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Biomedical subjects

N Watson

Publications and source records attributed to N Watson.

At least 19 recordsLinked to original sources
PubMed1992

Bile acids influence the growth, oestrogen receptor and oestrogen-regulated proteins of MCF-7 human breast cancer cells.

The effects of the major human serum bile acid, glycochenodeoxycholic acid (GCDC), as well as unconjugated chenodeoxycholic acid (CDC), on the MCF-7 human breast cancer cell line have been studied in vitro under oestrogen and bile acid deprived culture conditions. GCDC increased the growth of the breast cancer cells over the range 10-300 microM. At concentrations in excess of the bile acid binding capacity of the medium cell growth was prevented. In contrast 10 microM CDC tended to reduce cell growth. Oestrogen (ER) and progesterone (PgR) receptors, pS2 and total cathepsin D were quantified by monoclonal antibody based immunoassays. Ten to 100 microM GCDC and 10 microM CDC down-regulated ER protein and this was accompanied by induction of the oestrogen-regulated proteins PgR, pS2 and possibly cathepsin D, including increased secretion of the latter two proteins into the culture medium. All these changes were quantitatively similar to those observed with 10 nM oestradiol. The bile acid effects on ER and PgR were not due to interference with the assay procedures. Cells incubated with 50 microM GCDC or 10 microM CDC had higher pmolar concentrations of the bile acids than controls. This study suggests that naturally occurring bile acids influence the growth and steroid receptor function of human breast cancer cells.

Bile Acids and Salts↗
PubMed1992

Actions of methoctramine, a muscarinic M2 receptor antagonist, on muscarinic and nicotinic cholinoceptors in guinea-pig airways in vivo and in vitro.

1. The effects of the muscarinic M2 receptor antagonist methoctramine, on contractions of airway smooth muscle induced by cholinergic nerve stimulation and by exogenously applied acetylcholine (ACh), have been investigated in vivo and in vitro in guinea-pigs. 2. Stimulation of the preganglionic cervical vagus nerve in anaesthetized guinea-pigs, caused bronchoconstriction and bradycardia which were mimicked by an intravenous dose of ACh. The muscarinic M2 antagonist, methoctramine (7-240 nmol kg-1), inhibited the bradycardia induced by both vagal stimulation and ACh (ED50: 38 +/- 5 and 38 +/- 9 nmol kg-1, respectively). In this dose-range, methoctramine facilitated vagally-induced bronchoconstriction (ED50: 58 +/- 5 nmol kg-1), despite some inhibition of ACh-induced bronchoconstriction (ED50: 81 +/- 11 nmol kg-1). The inhibition of ACh-induced bronchoconstriction and hypotension was dose-dependent, but was not statistically significant until doses of 120 nmol kg-1 and 240 nmol kg-1 respectively. 3. In the guinea-pig isolated, innervated tracheal tube preparation, methoctramine (0.01-1 microM) caused facilitation of contractions induced by both pre- and postganglionic nerve stimulation, whereas contractions induced by exogenously applied ACh were unaffected. Higher concentrations of methoctramine (greater than or equal to 10 microM), reduced responses to both nerve stimulation and exogenous ACh, indicating blockade of post-junctional muscarinic M3 receptors. 4 ACh caused a slow maintained increase in tone of the tracheal tube and at the same time reduced the contractions induced by nerve stimulation. This inhibitory effect of ACh on neuronally mediated responses was antagonized by methoctramine (0.01-1 microM) in a concentration-dependent manner. However, the ACh-induced tone change was unaffected by methoctramine in this concentration-range, indicating a lack of muscarinic M3 receptor antagonist activity in this concentration-range.5. The effect of methoctramine on responses induced by pre- and postganglionic nerve stimulation was not identical. At concentrations of methoctramine of 1 ,microM and greater, preganglionic stimulation-induced contractions were reduced when compared to those induced by postganglionic stimulation, suggesting an inhibitory effect of methoctramine on ganglionic transmission. This ganglion blocking action of methoctramine was not due to its reported M1 receptor antagonist activity (blocking facilitatory Ml receptors in the ganglia) since pirenzepine was without effect in this preparation. We believe that the ganglionic blocking action of metoctramine is due to its nicotinic receptor antagonist properties, since the concentration of methoctramine inhibiting ganglionic transmission in the tube preparation (1 microM) was shown to inhibit contractions induced by the nicotinic agonist, 1,1-dimethyl-4-phenyl-piperazine in tracheal strips.6. These results show that methoctramine is able to demonstrate adequately the presence of autoinhibitory receptors functionally both in vivo and in vitro and confirms their pre-junctional location on pulmonary cholinergic nerve terminals and their classification as muscarinic M2 subtypes. These results also indicate that while methoctramine is a potent muscarinic M2 receptor antagonist, it does not possess the required selectivity to discriminate between cholinoceptor subtypes in preparations, such as the airways, where mixed populations of muscarinic and nicotinic cholinoceptors exist.

