative vaginal loss was found. CONCLUSION: Routine antibiotic prophylaxis after loop diathermy excision is not justified.

Adult↗
PubMed1996

The preclinical development of bicalutamide: pharmacodynamics and mechanism of action.

OBJECTIVES. To describe the preclinical development of bicalutamide and clarify its pharmacodynamics and mechanisms of action. Bicalutamide was developed from a series of nonsteroidal compounds related to flutamide that showed a range of pharmacologic activity from full androgen agonist to pure antiandrogen, including progestational and antiprogestational properties. METHODS AND RESULTS. Bicalutamide is a pure antiandrogen that binds to rat, dog, and human prostate; the affinity compared with the natural ligand 5 alpha-dihydrotestosterone is low, but bicalutamide has an affinity for the rat androgen receptor approximately four times higher than hydroxyflutamide, the active metabolite of flutamide. Bicalutamide also binds to androgen receptors found in the LNCaP human prostate tumor and the Shionogi S115 mouse mammary tumor cell line, as well as androgen receptors transfected into CV-1 and HeLa cells. In all cases, bicalutamide behaves as a pure antiandrogen and inhibits gene expression and cell growth stimulated by androgen. Studies with the LNCaP cell line are particularly interesting, as these cells contain a mutated androgen receptor (codon 868, Thr-->Ala), which behaves idiosyncratically with other antiandrogens (cyproterone acetate and flutamide): both these antiandrogens act as agonists in this cell line and stimulate proliferation. Studies in vivo show that bicalutamide is a potent antiandrogen in the rat. In immature, castrated male rats treated daily with testosterone propionate, bicalutamide produces a profound inhibition of accessory sex organ (ventral prostate and seminal vesicles) growth at oral doses as low as 0.25 mg/kg; it is more active in this test than flutamide or cyproterone acetate. In mature male rats, daily oral doses of bicalutamide produce a dose-related reduction in weights of the ventral prostate glands and seminal vesicles: in this test, bicalutamide is around five times as potent as flutamide. In contrast to flutamide, which produces dose-related, marked increases in serum luteinizing hormone (LH) and testosterone as a consequence of the central inhibition of the negative feedback effects of androgens on the hypothalamic-pituitary-tests axis, bicalutamide has little effect on serum LH and testosterone; i.e., it is peripherally selective. The peripheral selectivity of bicalutamide in the rat is not due to differences between the prostate versus hypothalamic or pituitary receptors, as bicalutamide reverses the suppressive effect of testosterone on luteinizing hormone-releasing hormone (LHRH) secretion from hypothalamic slices in vitro and is as effective as flutamide at sensitizing the pituitary gland to secrete LH in response to administered LHRH. The peripheral selectivity of bicalutamide has now been shown to be due to poor penetration across the blood-brain barrier: tissue distribution studies with [3H]bicalutamide show that although it is concentrated in the organs of metabolism and secretion as well as in the prostate, the pituitary glands, and the seminal vesicles, levels in the hypothalamus and the central nervous system (CNS) are much lower than in blood. Indeed, it is probable that levels found in the CNS reflect levels of blood contamination. In dogs, bicalutamide has exquisite potency and causes dose-related atrophy of the prostate gland and epididymides; with an oral ED50 of 0.1 mg/kg, it is around 50 times as potent as flutamide in this species and also more potent than the steroidal antiandrogen WIN49596 and the 5 alpha-reductase inhibitor MK-906. Even at substantial multiples of the active dose (up to 100 mg/kg orally), bicalutamide failed to increase serum testosterone, so it is also peripherally selective in the dog.

Androgen Antagonists↗
PubMed1992

Novel inhibitors of prolyl 4-hydroxylase. 2. 5-Amide substituted pyridine-2-carboxylic acids.

A series of 5-[(arylcarbonyl)amino]- and 5-(arylcarbamoyl)pyridine-2-carboxylic acids has been prepared and tested for activity as inhibitors of the enzyme prolyl 4-hydroxylase (EC 1.14.11.2). All the analogues prepared were inhibitors of the enzyme in vitro, the best compounds being equipotent with the known inhibitor pyridine-2,5-dicarboxylic acid (9). Like 9 these amidic analogues were not active in a cultured embryonic chick tendon cell model, considered to be a predictor of in vivo activity. The activity of the amides is not consistent with the model described for the mode of action of 9 with the enzyme and aspects of this are discussed.

Amides↗
PubMed1990

Structure and polymorphic map of human lipoprotein lipase gene.

