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Biomedical subjects

D R Ferguson

Publications and source records attributed to D R Ferguson.

At least 19 recordsLinked to original sources
PubMed2001

Direct toxicity of nonsteroidal antiinflammatory drugs for renal medullary cells.

Antipyretic analgesics, taken in large doses over a prolonged period, cause a specific form of kidney disease, characterized by papillary necrosis and interstitial scarring. Epidemiological evidence incriminated mixtures of drugs including aspirin (ASA), phenacetin, and caffeine. The mechanism of toxicity is unclear. We tested the effects of ASA, acetaminophen (APAF, the active metabolite of phenacetin), caffeine, and other related drugs individually and in combination on mouse inner medullary collecting duct cells (mIMCD3). The number of rapidly proliferating cells was reduced by approximately 50% by 0.5 mM ASA, salicylic acid, or APAF. The drugs had less effect on confluent cells, which proliferate slowly. Thus, the slow in vivo turnover of IMCD cells could explain why clinical toxicity requires very high doses of these drugs over a very long period. Caffeine greatly potentiated the effect of acetaminophen, pointing to a potential danger of the mixture. Cyclooxygenase (COX) inhibitors, indomethacin and NS-398, did not reduce cell number except at concentrations greatly in excess of those that inhibit COX. Therefore, COX inhibition alone is not toxic. APAF arrests most cells in late G(1) and S and produces a mixed form of cell death with both oncosis (swollen cells and nuclei) and apoptosis. APAF is known to inhibit the synthesis of DNA and cause chromosomal aberrations due to inhibition of ribonucleotide reductase. Such effects of APAF might account for renal medullary cell death in vivo and development of uroepithelial tumors from surviving cells that have chromosomal aberrations.

Acetaminophen↗
PubMed2001

Distribution of P2X(1) and P2X(3) receptors in the rat and human urinary bladder.

Adenosine 5'-triphosphate (ATP) is known to play a significant role as a neurotransmitter in smooth muscle. There is evidence to show that ATP can cause bladder contractions and may also be involved in the processing of sensory information in the urinary bladder. These effects are likely to be mediated by P2X receptors, namely P2X(1) and P2X(3), respectively. This study set out to investigate their distribution in rat and human urinary bladders. P2X(1) receptor immunoreactivity was found on detrusor muscle fibres and P2X(3) receptor immunoreactivity was found in the urothelium of both species. This is the first demonstration of a non-neuronal localisation for P2X(3) receptors. No clear evidence was found for the presence of P2X(3) receptors on calcitonin gene-related peptide-containing sensory nerves and therefore P2X(3) receptors may not have a direct role in the mediation of sensory responses to ATP in the urinary bladder.

Adenosine Triphosphate↗
PubMed2000

Activation of epithelial Na(+) channel activity in the rabbit urinary bladder by cAMP.

The rabbit urinary bladder actively absorbs Na(+) from the urine. The rate-limiting step in this process is the diffusion of Na(+) across the apical membrane of bladder epithelial cells, mediated by amiloride-sensitive epithelial Na(+) channels. We have investigated the effects of cAMP on epithelial Na(+) channel activity in the rabbit bladder by measuring the amiloride-sensitive short-circuit current across bladders mounted in Ussing chambers. Three agents that raise intracellular cAMP levels (forskolin, dibutyryl-cAMP and 3-isobutyl-1-methylxanthine (IBMX)) increased the amiloride-sensitive short-circuit current relative to control preparations. The forskolin-induced increase in amiloride-sensitive short-circuit current was significantly inhibited by the vesicle fusion inhibitor brefeldin A and the protein synthesis inhibitor cycloheximide. These findings, together with the magnitude and protracted time course of the cAMP effects, suggests that cAMP stimulates the insertion of new Na(+) channels into the apical membrane of the rabbit bladder epithelium.

1-Methyl-3-isobutylxanthine↗
PubMed2000

Cell cycle delay and apoptosis are induced by high salt and urea in renal medullary cells.

