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Biomedical subjects

A MacDonald

Publications and source records attributed to A MacDonald.

At least 19 recordsLinked to original sources
PubMed1992

Manual dilatation of the anus.

A group of 100 consecutive patients undergoing manual dilatation of the anus between 1980 and 1983 were reviewed retrospectively by examining the clinical presentation, diagnosis, treatment and outcome. Anal fissure was diagnosed in 46 patients, 22 had either first- or second-degree haemorrhoids, and stenosis of the anal canal was identified in seven. Manual dilatation of the anus was performed on 25 patients in the absence of a diagnosis. Dilatation failed to treat 26 anal fissures successfully. Where it was employed alone in ten cases of haemorrhoids and seven of anal stenosis, manual dilatation failed to cure seven and five patients respectively. Of the patients with no diagnosis, 23 were relieved of their symptoms following dilatation. Episodes of incontinence occurred in 27 patients, 21 of whom were female. There should be a reduced role for manual anal dilatation in the treatment of common anorectal disorders.

Adolescent↗
PubMed1992

A clinical and pharmacological study of high-dose mitozolomide given in conjunction with autologous bone marrow rescue.

In conjunction with autologous bone marrow rescue, high-dose mitozolomide was given i.v. to 16 patients with refractory malignancies at doses ranging from 100 to 400 mg/m2 over 1 h. Neutropaenia occurred consistently at 300 mg/m2, and three trivial infective episodes were recorded. Thrombocytopaenia occurred consistently at 150 mg/m2, and three patients experienced episodes of minor bleeding. The death of one subject was attributable to pulmonary thromboembolism during the bone marrow reinfusion. Transient emesis and mild alopecia were the only other toxicities. Three of six evaluable patients receiving greater than or equal to 300 mg/m2 exhibited measurable reductions in tumour dimensions, although these failed to fulfil the criteria for a partial response. Mitozolomide was undetectable in plasma at 12 h after drug administration. The plasma pharmacokinetic data fitted mono- or biexponential models in all patients. Model-independent pharmacokinetic parameters were: peak plasma drug concentration, 3.4-46 mg/l; AUC, 8-82 mg h l-1; clearance, 7.6-45 l/h; steady-state volume of distribution, 11-85 l; and plasma elimination half-life, 1.4-2.8 h. Dose-dependent pharmacokinetics were not observed, and only a small percentage of the delivered dose was eliminated unchanged in the urine. The maximally tolerated dose of mitozolomide given with autologous bone marrow rescue was greater than 400 mg/m2. At this dose myelosuppression was the only major toxicity, and the plasma drug levels and AUC values were comparable to those obtained after therapeutic doses in experimental models.

Adult↗
PubMed1992

A new oesophageal tube: assessment of collagen/vicryl composite membrane.

Collagen/vicryl composite membrane has been previously shown to be of use in an experimental model as a patch graft in the bladder and oesophagus. Attempts to use it as a circumferential tube graft have been unsuccessful due to the development of strictures at the site of anastomosis. We inserted a polytetrafluoroethylene (PTFE) stented collagen/vicryl bioprosthetic tube into rat omentum, which served as a vascular pedicle. Subsequent histology of the graft showed serial replacement of the bioprosthesis with host collagen and the development of a blood supply. In a second stage procedure, the bioprosthesis was anastomosed to the distal ileum and brought out on the skin to form a fistula. Squamous epithelium was subsequently identified growing the full length of the graft. Therefore, we have developed a vascularised bioprosthetic tube graft which will support the growth of unspecialised epithelium. This model could be of use in bridging congenital atresias or pathological strictures.

Anastomosis, Surgical↗
PubMed1992

Characterisation of ovine mast cells derived from in vitro culture of haemopoietic tissue.

Ovine mast cells generated in vitro from bone marrow (BMMC) were compared with mucosal mast cells (MMC) isolated from parasitised abomasum. Ultrastructurally, the granules of BMMC were partially developed and immature. Both cells types contained beta-hexosaminidase, arylsulfatase, histamine, dopamine and sheep mast cell proteinase (SMCP). Greater amounts of beta-hexosaminidase, but less SMCP, histamine and arylsulfatase were present in BMMC. Stimulation with calcium ionophore A23187 caused the secretion of granule constituents and generation of leukotriene C4 by BMMC in a dose-dependent manner. An additional [3H]diisopropylfluorophosphate-binding 31,500 mol. wt. serine esterase, antigenically related to SMCP (27,000 mol. wt.) was present in cultures of BMMC but was not detected in isolated MMC. Both enzymes were detected in BMMC by Day 7 of culture and were secreted concomitantly following stimulation of BMMC with ionophore.