Lipoprotein lipase (LPL) catalyzes the key step for the removal of triacylglycerol-rich lipoproteins from the circulation. In this paper, we report the cloning and structure of the normal human LPL gene, which was isolated in three overlapping lambda phage clones that span about 35 kilo bases (kb) of the genetic locus. The peptide coding region of the gene is approx. 23 kb in length and contains nine exons with intron sizes ranging from 0.7 to 8.7 kb. The entire 3' untranslated region is in the tenth exon. Specific sequences in this region support the hypothesis that two mRNA species found for human LPL are generated by differential utilization of polyadenylation signals. The first exon occurs in the 5' untranslated region and the region coding for the signal peptide. The second exon includes the protein domain coding for the N-linked glycosylation site that is required for the expression of enzyme activity. The fourth exon contains the region that was proposed as a lipid binding domain, the sixth for one putative heparin binding domain, and the eighth codes for a domain containing another N-linked glycosylation site. These results suggest that the unique structural and functional domains are confined to specific exons. The PvuII polymorphic site was located within the intron between exon 6 and 7 and the HindIII polymorphic site to the 3' flanking region. The location of these polymorphic sites suggests that the PvuII restriction fragment length polymorphism (RFLP) associated with lipase deficiency in a few Japanese kindred may be a linkage marker for a functional defect of LPL, while the HindIII RFLP associated with hypertriglyceridemia may be important for gene regulation of LPL.

Amino Acid Sequence↗
PubMed1989

Excitation thresholds for nerve pedicles: a preliminary report.

Ongoing interest in the rehabilitation of paralyzed musculature in the head and neck has focused on the electronic stimulation of nerve-muscle pedicles that have been reimplanted into the incapacitated effector(s). Despite visual and histochemical evidence of reinnervation, it is still not known whether the excitability of a nerve-muscle pedicle (or for that matter a direct nerve implant) is equivalent to or better than that of reinnervated or normal muscle. Such information is necessary for the eventual construction of an implantable stimulator. Eighteen rabbits were anesthetized with intramuscular xylazine and ketamine and the ansa hypoglossi nerve was cut on one side. A crossover nerve-muscle pedicle was brought in from the opposite sternothyroid muscle to the sternohyoid in nine animals; the other nine received a direct nerve implant. After a minimum neurotization period of 3 months and reexploration, an electrical stimulator capable of delivering square wave pulses of variable amplitude and width was used to determine the thresholds of contraction of the nerve pedicles, an intact motor nerve of similar size, a normal muscle, and the reinnervated strap in 16 evaluable rabbits. Strength duration curves were established. The data indicate that thresholds for nerve pedicles are equivalent to those of normal nerves and are significantly lower than those of muscle.

Animals↗
PubMed1988

Resolution of the nonsteroidal antiandrogen 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'- (trifluoromethyl)-propionanilide and the determination of the absolute configuration of the active enantiomer.

The nonsteroidal antiandrogen 4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2- hydroxy-2-methyl-3'-(trifluoromethyl)-propionanilide (1) (ICI 176334) has been resolved by chromatographic separation of the diastereomeric (R)-camphanyl esters of the precursor thioether 2 followed by hydrolysis and oxidation of the isolated enantiomers. In addition, an asymmetric synthesis of (S)-3-bromo-2-hydroxy-2-methylpropanoic acid (11) and subsequent conversion into the (S)-sulfone 6a has established that the more potent enantiomer of 1 has the R absolute configuration.

Androgen Antagonists↗
PubMed1988

Nonsteroidal antiandrogens. Synthesis and structure-activity relationships of 3-substituted derivatives of 2-hydroxypropionanilides.

A series of 3-(substituted thio)-2-hydroxypropionanilides and some corresponding sulfones and sulfoxides of general structure 7, in which R' is methyl or trifluoromethyl, were prepared and tested for antiandrogen activity. Members of the trifluoromethyl series (7, R' = CF3) generally exhibited partial androgen agonist activity whereas the members of the methyl series (7, R' = CH3) were pure antagonists. Lead optimization in the methyl series has led to the discovery of novel, potent antiandrogens, which are peripherally selective. One of these, (RS)-4'-cyano-3-[(4-fluorophenyl)sulfonyl]-2-hydroxy-2-methyl-3'- (trifluoromethyl)propionanilide, 40 (ICI 176334), is being developed currently for the treatment of androgen-responsive benign and malignant disease.

Androgen Antagonists↗
PubMed1987

ICI 176,334: a novel non-steroidal, peripherally selective antiandrogen.

Pure antiandrogens, like flutamide, antagonize androgen action both peripherally and centrally at the hypothalamic-pituitary axis, which leads to an increase in LH and testosterone secretion. A new non-steroidal antiandrogen ICI 176,334 [2RS)-4'-cyano-3-(4-fluorophenylsulphonyl)-2-hydroxy-2-methyl-3'- trifluoromethyl)propion-anilide) has now been discovered which causes regression of the accessory sex organs but does not increase serum concentrations of LH and androgens. ICI 176,334 binds to rat prostate androgen receptors with an affinity around fourfold that of hydroxyflutamide. When administered s.c. concurrently with testosterone propionate (200 micrograms/kg) for 7 days to immature castrated rats, ICI 176,334 (10 mg/kg) significantly (P less than 0.001) inhibited growth of the seminal vesicles and ventral prostate gland. Oral administration of ICI 176,334 at doses of 1, 5 and 25 mg/kg for 14 days to adult rats caused a dose-related reduction in accessory sex organ weights but had no effect on the testes. None of these doses caused a significant increase in serum LH and testosterone. Flutamide was around fourfold less potent and significantly increased serum LH and testosterone at the higher doses. ICI 176,334 was well tolerated. ICI 176,334 should, therefore, prove useful for the treatment of androgen-responsive benign and malignant diseases.

Androgen Antagonists↗