We investigated the effects of hyperosmolality on survival and proliferation of subconfluent cultures of mIMCD3 mouse renal collecting duct cells. High NaCl and/or urea (but not glycerol) reduces the number of viable cells, as measured with 3-(4, 5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT). Raising osmolality from a normal level (300 mosmol/kg) to 550-1,000 mosmol/kg by adding NaCl and/or urea greatly increases the proportion of cells in the G(2)M phase of the cell cycle within 8 h, as measured by flow cytometry. Up to 600 mosmol/kg the effect is only transient, and by 12 h at 550 mosmol/kg the effect reverses and most cells are in G(1). Flow cytometry with 5-bromodeoxyuridine (BrdU) pulse-chase demonstrates that movement through the S phase of the cell cycle slows, depending on the concentrations of NaCl and/or urea, and that the duration of G(2)M increases greatly (from 2.5 h at 300 mosmol/kg to more than 16 h at the higher osmolalities). Addition of NaCl and/or urea to total osmolality of 550 mosmol/kg or more also induces apoptosis, as demonstrated by characteristic electron microscopic morphological changes, appearance of a subdiploid peak in flow cytometry, and caspase-3 activation. The number of cells with subdiploid DNA and activated caspase-3 peaks at 8-12 h. Caspase-3 activation occurs in all phases of the cell cycle, but to a disproportionate degree in G(0)/G(1) and S phases. We conclude that elevated NaCl and/or urea reduces the number of proliferating mIMCD3 cells by slowing the transit through the S phase, by cell cycle delay in the G(2)M and G(1), and by inducing apoptotic cell death.

Animals↗
PubMed1998

Pretreatment with methylprednisolone to prevent ERCP-induced pancreatitis: a randomized, multicenter, placebo-controlled clinical trial.

OBJECTIVE: Pancreatitis remains the major complication of endoscopic retrograde cholangiopancreatography (ERCP). Uncontrolled data suggest a lower incidence of pancreatitis in patients with a history of iodine sensitivity when given pretreatment with corticosteroids. We conducted a clinical trial to assess the efficacy of a commonly prescribed corticosteroid, methylprednisolone, to prevent ERCP-induced pancreatitis. METHODS: Patients were entered into a randomized, multicenter, double-blind, placebo-controlled study of intravenous methylprednisolone (125 mg) versus a saline placebo immediately before the ERCP. All patients were evaluated for early and late complications. RESULTS: Two hundred eighty-six patients were randomized. Thirty-one randomized patients were excluded for technical reasons at the time of ERCP. Overall, the incidence of pancreatitis was 16 of 129 (12.4%, 95% CI: 6.7-18.1%) in the methylprednisolone group and 11 of 126 (8.7%, 95% CI: 4.4-15.1%) in the placebo group, which was not significantly different (p = 0.34). Although there was a higher rate of sphincterotomy performed in the methylprednisolone group compared to the control group (31.8% vs 16.8%, p = 0.005), the incidence of pancreatitis was not different when patients undergoing sphincterotomy were analyzed separately (13.6% in the methylprednisolone group and 9.6% in the placebo group,p = 0.50). There was no significant difference between the two groups for those with ERCP-induced pancreatitis in hospital length of stay (p = 0.22), days of parenteral analgesia (p = 0.09), or days of parenteral nutrition (p = 0.15). CONCLUSION: Intravenous methylprednisolone is not beneficial in preventing ERCP-induced pancreatitis.

Analgesia↗
PubMed1997

ATP is released from rabbit urinary bladder epithelial cells by hydrostatic pressure changes--a possible sensory mechanism?

1. The responses of rabbit urinary bladder to hydrostatic pressure changes and to electrical stimulation have been investigated using both the Ussing chamber and a superfusion apparatus. These experiments enabled us to monitor changes in both ionic transport across the tissue and cellular ATP release from it. 2. The urinary bladder of the rabbit maintains an electrical potential difference across its wall as a result largely of active sodium transport from the urinary (mucosal) to the serosal surface. 3. Small hydrostatic pressure differences produced by removal of bathing fluid from one side of the tissue caused reproducible changes in both potential difference and short-circuit current. The magnitude of these changes increases as the volume of fluid removed increases. 3. Amiloride on the mucosal (urinary), but not the serosal, surface of the membrane reduces the transepithelial potential difference and short-circuit current with an IC50 of 300 nM. Amiloride reduces the size of, but does not abolish, transepithelial potential changes caused by alterations in hydrostatic pressure. 4. Field electrical stimulation of strips of bladder tissue produces a reproducible release of ATP. Such release was demonstrated to occur largely from urothelial cells and is apparently non-vesicular as it increases in the absence of calcium and is not abolished by tetrodotoxin. 5. It is proposed that ATP is released from the urothelium as a sensory mediator for the degree of distension of the rabbit urinary bladder and other sensory modalities.

Adenosine Triphosphate↗
PubMed1995

A prospective, double-blind trial of somatostatin analog (octreotide) versus glucagon for the inhibition of small intestinal motility during endoscopic retrograde cholangiopancreatography.

