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Biomedical subjects

R J Webb

Publications and source records attributed to R J Webb.

At least 19 recordsLinked to original sources
PubMed2005

Vasography in urethral stricture: novel application of an old technique.

Urethral stricture disease in men has traditionally been investigated with ascending and voiding cystourethrography as well as urethroscopy. The main emphasis during the preoperative assessment is on establishing the exact extent of the disease process in order to plan appropriate management. We describe a technique that represents a novel approach to the assessment of proximal urethral stricture and in selected cases would be of immense help in defining its precise nature and planning definitive treatment.

Catheterization↗
PubMed2003

Artemisinins target the SERCA of Plasmodium falciparum.

Artemisinins are extracted from sweet wormwood (Artemisia annua) and are the most potent antimalarials available, rapidly killing all asexual stages of Plasmodium falciparum. Artemisinins are sesquiterpene lactones widely used to treat multidrug-resistant malaria, a disease that annually claims 1 million lives. Despite extensive clinical and laboratory experience their molecular target is not yet identified. Activated artemisinins form adducts with a variety of biological macromolecules, including haem, translationally controlled tumour protein (TCTP) and other higher-molecular-weight proteins. Here we show that artemisinins, but not quinine or chloroquine, inhibit the SERCA orthologue (PfATP6) of Plasmodium falciparum in Xenopus oocytes with similar potency to thapsigargin (another sesquiterpene lactone and highly specific SERCA inhibitor). As predicted, thapsigargin also antagonizes the parasiticidal activity of artemisinin. Desoxyartemisinin lacks an endoperoxide bridge and is ineffective both as an inhibitor of PfATP6 and as an antimalarial. Chelation of iron by desferrioxamine abrogates the antiparasitic activity of artemisinins and correspondingly attenuates inhibition of PfATP6. Imaging of parasites with BODIPY-thapsigargin labels the cytosolic compartment and is competed by artemisinin. Fluorescent artemisinin labels parasites similarly and irreversibly in an Fe2+-dependent manner. These data provide compelling evidence that artemisinins act by inhibiting PfATP6 outside the food vacuole after activation by iron.

Animals↗
PubMed2002

Gap-junctional communication in mouse cumulus-oocyte complexes: implications for the mechanism of meiotic maturation.

The mechanisms underlying the hormonal stimulation of meiotic maturation are not understood. The most prevalent hypothesis is that hormone-induced maturation is stimulated by an increase in the intracellular messengers, cAMP or Ca2+. This study investigated whether Ca2+ transients in somatic cells can lead to Ca2+ transients in the oocyte, and whether hormones that stimulate meiotic maturation of mouse oocytes in vitro and in vivo stimulate an increase in intracellular Ca2+. Of a range of potential agonists of Ca2+ release, ATP and UTP were the only agents that stimulated Ca2+ release in cumulus cells. ATP-induced Ca2+ release is from intracellular stores, as the response is not blocked by chelation of extracellular Ca2+, but is inhibited by the Ca2+-ATPase inhibitor, thapsigargin. ATP and UTP are equipotent, consistent with the receptor being of the P2Y2 type. Confocal microscopy was used to show that ATP-induced Ca2+ release in cumulus cells leads to a Ca2+ increase in the oocyte. Inhibition of gap-junctional communication using carbenoxolone, as assayed by dye transfer, inhibited the diffusion of the Ca2+ signal from the cumulus cells to the oocyte. Thus, provided that a Ca2+ signal is generated in the somatic cells in response to maturation-inducing hormones, it is feasible that a Ca2+ transient is generated in the oocyte. However, FSH and EGF, both of which stimulate maturation in vitro, have no effect on Ca2+ in cumulus--oocyte complexes. Furthermore, LH, which leads to meiotic maturation in vivo, did not stimulate Ca2+ release in acutely isolated granulosa cells from preovulatory mouse follicles. These studies indicate that ATP may play a role in modulating ovarian function and that diffusion of Ca2+ signals through gap junctions may provide a means of communication between the somatic and germ cells of the ovarian follicle. However, our data are not consistent with a role for Ca2+-mediated communication in hormone-mediated induction of meiosis in mice.

Adenosine Triphosphate↗
PubMed2001

Ureteric stenting for repair of accidental ureteric injuries.

Intra-operative injury to the ureter is a well known but fortunately uncommon complication of any major pelvic surgical procedure. If recognised on table, it can be repaired by either a substitution ureteroplasty or end-to-end anatomical repair depending upon the extent of tissue loss. Either of these anastomoses could be secured by total internal stent placement. We describe an improvised technique of intra-operative open ureteric stenting particularly when radiological assistance is not available, i.e. during emergency situations.