Abomasum↗
PubMed1992

Divergent responses to epidermal growth factor in hormone sensitive and insensitive human prostate cancer cell lines.

The present study was undertaken to compare the relationship between response to exogenous epidermal growth factor (EGF) and the expression of the EGF-receptor (EGF-R) in an androgen sensitive (LNCaP) and insensitive (DU145) prostate cancer cell line. Although both cell lines demonstrated a single EGF-R binding site of similar high affinities (mean dissociation constant (Kd) +/- S.D. for DU145 = 1.0 +/- 0.6 nmol l-1; LNCaP = 2.8 +/- 2.2 nmol l-1) the number of binding sites (RT) for the hormone insensitive DU145 cells (mean +/- S.D. = 2.5 +/- 1.0 x 10(5) sites/cell) and 10-fold greater than that expressed in the androgen responsive LNCaP cell line (mean +/- S.D. = 2.0 +/- 1 x 10(4) sites/cell). Additionally exogenous EGF only minimally affected the growth and DNA synthesis of DU145 cells whereas LNCaP cells showed a significant response which was dose dependent. The autologous production of EGF-like molecules by DU145 cells is believed to reduce the cells needs for exogenous mitogens, thereby rendering the cells autostimulatory. Treatment of LNCaP cells with Mibolerone--a synthetic androgen--did not affect either the expression of the EGF receptor or the proliferative response observed with EGF. Western blot analysis, using monoclonal antibodies directed against the EGF receptor revealed a band of approximately 170 kD with DU145 cell lysates but the LNCaP EGF receptor was not detected using this technique.

Blotting, Western↗
PubMed1992

Contributions of alpha 1-adrenoceptors, alpha 2-adrenoceptors and P2x-purinoceptors to neurotransmission in several rabbit isolated blood vessels: role of neuronal uptake and autofeedback.

1. The roles of autofeedback and neuronal uptake in neurotransmission produced by electrical field stimulation in several rabbit isolated blood vessels were examined. 2. Blocking drugs were used to separate the possible purinergic and noradrenergic contributions to the end organ response: prazosin, antagonist at postjunctional alpha 1-adrenoceptors; rauwolscine and yohimbine, antagonists at pre- and postjunctional alpha 2-adrenoceptors; alpha,beta-methylene ATP, desensitizing agent at postjunctional P2x-purinoceptors. In addition to desensitizing postjunctional P2x-purinoceptors, alpha,beta-methylene ATP potentiated the noradrenergic component of the nerve-induced responses. 3. In the presence of an intact neuronal uptake mechanism, the vessels showed different contributions of purinergic (via P2x-purinoceptors) and noradrenergic (via alpha 1-adrenoceptors and alpha 2-adrenoceptors) components to the end organ response to nerve stimulation: saphenous artery (approximately equal contributions from P2x-purinoceptors and alpha 1-adrenoceptors), ileocolic artery (mainly P2x-purinoceptors with a smaller contribution from alpha 1-adrenoceptors), plantaris vein (mainly alpha 1-adrenoceptors with a small contribution from alpha 2-adrenoceptors and P2x-purinoceptors) and saphenous vein (alpha 1-adrenoceptors). 4. The presence of alpha 2-adrenoceptor-mediated autofeedback could be demonstrated for both purinergic and noradrenergic components of the nerve-induced responses in the artery preparations. In the veins, potentiation of nerve-induced responses by alpha 2-adrenoceptor antagonists could not be studied due to blockade of postjunctional alpha 2-adrenoceptor-mediated vasoconstriction. 5. Blockade of neuronal uptake with cocaine potentiated the noradrenergic component of the nerve-induced responses. Both alpha 1-adrenoceptor- and alpha 2-adrenoceptor-mediated components were potentiated, with a relatively greater potentiation of the alpha 2-adrenoceptor-mediated component. In the case of saphenous vein an alpha 2-adrenoceptor-mediated component which was previously absent was uncovered.6. Blockade of neuronal uptake with cocaine had no effect or reduced the purinergic component of responses, the latter effect presumably due to enhanced alpha 2-adrenoceptor-mediated autofeedback.7. In the presence of cocaine, nerve-induced responses in the saphenous vein were biphasic. Rauwolscine potentiated the first phase and inhibited the second phase thus demonstrating effects of pre- and postjunctional alpha 2-adrenoceptor-mediated activation in the same preparation.8. In conclusion, neuronal uptake and autofeedback processes play important and complex interacting parts in determining the relative contributions of alpha 1,- and alpha 2-adrenoceptors and P2.-purinoceptors in the end organ response to neurotransmission in blood vessels.