BACKGROUND: Glucagon is effective when used as an antimotility agent during ERCP, but at high doses it may cause nausea and vomiting. Octreotide acetate, a long-acting synthetic analog of somatostatin, inhibits contractility of the small intestine and is generally well tolerated. The purpose of this study was to determine if octreotide given prior to ERCP reduced the requirement for glucagon and enhanced patient tolerance for the procedure. METHODS: Patients undergoing ERCP (n = 100) performed for a variety of indications (but not sphincter of Oddi manometry) were randomly assigned to receive normal saline solution or octreotide at a total dose of 25 micrograms, 50 micrograms, or 100 micrograms diluted in normal saline solution prior to the procedure. Glucagon was subsequently administered (as needed, to inhibit intestinal motility) by endoscopists who were blinded to the test substance given prior to the procedure. RESULTS: For all treatment groups, the dose of glucagon required to inhibit intestinal motility in patients who received octreotide prior to the procedure was not significantly different from the dose administered to patients who received normal saline solution. There was no significant difference in the incidence of nausea and vomiting when individual test groups were compared to the control group. CONCLUSION: Nausea and vomiting after ERCP were uncommon in all treatment groups. Administration of octreotide prior to ERCP did not significantly reduce the dose of glucagon required to inhibit intestinal motility. Tolerance for ERCP was similar for patients given octreotide when compared with those given glucagon to inhibit small intestinal motility.

Adult↗
PubMed1995

Inhibitory actions of GABA on rabbit urinary bladder muscle strips: mediation by potassium channels.

1. The actions of gamma-aminobutyric acid (GABA) upon rabbit urinary bladder muscle were investigated to determine whether they were mediated through potassium channels. 2. In vitro experiments were undertaken in which bladder muscle strips were caused to contract with carbachol. Addition of GABA or baclofen reduced the size of such evoked contractions in the case of GABA by 20.7 +/- 3.2%, in the case of baclofen by 22.4 +/- 2.2%. 3. Electrical stimulation of autonomic nerves in bladder wall strips also evoked contractions which were significantly smaller in potassium-free Krebs solution. The size of contractions produced by carbachol on the other hand were unaffected by the absence of potassium in the Krebs solution. 4. The inhibitory actions of GABA and baclofen on carbachol-induced contractions of bladder muscle were detected at much lower concentrations in potassium-free compared with potassium containing solutions. 5. The inhibitory effects of baclofen were completely reversed by tetraethyl ammonium chloride between 1 and 5 mM, caesium chloride between 0.5 and 3 mM and barium chloride between 0.5 and 2.5 mM. The actions of baclofen were only partially reversed by 4-amino-pyridine between 1 and 5 mM. 6. It was concluded that the GABAB receptor-mediated inhibitory actions on rabbit urinary bladder smooth muscle cells were produced by activation of potassium channels.

Animals↗
PubMed1994

Inhibition in the human urinary bladder by gamma-amino-butyric acid.

OBJECTIVE: To investigate the effects of gamma-amino-butyric acid (GABA) on detrusor activity in man to determine whether it has any inhibitory effect on detrusor contraction. The inhibitory neurotransmitter GABA has been found in mammalian urinary bladders and the effects of GABA on detrusor activity in the rabbit bladder has previously been described [1]. MATERIALS AND METHODS: Human detrusor muscle strips, obtained at cystectomy, were made to contract by electrical stimulation of their autonomic nerves or by the addition of carbachol in a superfusion apparatus. GABA and its analogues were added to the superfusion chamber and any changes in the responses were measured. RESULTS: The electrically evoked nerve-mediated contractions in human bladder muscle were exclusively cholinergic. GABA inhibited nerve-mediated contractions in human detrusor muscle-strips by the activation of the GABAB receptor, since baclofen (a GABAB receptor agonist) produced similar inhibition and muscimol (a GABAA receptor agonist) did not. There was no inhibition of carbachol-mediated contractions by GABA. CONCLUSION: This in vitro study shows that GABA has a peripherally mediated inhibitory effect on excitatory neurotransmission in human detrusor muscle. The site of action is on the post-ganglionic nerves and appears to be mediated via the GABAB receptor.

Aged↗
PubMed1994

Primary sclerosing cholangitis.