Animals↗
PubMed1992

Identification of elements involved in transcriptional regulation of the Escherichia coli cad operon by external pH.

Expression of the lysine decarboxylase gene (cadA) of Escherichia coli is induced upon external acidification. To dissect the molecular mechanisms responsible for this regulation, we analyzed a 4.2-kbp region upstream from cadA. DNA sequencing revealed two long open reading frames upstream of and on the same strand as cadA. One of these, cadB, is 444 codons long and is situated immediately upstream of cadA. Transcriptional fusions between fragments upstream of cadA and lacZ, Northern (RNA) hybridization, primer extension, and site-directed mutagenesis experiments defined a promoter, Pcad, upstream of cadB that was responsible for pH-regulated expression of cadA. Upstream of Pcad is an open reading frame, cadC, consisting of 512 codons. The predicted amino terminal region of the cadC gene product (CadC) resembles the carboxy-terminal domain of prokaryotic transcriptional activators involved in environmental sensing. Tn10 insertions within or immediately upstream of cadC abolished Pcad activity, suggesting that cadC encodes a positive transcription factor. Expression of plasmid-borne cadC in the Tn10 mutants restored Pcad activity, while introduction of a plasmid expressing truncated CadC resulted in the inability to complement. The presence of Pcad on a multicopy plasmid was found to lower expression arising from chromosomal Pcad, suggesting that a positive-acting factor is limiting. Our data suggests that cadA, cadB, and the acid-inducible Pcad comprise, at least in part, the cad operon which is under control of the cadC product.

Amino Acid Sequence↗
PubMed1992

The effects of plasma estradiol levels on increases in vertebral and femoral bone density following therapy with estradiol and estradiol with testosterone implants.

Percutaneous estradiol (E2) implants effectively preserve bone density in postmenopausal women. However, these implants are often given with testosterone, which may itself have an anabolic effect on bone. To determine whether testosterone confers any additional bone-sparing effect, we studied 50 postmenopausal women randomly allocated to receive E2 (75 mg) alone or with testosterone (100 mg) every 6 months for 1 year. Women with an intact uterus received cyclic norethindrone (5 mg) for 10 days of each calendar month. Twenty-five untreated women were recruited to act as a reference group. Bone density was measured at the lumbar spine and proximal femur by dual x-ray densitometry. By 1 year, bone density at the lumbar spine had fallen by 1.8% in the reference group. In the women treated with E2 alone, it increased significantly by 7.8% (P less than .0001) and in those receiving E2 with testosterone, it increased by 6.3% (P less than .0001). At the femoral neck, bone density decreased by 3% in the controls and increased by approximately 4% in both treated groups (P less than .0001). The increase in bone density at these sites was unrelated to the woman's chronological age, menopausal age, or initial bone density. However, it correlated significantly with the serum E2 levels attained after 1 year of therapy. In no treated patients did bone density decrease significantly. These data show that testosterone confers no additional bone-sparing effect in postmenopausal women.

Bone Density↗
PubMed1991

Effects of captopril on glucose tolerance in elderly patients with congestive cardiac failure.

A prospective study was carried out to investigate the effects of the ACE inhibitor captopril on glucose tolerance in 14 elderly patients, aged 76 to 89 years, who had co-incident cardiac failure and stable Type II diabetes mellitus. Patients were maintained on their diet and diabetic therapy and were given 12.5 mg captopril twice daily. Clinical findings, including signs of cardiac failure, body weight and blood pressure, biochemical profile and chest X-ray appearance were documented at each visit. Blood glucose tolerance testing was carried out immediately before starting captopril and again 28 days later. A reduction in symptoms of heart failure occurred in all patients and 5 of them reduced their New York Heart Association grade of heart failure. Significant improvement in glucose tolerance occurred in all patients. Four were able to reduce hypoglycaemic therapy and 1 was able to stop his hypoglycaemic agents. This potentially valuable additional benefit of captopril in improving glucose tolerance has not yet been shown to occur with other ACE inhibitors.

Aged↗
PubMed1991

A cross-sectional study of the effects of long-term percutaneous hormone replacement therapy on bone density.