Animals↗
PubMed1992

Hypersensitivity to acetaldehyde-protein adducts.

Acetaldehyde, the first product in the metabolism of ethanol, is known to condense with plasma proteins, forming stable adducts. We have previously shown that these adducts can be recognized as foreign by the immune system. In the present study the existence of type I hypersensitivity-mediating antibodies against these adducts was investigated in humans and in animals. Immunization of mice with acetaldehyde-protein condensates, followed by adoptive transfer of splenocytes, led to the production of IgE anti-acetaldehyde adducts. A monoclonal IgE antibody was obtained by the hybridization technique. This antibody recognized acetaldehyde adducts, independently of the carrier protein used, indicating that the acetaldehyde moiety behaves as a hapten. The affinity of the antibody for the acetaldehyde adduct of polylysine was 7 orders of magnitude higher than that for polylysine. Passive immunization by intradermal or intravenous administration of this monoclonal antibody to rats rendered the animals hypersensitive to acetaldehyde-protein conjugates, as shown by marked anaphylaxis. A study was conducted to determine the existence of naturally occurring hypersensitivity reactions to alcohol in > 1000 non-Oriental individuals. A prevalence of severe hypersensitivity reactions of 0.46% was found. The reactions were severe enough to deter these individuals from consuming all types of alcoholic beverages. Individuals presenting such reactions had significantly elevated levels of circulating anti-acetaldehyde-protein IgE antibodies.

Acetaldehyde↗
PubMed1991

Relationship between outlet obstruction constipation and obstructed urinary flow.

Ten women with symptoms and radiological features of outlet obstruction constipation underwent urodynamic bladder studies. The results were compared with ten age- and sex-matched controls. The mean (s.e.m.) peak flow rate for patients was 19.4 (6.4) ml/s compared with 32.1 (7.2) ml/s for controls (P less than 0.05). The mean (s.e.m.) voiding time for patients was 62.9 (23.7) s against a corresponding value of 15.6 (6) for controls (P less than 0.05). The mean (s.e.m.) bladder volume in patients was 482 (80) ml compared with a control value of 254 (112) ml (P less than 0.03). The mean (s.e.m.) detrusor pressure during the voiding phase was 53.3 (12) cmH2O. These results demonstrate that patients with outlet obstruction constipation have a generalized pelvic floor disorder resulting in obstructed urinary flow.

Constipation↗
PubMed1991

Characterization of catecholamine-mediated relaxations in rat isolated gastric fundus: evidence for an atypical beta-adrenoceptor.

1. Experiments were carried out in order to characterize the receptors mediating relaxant responses to catecholamines in the rat gastric fundus. The effects of noradrenaline, isoprenaline and the 'atypical' or beta 3-adrenoceptor agonist, BRL 37344, on methacholine-induced tone were measured. Prazosin, propranolol and cyanopindolol were used as antagonists. 2. Relaxant responses to noradrenaline, in the presence of propranolol (1 microM) were antagonized in a concentration-dependent manner by prazosin (0.01 to 1 microM), although this antagonism was weak and non-competitive in nature. Relaxant responses to isoprenaline, in the presence of prazosin (0.1 microM), were antagonized only by the highest concentration of propranolol (1 microM) giving a pKB of 6.3 BRL 37344 also relaxed the rat gastric fundus in the presence of prazosin (0.1 microM), and the responses to BRL 37344 were unaffected by propranolol (1 microM). 3. Tachyphylaxis to BRL 37344 was observed, a second concentration-response curve being significantly shifted to the right. Exposure of tissues to BRL 37344 (1 microM) between concentration-response curves also caused an 11 fold rightward shift in the response to isoprenaline. 4. In the presence of prazosin (0.1 microM) and propranolol (1 microM), the rank order of potency of the agonists was: (-)-isoprenaline (1.0) greater than (-)-noradrenaline (0.39) greater than BRL 37344 (0.10). 5. Responses to BRL 37344 in the presence of prazosin (0.1 microM) and propranolol (1 microM) were antagonized by (+/-)-cyanopindolol (1 microM), with a pKB of 6.56. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (+/-)-cyanopindolol (0.1-1 microM), with the slope of a Schild plot close to unity and a pA2 value of 7.44. 6. The resistance to blockade by prazosin and propranolol and the antagonism by cyanopindolol of the responses mediated by isoprenaline and BRL 37344 suggest that atypical beta-adrenoceptors similar to 'atypical',beta-adrenoceptors in rat adipocytes and other tissues are present in the rat gastric fundus.