Primary sclerosing cholangitis (PSC) remains a disease of unknown etiology. The close association of PSC and inflammatory bowel disease (IBD), especially ulcerative colitis (UC), has been reconfirmed in numerous studies. Much has been learned about the pathogenesis, although the specific cause remains unknown. Copper overload and chronic hepatic bacterial infection have virtually been excluded as causes of PSC. Cytomegalovirus and reovirus remain under investigation. Familial clustering and HLA subtype similarities are seen in PSC with and without IBD. The finding of antineutrophil cytoplasmic antibodies (ANCA) in patients with PSC and those with UC suggests immunological features in the pathogenesis of PSC. Collected series of patients have better characterized clinical features of PSC. Endoscopic retrograde cholangiopancreatography (ERCP) and percutaneous transhepatic cholangiography (PTC) have provided both diagnostic features and means of therapeutic intervention. Treatment of PSC is symptomatic (pruritus control and vitamin deficiency correction); or experimental (D-penicillamine, ursodeoxycholic acid [UDCA], methotrexate, or corticosteroids). Liver transplantation remains the ultimate treatment for end-stage PSC. Statistical analyses of clinical and laboratory variables in PSC help to determine prognosis and proposed timing for transplantation to achieve maximal longevity and quality of life. PSC affects middle-aged people and is expensive to treat over the natural course of the disease, making it an economically and medically important disease.

Adult↗
PubMed1993

Surgical decisions in the management of duodenal perforation complicating endoscopic sphincterotomy.

The management of duodenal perforation associated with endoscopic sphincterotomy is controversial. Despite the fact that many patients recover without surgery, surgical opinion tends to favor immediate operation upon diagnosis since the mortality is high when sepsis is advanced. To refine the criteria for operative management, all duodenal perforations after endoscopic sphincterotomy over a 5-year period were studied. In a series of 464 consecutive endoscopic sphincterotomies, 8 duodenal perforations occurred; additionally, 4 patients with duodenal perforation were referred from elsewhere for management. Six patients were managed initially with nonoperative treatment (group I), and six underwent exploratory surgery upon diagnosis or hospital transfer (group II). One patient in group I was operated on 4 days after diagnosis. Of the seven surgically treated patients, three had repair of the duodenal perforation and drainage of the abscess or phlegmon, but four had no gross inflammation or visible duodenal perforation requiring repair at exploration. The clinical features of abdominal pain with physical signs significantly correlated with operative findings of pus or phlegmon (p < 0.05). Improvement in symptoms within 24 hours is correlated with spontaneous recovery (p < 0.01). Neither the presence of retroperitoneal air nor contrast leak is predictive of the need for surgery, and neither correlated with the size of the perforation. It is concluded that duodenal perforation may be treated successfully without surgery when the symptoms are mild and improve rapidly with medical treatment, but surgery should be undertaken if pain and abdominal signs are prominent, if suppuration is suspected, or if symptoms do not improve after a brief period of nonoperative management.

Abdominal Pain↗
PubMed1993

Placement of a feeding button ("one-step button") as the initial procedure.

The procedure of choice for enteral feeding access is now percutaneous endoscopic gastrostomy (PEG). Standard PEG tubes have the disadvantages of clogging, stomal enlargement, and external bulkiness. Button replacement tubes can covert the more cumbersome PEG tubes to low external profile devices. A procedure and an early experience is described for placement of a button as a single-step procedure. This procedure is an over-the-wire, "push" procedure. Sixty-nine buttons were placed, 47 (61%) for neurologic reasons and 22 (32%) for cancer and other reasons. In 49 of the 69 (71%), there was no difficulty at all with insertion, and in only two (3%) could the button not be placed. Complications were assessed at 48 h and at 3 wk. No complications were found in 61 (90%). In only two patients (3%) were there serious complications (gastro-colon-cutaneous fistula and "peritonitis"). The One-Step Button represents a rapid, safe procedure for the placement of a low-profile PEG with its attendant advantages.

Animals↗
PubMed1992

Inhibitory role of gamma-amino-butyric acid in the rabbit urinary bladder.

Gamma-amino-butyric acid (GABA) is an established inhibitory neurotransmitter in the central nervous system (CNS) and it has also been identified in the bladder. We have investigated in the rabbit the effect of GABA on detrusor activity. Rabbit detrusor muscle strips were made to contract by electrical stimulation of their autonomic nerves or by the addition of carbachol. The addition of GABA caused substantial inhibition of muscle contraction. GABA acts on 2 classes of receptors-GABAA and GABAB. The inhibition was mediated via the GABAB receptors as its effect was mimicked by baclofen (a GABAB agonist) and inhibited by 2-hydroxysaclofen (a GABAB receptor antagonist). Inhibition was not prevented by bicuculline (a GABAA receptor antagonist). This inhibition may be due to a direct muscle effect since the inhibition, which occurred with carbachol-induced contraction, was not abolished by the addition of tetrodotoxin. GABA, acting via the GABAB receptor, produces substantial inhibition of muscle contraction in the rabbit urinary bladder. This raises the possibility of using GABAB analogues in the treatment of detrusor instability.