Anastomosis, Surgical↗
PubMed2000

The importance of carboxyl groups on the lumenal side of the membrane for the function of the Ca(2+)-ATPase of sarcoplasmic reticulum.

The conventional model for transport of Ca(2+) by the Ca(2+)-ATPase of skeletal muscle sarcoplasmic reticulum (SR) involves a pair of binding sites for Ca(2+) that change upon phosphorylation of the ATPase from being high affinity and exposed to the cytoplasm to being low affinity and exposed to the lumen. However, a number of recent experiments suggest that in fact transport involves two separate pairs of binding sites for Ca(2+), one pair exposed to the cytoplasmic side and the other pair exposed to the lumenal side. Here we show that the carbodiimide 1-ethyl-3-[3-(dimethylamino)-propyl] carbodiimide (EDC) is membrane-impermeable, and we use EDC to distinguish between cytoplasmic and lumenal sites of reaction. Modification of the Ca(2+)-ATPase in sealed SR vesicles with EDC leads to loss of ATPase activity without modification of the pair of high affinity Ca(2+)-binding sites. Modification of the purified ATPase in unsealed membrane fragments was faster than modification in SR vesicles, suggesting the presence of more quickly reacting lumenal sites. This was confirmed in experiments measuring EDC modification of the ATPase reconstituted randomly into sealed lipid vesicles. Modification of sites on the lumenal face of the ATPase led to loss of the Ca(2+)-induced increase in phosphorylation by P(i). It is concluded that carboxyl groups on the lumenal side of the ATPase are involved in Ca(2+) binding to the lumenal side of the ATPase and that modification of these sites leads to loss of ATPase activity. The presence of MgATP or MgADP leads to faster inhibition of the ATPase by EDC in unsealed membrane fragments than in sealed vesicles, suggesting that binding of MgATP or MgADP to the ATPase leads to a conformational change on the lumenal side of the membrane.

Amino Acid Sequence↗
PubMed1998

Hydrophobic mismatch and the incorporation of peptides into lipid bilayers: a possible mechanism for retention in the Golgi.

Preferential interaction of trans-membrane alpha-helices whose hydrophobic length matches the hydrophobic thickness of the lipid bilayer could be a mechanism of retention in the Golgi apparatus. We have used fluorescence methods to study the interaction of peptides Ac-K2-G-Lm-W-Ln-K2-A-amide (Pm+n) with bilayers of phosphatidylcholines with chain lengths between C14 and C24. The peptide P22 (m = 10, n = 12) incorporates into all bilayers, but P16 (m = 7, n = 9) does not incorporate into bilayers when the fatty acyl chain length is C24 and only partly incorporates into bilayers where the chain length is C22. The strongest binding is seen when the hydrophobic length of the peptide matches the calculated hydrophobic thickness of the bilayer. It is suggested that a too-thin bilayer can match to a too-long peptide both by stretching of the lipid and by tilting of the peptide. However, a too-thick bilayer can only match a too-thin peptide by compression of the lipid, which becomes energetically unfavorable when the difference between the bilayer thickness and the peptide length exceeds about 10 A. The presence of cholesterol in the bilayer leads to a marked reduction in the incorporation of P16 into bilayers where the chain length is C18. Hydrophobic mismatch could explain retention of proteins with short trans-membrane alpha-helical domains in the Golgi, the effect following largely from the low concentration of cholesterol in the Golgi membrane compared to that in the plasma membrane.

Cell Compartmentation↗
PubMed1997

Shades of greener grass.

Neither system or culture is perfect; a blend just might be. I can't say that one is definitely better, only different. Many Canadian doctors have emigrated only to return within a year or two, frustrated with a market-driven health care system and a much more eclectic and individualistic society. Yes, family physicians can earn more money here and have better access to diagnostics and treatment. But that has to be balanced with a larger bureaucracy and-at least on the surface-less freedom to access those resources. With time and the ubiquitous fiscal imperative, both countries could emerge from their respective crises at similar destinations, but by separate paths. Traveling and particularly working in another culture has been a positive experience for our family. It might not be for everyone. Each physician, with his or her family, must weigh the pros and cons of such a decision. To boldly go where you've never been before, to move or not to move: that is the question.

Adaptation, Psychological↗
PubMed1992

Obstetrical epidural anaesthesia in a rural Canadian hospital.