Adrenergic alpha-Agonists↗
PubMed1991

Different sensitivities of rabbit isolated blood vessels exhibiting co-transmission to the slow calcium channel blocker, nifedipine.

1. Antagonist drugs were used to separate the purinergic and adrenergic contributions as well as the adrenoceptor sub-types involved in the sympathetic vasoconstrictor responses produced by electrical field stimulation in rabbit isolated ileocolic and proximal saphenous arteries. Blocking drugs were applied either alone or in various combinations and sequences. 2. Nifedipine attenuated vasoconstrictor responses to sympathetic nerve stimulation both in the presence and in the absence of alpha-adrenoceptor blocking agents. However in the presence of alpha,beta-methylene ATP, nifedipine produces at best only a small attenuation of the vasoconstrictor response. 3. These results suggest that the purinergic component of the response to sympathetic nerve stimulation, at least in these tissues, can be antagonized by nifedipine, whereas the alpha 1-adrenoceptor-mediated response is relatively resistant.

Adenosine Triphosphate↗
PubMed1990

Production and response of a human prostatic cancer line to transforming growth factor-like molecules.

Serum-free media conditioned by the androgen insensitive human prostate cancer cell line DU145 showed immunological transforming growth factor-alpha (TGF alpha) activity, as well as competing activity in epidermal growth factor (EGF) radioreceptor assays (RRA). Furthermore, there were factors in the conditioned media which inhibited and stimulated DNA synthesis by DU145 cells in a dose-dependent fashion. Fractionation of the concentrated conditioned media by reverse-phase high performance liquid chromatography revealed several peaks containing EGF-like competitive activity only one of which demonstrated TGF alpha activity. However, none of the peaks corresponded to immunoreactive EGF. Measurement of EGF receptors on DU145 cells by competition and saturation analysis revealed high levels of receptors (mean +/- s.d. = 2.5 +/- 1 x 10(5) surface receptors per cell) which were of high affinity (Kd +/- s.d. = 1.0 +/- 0.5 nmol l-1). Although DU145 cells express high levels of EGF receptors, DNA synthesis was only minimally affected by exogenous EGF and TGF alpha.

Chromatography, High Pressure Liquid↗
PubMed1990

The effect of introducing endoscopic therapy on surgery and mortality rates for peptic ulcer hemorrhage. A single center analysis of 1,125 cases.

The introduction of early endoscopic diagnosis has not been associated with a reduction in either surgical intervention or overall mortality for peptic ulcer hemorrhage. Recent studies have suggested that endoscopic therapy can reduce rebleeding rates from peptic ulceration. We report a 2-year experience of the influence of endoscopic heater probe (HP) (Olympus CD 10Z) therapy on the outcome of patients admitted with peptic ulcer hemorrhage. Eight hundred and sixty-two patients admitted with peptic ulcer hemorrhage over a 5-year period (1978/9 and 1983/5) before endoscopic therapy (PRE-HP), and 263 patients admitted with peptic ulcer hemorrhage after introduction of endoscopic therapy (POST-HP: 1986-1988) were assessed. All 1,125 patients were managed by a joint physician/surgeon team. The introduction of HP therapy was associated with a reduction in surgical intervention and overall mortality rates for gastric ulceration from 16% and 8.9% PRE-HP to 7% and 2.6% POST-HP respectively (p less than 0.05). A similar but non-significant trend was noted for duodenal ulceration. The beneficial effects of HP therapy appear to be due to a reduction in the need for surgical hemostasis in patients with an ulcer base visible vessel. Our results suggest that a more widespread use of endoscopic therapy may result in an improved outcome from peptic ulcer hemorrhage.

Endoscopy↗
PubMed1990

Evidence for the existence of 'atypical' beta-adrenoceptors (beta 3-adrenoceptors) mediating relaxation in the rat distal colon in vitro.