Animals↗
PubMed1990

Effect of capsaicin on the rabbit urinary bladder. What is the function of sensory nerves that contain substance P?

The sensory innervation of the rabbit urinary bladder was studied using local application of the specific sensory neurotoxin capsaicin (8-methyl-N-vanillyl-6-nonenamide). This agent has its major effect by damaging small diameter unmyelinated sensory nerves. The drug produced a 51% reduction in the bladder content of the neuropeptide substance P. It therefore appears that a substantial proportion of the bladder's content of the peptide is to be found in capsaicin-sensitive sensory nerves. Cystometrograms carried out before and after treatment with capsaicin were similar; this suggests that capsaicin-sensitive sensory nerves may not be of importance in the afferent limb of the micturition reflex. In vitro muscle strip studies demonstrated a small reduction in the sensitivity of the detrusor muscle to electrical stimulation of its intramural nerves. It is possible that in vitro intramural nerve stimulation leads to release of neurotransmitters from sensory as well as motor nerves. It is proposed that small diameter sensory nerves in the bladder wall may have a role in the transmission of the sensation of pain and in the triggering of inflammatory reactions rather than forming the afferent limb of the micturition reflex.

Animals↗
PubMed1990

Effect of bladder outflow obstruction on the innervation of the rabbit urinary bladder.

The effects of bladder outflow obstruction on the innervation of the bladder were studied using a rabbit animal model. Partial occlusion of the bladder neck was obtained by the placement of a silk ligature at that level; control animals underwent a sham procedure. After a 3-month period, the presence of outflow tract obstruction was confirmed using urodynamic studies. The animals were then killed and pharmacological assessments of the bladder innervation undertaken. Detrusor muscle strip studies provided evidence of damage to the cholinergic innervation of the detrusor. Also, muscle strips from obstructed animals showed reduced inhibitory responses to beta-adrenergic stimulation with isoprenaline. In addition to these muscle strip studies, the bladder content of the neuropeptide substance P was assayed, but no significant change was observed in response to obstruction. This finding suggests that substance P-containing sensory nerves may be spared from the denervating effect of bladder outflow obstruction.

Animals↗
PubMed1989

The effect of enalapril on the renal response to tilting in humans.

1. Seventeen normal subjects were tilted on a tilt table and changes in blood pressure, heart rate and renal function were monitored in the absence of drug treatment; the same measurements were repeated during treatment with enalapril in eight of these subjects. 2. In the absence of drug, tilting of the whole body to the 45 degree head up position caused an antidiuresis, antinatriuresis and antikaliuresis; the antinatriuresis resulted from a transient fall in glomerular filtration and from a sustained increase in the tubular reabsorption of sodium, as reflected by a prolonged fall in fractional sodium excretion. 3. Enalapril caused a reduction in blood pressure in the upright position; there was no effect on heart rate. The antinatriuresis of tilt was significantly blunted by enalapril. This resulted from blunting of the transient fall in creatinine clearance and of the increase in tubular sodium reabsorption. Urinary potassium excretion during tilting was not altered by enalapril. 4. These findings are consistent with a direct intrarenal action of angiotensin II, mediating some of the alterations in renal function apparent on assumption of the upright position.

Adult↗
PubMed1989

Neurotransmission in pig renal artery: the actions of angiotensin II and dopamine.

1. Electrical stimulation of pig renal arteries causes contractions which are potentiated in the presence of angiotensin II (5 x 10(-8) M). 2. The potentiation is followed by a long-lasting inhibitory phase which is mimicked by dopamine and 2-amino-6,7,dihydroxy-1,2,3,4,-tetrahydronaphthalene (ADTN), but blocked by sulpiride (5 x 10(-8) M). 3. Release of noradrenaline from renal artery rings by 25 mM K+ was measured by h.p.l.c. and found to be increased by 5 x 10(-8) M angiotensin II. As this was done in the presence of 1 x 10(-6) M desmethylimipramine it was concluded that the increase was due to increase neuronal release of noradrenaline, not inhibition of neuronal uptake. 4. The experiments indicate that dopamine is present in the artery wall and produces its effects through DA2-receptors.

Angiotensin II↗