Few rural hospitals offer obstetric epidural analgesia services and of those that do, there is a paucity of information about these anaesthetics. A retrospective review was conducted of all obstetrical epidurals from 1984-1988 in an 85-bed hospital in Saskatchewan to examine the indications, complications, and infant outcomes. During that period there were 1224 deliveries. From a total of 915 vaginal deliveries, 42 (4.6%) received an epidural. Caesarean sections numbered 309: 183 (59.3%) were with epidural analgesia of which 69 were urgent and 114 elective. The overall complication rate was 23% with the most important being hypotension (12%), dural punctures (1.8%), inadequate block requiring an intravenous supplement (4.0%) or a general anaesthetic (3.1%). Infant outcomes were favourable except for two unrelated intra-uterine deaths preceding labour.

Anesthesia, Epidural↗
PubMed1992

Ambulatory monitoring of bladder pressure in low compliance neurogenic bladder dysfunction.

Upper tract dilatation is an important complication of neurogenic bladder dysfunction. Risk factors include incomplete bladder emptying with large residual volumes of urine and high tonic increases in bladder pressures during artificial filling. However, on natural bladder filling many of these patients do not have high tonic increases in detrusor pressures. We compared conventional urodynamic studies with ambulatory monitoring during natural bladder filling in 66 patients with low compliance neurogenic bladder dysfunction. There were marked differences in the tonic increase in bladder pressure during filling and in compliance during artificial bladder filling compared with ambulatory monitoring. Faster filling rates during artificial filling resulted in greater end filling pressures and lower compliance but the lowest increases in bladder pressure were found during ambulatory monitoring with natural bladder filling. During natural bladder filling significantly more patients had phasic changes in detrusor pressure; a high intensity of phasic activity during ambulatory monitoring correlated with high end filling pressures during artificial bladder filling. Upper tract dilatation was associated with large volumes of residual urine, high resting bladder pressures and low bladder compliance on filling at 100 ml. per minute. However, upper tract dilatation was most strongly associated with high intensity phasic pressure activity during natural bladder filling in combination with high residual urine volumes and high resting bladder pressures. On multivariate statistical analysis the intensity of phasic pressure activity during ambulatory monitoring was the best discriminator between patients with dilated and normal upper tracts. Our study has highlighted important differences in the results obtained by artificial filling cystometry and ambulatory monitoring during natural bladder filling. In particular, high increases in pressure did not occur during natural bladder filling, apparently being replaced by phasic activity. Within this group of patients who had the high risk factor of low bladder compliance measured during artificial bladder filling, a combination of greater residual urine volumes, greater resting pressures and greater phasic activity during natural bladder filling was found in patients with upper tract dilatation.

Adolescent↗
PubMed1992

Electromyographic abnormalities in the urethral and anal sphincters of women with idiopathic retention of urine.

Previous concentric needle studies of the urethral sphincter in women with idiopathic urinary retention have found evidence of denervation and reinnervation as well as abnormal patterns of muscle fibre discharge--complex repetitive discharges (CRDs). In order to test the hypothesis that these abnormalities represented a more widespread disease process of pelvic floor function, we carried out an electromyographic (EMG) study of both anal and urethral sphincters in 18 women with idiopathic urinary retention. The urethral sphincter EMG was abnormal in 15 patients. These abnormalities included polyphasic and long duration potentials. Complex repetitive discharges were identified in 8 women. However, abnormalities of the anal sphincter were found in 14 of the 15 patients with abnormal urethral sphincter EMGs, polyphasic and abnormally long duration potentials being found in the anal sphincters of all 14 patients. In addition, 7 of the 8 women who had complex repetitive discharges in the urethral sphincters had similar complex repetitive discharges in their anal sphincters. Women with complex repetitive discharges had a significantly greater proportion of abnormal potentials than women with no such repetitive discharges. These results support the previous findings of electromyographic urethral sphincter abnormalities in women with idiopathic urinary retention, but also suggest that these abnormalities reflect a widespread disease process involving the pelvic floor in such patients.

Adult↗
PubMed1991

Filling and voiding pressures measured by ambulatory monitoring and conventional studies during natural and artificial bladder filling.