1. Experiments were carried out to characterize the adrenoceptors mediating relaxant responses in the rat distal colon. Three agonists were used: noradrenaline, isoprenaline and the beta 3-adrenoceptor agonist BRL 37344. Phentolamine, propranolol and (+/- )-cyanopindolol were tested as antagonists. Tone in the rat distal colon was induced with KCl (30-40 mM) as a spasmogen, and relaxations of this KCl-induced tone produced by the agonists were measured. 2. Relaxant responses to noradrenaline that were obtained in the presence of propranolol (1 microM) were not antagonized by phentolamine (0.01 to 1 microM). Relaxant responses to isoprenaline that were obtained in the presence of phentolamine (1 microM) were antagonized in a concentration-dependent manner by propranolol (0.01 to 3 microM), although this antagonism was weak and non-competitive. Relaxant responses to BRL 37344 that were obtained in the presence of phentolamine (1 microM) were only weakly antagonized by high (1 microM) concentrations of propranolol. 3. Tachyphylaxis to BRL 37344 was observed, a second concentration-response curve being shifted to the right by 15 fold. Exposure of the tissues to BRL 37344 (1 microM) between concentration-response curves also caused rightward shifts in the responses to noradrenaline (18 fold) and isoprenaline (19 fold) but not to papaverine. 4. In the presence of phentolamine (1 microM) and propranolol (1 microM), the rank order of potency of the agonists was: (-)-isoprenaline (1.0) greater than or equal to BRL 37344 (0.93) greater than (-)-noradrenaline (0.3). 5. Responses to BRL 37344 in the presence of phentolamine (1 microM) and propranolol (1 microM) were antagonized by (+/-)-cyanopindolol (I microM), with an apparent pA2 value of 6.67. Responses to isoprenaline, under the same conditions, were antagonized in a competitive manner by (+/-)-cyanopindolol (0.1 to 10 microM), with the slope of the Schild plot close to unity and a pA2 value of 7.12. 6. The resistance of the relaxant responses to antagonism by phentolamine and propranolol, along with the relatively high potency of the beta 3-adrenoceptor agonist BRL 37344 and the antagonism of 'resistant' responses by (+/-)-cyanopindolol would suggest that 'atypical' beta 6-adrenoceptors, similar to the beta 3-adrenoceptors of rat adipocytes and other tissues, exist in the rat distal colon.

Adrenergic alpha-Antagonists↗
PubMed1990

Pre- and post-junctional alpha-adrenoceptor-mediated responses in the rat gastric fundus in-vitro.

The effects of alpha 1- and alpha 2-adrenoceptor agonists on smooth muscle tone and on cholinergic excitatory and non-adrenergic, non-cholinergic inhibitory responses to field stimulation have been investigated in the rat gastric fundus in-vitro. None of the alpha-adrenoceptor agonists tested, noradrenaline, phenylephrine, cirazoline, guanoxabenz or UK-14,304 showed any contractile effects at concentrations up to 30 microM. In preparations where tone was raised by barium (0.5-2 mM), the mixed alpha 1- and alpha 2-adrenoceptor agonist noradrenaline (0.01-10 microM), and the selective alpha 1-adrenoceptor agonists cirazoline (0.01-10 microM) and phenylephrine (0.01-10 microM) produced concentration-dependent relaxations which were antagonized by the alpha 1-adrenoceptor antagonist prazosin (0.01-1.0 microM). The selective alpha 2-adrenoceptor agonists UK-14,304 (0.03-30 microM) and guanoxabenz (0.03-30 microM), had no relaxant effects in raised tone. UK-14,304 (0.03-1.0 microM) produced a concentration-dependent inhibition of cholinergic nerve-induced responses which was antagonized by the alpha 2-adrenoceptor antagonist idazoxan (0.03-1.0 microM) but not by prazosin (0.03-1.0 microM). Noradrenaline (0.03-1.0 microM) also produced an inhibition of cholinergic nerve-induced responses which was antagonized by idazoxan (0.03-1.0 microM). A small component of the noradrenaline inhibitory effects was antagonized by prazosin (10%). Cirazoline (0.03-1.0 microM) produced a small inhibition of cholinergic nerve-induced responses which was antagonized by prazosin (0.03-1.0 microM). The prazosin-sensitive components of the inhibitory effects of noradrenaline and cirazoline occurred at concentrations which also produced post-junctional relaxation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗
PubMed1990

Two enteric coated microspheres in cystic fibrosis.

In a randomised single blind crossover study in children with cystic fibrosis and pancreatic insufficiency, two enteric coated microsphere preparations of pancreatin were compared on a capsule for capsule basis, by measuring the coefficient of fat absorption, nitrogen excretion, weight change, and symptom scores after four weeks' treatment with each preparation. Thirty nine subjects were randomly allocated to receive Pancrease followed by Creon or vice versa. Each individual subject received the same number of capsules per day in each study period. Data from 27 children (Pancrease/Creon, n = 13 and Creon/Pancrease, n = 14) wer suitable for analysis. Results showed no significant differences between the two preparations in any variable studied. We conclude that there is no significant difference between Pancrease and Creon when compared on a capsule for capsule basis.

Adolescent↗