The effect of hormone implants on the bone density of postmenopausal women was studied in 110 patients (mean age 54.7 years; mean menopausal age 8.6 years, range 2-30) who had received hormone replacement in the form of estradiol (50-75 mg) and testosterone (100 mg) pellets at 6-month intervals for 2-24 years (mean 5.2). They were compared with 254 untreated women (mean age 55.0 years; mean menopausal age 6.8 years, range 1-37). The bone density at the spine, measured by quantitative digital radiography, was 1.123 grams hydroxyapatite (gHa)/cm2 in the treated group and 0.951 gHa/cm2 in the controls (P less than .0001). The total bone density at the proximal femur was 1.002 gHa/cm2 in the treated group, compared with 0.914 gHa/cm2 in the controls (P less than .0001). There were significant differences in the density of the trochanteric, intertrochanteric, and neck areas of the proximal femur as well as the Ward triangle (all P less than .0001). These differences became significant from the age of 55 at the neck of the femur, Ward triangle, and lumbar spine, and from age 60 for all other values. Subcutaneous estradiol and testosterone prevent postmenopausal osteoporosis and maintain normal bone density for as long as treatment is continued.

Adult↗
PubMed1990

Point mutations in a pBR322-based expression plasmid resulting in increased synthesis of bovine growth hormone in Escherichia coli.

The bGH cDNA coding for bovine growth hormone (bGH) is expressed poorly in Escherichia coli using a pBR322-based expression plasmid. Random mutagenesis of the plasmid gave rise to two types of plasmid mutants which increased the expression of bGH. One class had single base changes in the first four codons of the bGH sequence. The second class had single base changes in regions of the plasmid involved in controlling plasmid replication but had little effect on plasmid copy number.

Amino Acid Sequence↗
PubMed1990

Spontaneous complete remission of chronic myeloid leukaemia following haematological relapse after allogeneic bone marrow transplantation.

A 31-year-old woman with Philadelphia (Ph) chromosome-positive chronic myeloid leukaemia (CML) underwent allogenic bone marrow transplantation during accelerated phase. Non-T-cell-depleted marrow from a male sibling mismatched at one Class 2 histocompatibility locus was infused after conditioning with total body irradiation and intravenous cyclophosphamide. Cyclosporin and methotrexate were given for prevention of graft-versus-host disease (GVHD). Prompt engraftment occurred with donor karyotype cells, followed by transient moderate acute GVHD. However, by day 60 after BMT, haematological relapse occurred with increasing splenomegaly, leucocytosis, increasing marrow fibrosis, and cytogenetic mosaicism, consisting of 47% donor metaphases with 53% Ph-positive host metaphases, some containing additional structural changes. Thirty days later further cytogenetic progression was evident. A slowly progressive fungal pneumonia concurrently present was treated with intravenous amphotericin and gradual reduction of cyclosporin. Subsequently, without further cytotoxic chemotherapy, pancytopenia and bone marrow hypoplasia developed, and on day 144 only donor karyotype marrow cells were seen. Chromosomes have remained of donor type on subsequent occasions, and the patient has a normal performance status 25 months after BMT. The patient's course illustrates that factors operating after allogeneic BMT contribute to longterm control of CML. The factors potentially responsible for this spontaneous remission, after early relapse, are discussed.

Adult↗
PubMed1990

Hormone implants and tachyphylaxis.

The serum oestradiol levels of 1388 women treated with hormone implants at a menopause clinic were reviewed in 1988. Thirty-eight (3%) were found to be above 1750 pmol/l. Of these 38 women with supraphysiological oestradiol levels 23 had started therapy for menopausal symptoms and 15 for the premenstrual syndrome (PMS). Of the 23 women treated for menopausal symptoms 11 had a history of psychiatric referral for depression and nine had undergone a surgical menopause. Nine of the 15 women with PMS had a history of psychiatric referral for depressive symptoms. We conclude that the women who attain supraphysiological levels of oestradiol on implant therapy have a high frequency of psychopathology or surgical menopause and may require higher oestradiol levels for adequate control of symptoms.

Adult↗
PubMed1990

Auditory filter shapes at 8 and 10 kHz.