A total of 20 men awaiting elective prostatectomy for bladder outflow obstruction underwent conventional medium filling cystometry and ambulatory monitoring of bladder pressures during natural bladder filling. Total bladder capacity was similar during both tests (medium filling cystometry 256 +/- 138 ml. and ambulatory monitoring 248 +/- 120 ml., p not significant) as was the voided volume (medium filling cystometry 180 +/- 100 ml. and ambulatory monitoring 179 +/- 88 ml., p not significant). However, the peak urinary flow rate at the end of medium filling cystometry (4 +/- 6 ml. per second) was significantly lower than during ambulatory monitoring (9 +/- 4 ml. per second, p less than 0.05). The bladder contraction pressure during medium filling cystometry (79 +/- 44 cm. water) was significantly lower than during ambulatory monitoring (107 +/- 39 cm. water, p less than 0.005). Bladder pressures during voiding recorded after natural filling were significantly greater than after artificial filling. This finding may have significant implications for the use of conventional cystometry to study conditions such as outflow obstruction.

Aged↗
PubMed1991

Urodynamic study of ileocystoplasty in the treatment of idiopathic detrusor instability.

Enterocystoplasty is being used with increasing frequency in the treatment of patients with idiopathic detrusor instability. We have performed a prospective clinical and urodynamic study of this procedure in 11 patients using both conventional (CMG) and ambulatory monitoring techniques (AM). Nine of 11 patients were satisfied with the symptomatic outcome, but 7 relied on clean intermittent self-catheterisation (CISC) to achieve a good result. Urodynamic studies demonstrated a significant increase in residual urine volume from 48 +/- 72 ml before to 347 +/- 298 ml after operation, but there was only a small and statistically insignificant increase in cystometric capacity. Detrusor instability, present before operation in all patients, could still be demonstrated in over half of them after operation. However, a significant decrease in the severity of instability was found after operation as assessed by an increased volume at first unstable contraction. The bladder volume before operation at which the first unstable contraction occurred was smaller in those who still had persistent instability after enterocystoplasty compared with those in whom instability could not be identified after operation. These results suggest that all patients about to undergo ileocystoplasty should be trained in the use of CISC. In selected patients with idiopathic detrusor instability refractory to other treatment, this procedure can yield satisfactory results.

Adult↗
PubMed1991

Ambulatory monitoring and electronic measurement of urinary leakage in the diagnosis of detrusor instability and incontinence.

The ability of conventional artificial filling urodynamic studies (CMG) and ambulatory monitoring during natural bladder filling (AM) to detect phasic detrusor activity (detrusor instability) and incontinence was studied in 52 patients suspected on clinical grounds of having bladder dysfunction, but in whom a CMG had not provided an adequate explanation of their symptoms. Detrusor instability (DI) was found on AM in 31 patients who were not unstable on conventional CMG using the criteria of the International Continence Society: DI was diagnosed on filling in 20 patients and on provocation in a further 11. Incontinence was demonstrated by electronic nappy testing in 23 patients: 13 had urge incontinence due to DI, 7 had genuine stress incontinence alone and 3 had both genuine stress incontinence and detrusor instability. Thus DI was diagnosed significantly more frequently by AM than by CMG. Ambulatory monitoring was more sensitive in the diagnosis of instability and incontinence and it may prove to be a valuable aid in the diagnosis of bladder dysfunction not detected during conventional cystometry.

Adult↗
PubMed1991

Bladder augmentation and replacement. Urodynamic and clinical review of 25 patients.

Bladder augmentation has a role in the management of patients with neuropathic bladder dysfunction and in urinary undiversion. Several reports attest to its clinical value, but there have been few detailed urodynamic studies of its effects. We have carried out a prospective review over a 4-year period of 25 patients undergoing bladder augmentation or substitution assessed by conventional and ambulatory urodynamic studies. All patients had a detubularised reservoir made of ileum in 6, and of the ileocaecal segment in the remainder. Six patients also had an artificial sphincter fitted and 2 underwent colposuspension. There was no mortality. After operation, bladder capacity increased from 122 +/- 91 ml to 659 +/- 431 ml and there were significant decreases in the pressure rise during filling and increases in bladder compliance. Hyper-reflexia was present in 74% before operation and 23% after operation. Regular phasic activity was observed in 77% of patients at the end of filling after operation, probably due to bowel activity despite detubularisation. Four patients described urge incontinence associated with this activity. After operation, one man had persistent major stress incontinence. He has since undergone insertion of an artificial urinary sphincter (AUS) and is now completely dry. Of the remainder, 10 patients had minor, infrequent defects in continence, 9 patients with leakage when the bladder was full and 4 with occasional leakage at night. With the exception of the patient with major stress incontinence, all but one felt the operation had been worthwhile--40% reporting complete success and 52% excellent improvement. Reconstruction of the neuropathic lower urinary tract is a major surgical procedure, but the final clinical outcome is very satisfactory.

Adolescent↗