Auditory filter shapes were derived from notched-noise masking data at center frequencies of 8 kHz (for three spectrum levels, N0 = 20, 35, and 50 dB) and 10 kHz (N0 = 50 dB). In order to minimize variability due to earphone placement, insert earphones (Etymotic Research ER2) were used and individual earmolds were made for each subject. These earphones were designed to give a flat frequency response at the eardrum for frequencies up to 14 kHz. The filter shapes were derived under the assumption that a frequency-dependent attenuation was applied to all stimuli before reaching the filter; this attenuation function was estimated from the variation of absolute threshold with frequency for the three youngest normally hearing subjects in our experiments. At 8 kHz, the mean equivalent rectangular bandwidths (ERBs) of the filters derived from the individual data for three subjects were 677, 637, and 1011 Hz for N0 = 20, 35, and 50 dB, respectively. The filters at N0 = 50 dB were roughly symmetrical, while, at the lower spectrum levels, the low-frequency skirt was steeper than the high-frequency skirt. The mean ERB at 10 kHz was 957 Hz. At this frequency, the filters for two subjects were steeper on the high-frequency side than the low-frequency side, while the third subject showed a slight asymmetry in the opposite direction.

Adult↗
PubMed1989

The relation between oral movement control and speech.

A large series of neurological patients, selected solely on the basis that they had damage restricted to one hemisphere of the brain, was given a variety of tests of basic speech and praxic function. Within the left-damaged group, patients were further identified as aphasic or nonaphasic, based on preexisting standard tests of aphasia. Subgroups of aphasics were studied on the basis of lesion location, rather than on the basis of aphasia type. The focus of the study was the relation between the production of speech and nonspeech oral movements, particularly across anterior and posterior lesions. Reproduction of single nonverbal oral movements and of single isolated speech sounds was found to be very highly correlated, and both depended selectively on the left anterior region of the brain. This same region was critically important for rapid repeated articulation of a syllable, suggesting that it mediates control at some "unit" level of movement, in a phenomenological sense, for both speech and nonspeech movements. Other "speech" regions in the left hemisphere appeared to be dispensable for the production of single oral movements, whether these were verbal or nonverbal movements. However, for most aphasic patients, an area in the left posterior region was inferred to be essential for production of multiple oral movements, whether nonverbal or verbal, suggesting a critical role in the accurate selection of movements. Within the posterior region, there was further differentiation for multisyllabic speech into a parietal system, which appeared to mediate primarily praxic function, and a temporal system, which appeared to mediate verbal-echolalic function. Aphasias from anterior and posterior lesions resembled "Broca's" and "Wernicke's" aphasia only insofar as they differed in fluency, with anterior aphasics clearly less fluent. Tests of speech comprehension did not differentiate the groups. It is suggested that classifying aphasic patients via lesion location rather than aphasic typology might yield a view of functional subsystems different from those commonly accepted.

Adult↗
PubMed1989

Monitoring the course of cervical carcinoma with the squamous cell carcinoma serum radioimmunoassay.

Serum samples were collected from 611 gynecologic patients for measurement of squamous cell carcinoma antigen levels using the Abbott Laboratories squamous cell carcinoma antigen radioimmunoassay kit. Sixteen of 83 patients (19.3%) with cervical dysplasia and 72 of 135 (53.3%) with primary or recurrent cervical carcinoma had levels above 2.4 ng/mL. In contrast, only seven of 373 women (1.9%) without genital tract squamous cell intraepithelial neoplasia or carcinoma had squamous cell carcinoma antigen levels above 2.4 ng/mL. Fifty-six patients with cervical cancer were followed for correlation of squamous cell carcinoma antigen levels to disease course, and 20 had persistent or recurrent disease after therapy; rising squamous cell carcinoma antigen levels predicted disease in 15 of these 20 patients with recurrence (13 of 15 with elevated pre-treatment levels and two of five with normal pre-treatment levels). Rising squamous cell carcinoma antigen levels preceded the clinical detection of disease in ten patients by a mean of 4.6 months (range 2-7.5 months); in the remaining five, squamous cell carcinoma antigen levels were elevated only when disease recurrence was documented. Although measurement of squamous cell carcinoma antigen levels is not a sensitive screening method for cervical cancer (sensitivity 53.3%), the test has good specificity (94.3%); the majority of patients with false-positive elevations had other genital tract squamous cell neoplasias. The squamous cell carcinoma antigen assay may be a useful aid for monitoring the disease course of cervical carcinoma.

Antigens, Neoplasm↗
PubMed1988

A new revision of the sequence of plasmid pBR322.

A revised sequence in the region immediately upstream from the rop gene of pBR322 is reported. Two base pairs in the accepted sequence do not exist in the plasmid DNA. Specifically, a TA base pair is missing at sequence coordinate 1893 [Sutcliffe, Cold Spring Harbor Symp. Quant. Biol. 43 (1979) 77-90] and an AT base pair is missing at position 1915, giving a total size for pBR322 of 4361 bp. These changes are in a potential translation initiation sequence and probably reflect errors in the original sequence rather than recent evolution of the plasmid.

Base Composition↗