Biomedical subjects

C J Fowler

Publications and source records attributed to C J Fowler.

At least 19 recordsLinked to original sources

PubMed2001

Human platelet calcium mobilisation in response to beta-amyloid (25-35): buffer dependency and unchanged response in Alzheimer's disease.

In the present study, the effects of beta-amyloid (25-35) (Abeta (25-35)) upon calcium signalling by the human platelet has been investigated. When assays were conducted using HEPES buffers, Abeta (25-35), but not the inactive peptide Abeta (35-25), produced a robust increase in intracellular calcium that remained after removal of extracellular calcium but was abolished by the phospholipase C inhibitor U-73122. There was no significant difference between the calcium response to Abeta (25-35) in platelets from patients with Alzheimer's disease and from age-matched controls. In contrast to the robust effects on calcium mobilisation in HEPES buffers, very little calcium response to Abeta (25-35) was seen when Krebs (pH 7.8) buffer was used.

Adult↗

PubMed2001

Brain responses to changes in bladder volume and urge to void in healthy men.

Knowledge of how changes in bladder volume and the urge to void affect brain activity is important for understanding brain mechanisms that control urinary continence and micturition. This study used PET to evaluate brain activity associated with different levels of passive bladder filling and the urge to void. Eleven healthy male subjects (three left- and eight right-handed) aged 19-54 years were catheterized and the bladder filled retrogradely per urethra. Twelve PET scans were obtained during two repetitions of each of six bladder volumes, with the subjects rating their perception of urge to void prior to and after each scan. Increased brain activity related to increasing bladder volume was seen in the periaqueductal grey matter (PAG), in the midline pons, in the mid-cingulate cortex and bilaterally in the frontal lobe area. Increased brain activity relating to decreased urge to void was seen in a different portion of the cingulate cortex, in premotor cortex and in the hypothalamus. Both activation patterns were predominantly bilaterally symmetric and none of the effects could be attributed to the presence of the catheter. However, in some subjects, mostly those reporting intrusive sensations from the urethral catheter, there was a discrepancy between filling volume and urge so that they reported high urge with low volumes. As this 'mismatch' decreased, activation increased bilaterally in the somatosensory cortex. Our findings support the hypothesis that the PAG receives information about bladder fullness and relays this information to areas involved in the control of bladder storage. Our results also show that the network of brain regions involved in modulating the perception of the urge to void is distinct from that associated with the appreciation of bladder fullness.

Adult↗

PubMed2001

Efficacy of sacral nerve stimulation for urinary retention: results 18 months after implantation.

PURPOSE: We investigate the efficacy of sacral neurostimulation in patients with idiopathic urinary retention in a prospective, randomized multicenter trial. MATERIALS AND METHODS: A total of 177 patients with urinary retention refractory to standard therapy were enrolled in the study. Greater than 50% improvement in baseline voiding symptoms during a 3 to 7-day percutaneous test stimulation qualified a patient for surgical implantation of an InterStim parallel system. Of the patients who qualified for implantation 37 were randomly assigned to a treatment and 31 to a control group. Patients in the treatment group underwent early surgical implantation of the sacral nerve stimulation system, while implantation was delayed in the control group for 6 months. Followup evaluations, including voiding diary analysis and temporary deactivation of the stimulator at 6 months, were conducted at 1, 3, 6, 12 and 18 months after implantation in the treatment group, and after 3 and 6 months in the control group. RESULTS: Compared to the control group, patients implanted with the InterStim system had statistically and clinically significant reductions in the catheter volume per catheterization (p <0.0001). Of the patients treated with implants 69% eliminated catheterization at 6 months and an additional 14% had a 50% or greater reduction in catheter volume per catheterization. Therefore, successful results were achieved in 83% of the implant group with retention compared to 9% of the control group at 6 months. Temporary inactivation of sacral nerve stimulation therapy resulted in a significant increase in residual volumes (p <0.0001) but effectiveness of sacral nerve stimulation was sustained through 18 months after implant. CONCLUSIONS: Results of this prospective, randomized clinical study demonstrate that sacral nerve stimulation is effective for restoring voiding in patients with retention who are refractory to other forms of treatment.

Adult↗

PubMed2001

Long-term effectiveness of sacral nerve stimulation for refractory urge incontinence.

OBJECTIVES: To evaluate the long-term efficacy of sacral nerve stimulation for refractory urinary urge incontinence. STUDY DESIGN AND METHODS: Urge incontinent patients qualified for surgical implantation of a neurostimulator system after trial screening with percutaneous test stimulation. Surgical implantation of the InterStim System (Medtronic Inc., Minneapolis, Minn., USA) was performed in cases where a >50% reduction in incontinence symptoms was documented during the 3- to 7-day test stimulation period. The InterStim System consists of an implantable pulse generator, a transforamenally placed quadripolar lead, and an extension that connects these two devices for unilateral stimulation of the S3 or S4 sacral nerve. Efficacy for 96 implanted patients was based on urinary symptom changes as quantified in voiding diaries collected at baseline and annually after surgical implantation. RESULTS: As compared to baseline, the group of 96 implanted patients demonstrated significant reductions in urge incontinent symptoms at an average of 30.8+/-14.8 (range 12-60) months with respect to the number of urge incontinent episodes per day, severity of leaking, and the number of absorbent pads/diapers replaced per day due to incontinence (all p<0.0001, respectively). Gender, pretreatment variables, and age were not found to be relevant factors that affected these results. 11 of the 96 patients underwent device explant due to lack of efficacy, pain or bowel dysfunction. These data were conservatively included in the efficacy results. No permanent injuries associated with the devices or therapy were reported. CONCLUSION: Sacral nerve stimulation is an effective treatment for refractory urge incontinence with sustained long-term benefit through an average of 30.8 months.

Adult↗

PubMed2000

Serum-dependent effects of tamoxifen and cannabinoids upon C6 glioma cell viability.

In the present study, the effects of the combination of tamoxifen ((Z)-2[p-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine citrate) and three cannabinoids (Delta(9)-tetrahydrocannabinol [Delta(9)-THC], cannabidiol, and anandamide [AEA]) upon the viability of C6 rat glioma cells was assessed at different incubation times and using different culturing concentrations of foetal bovine serum (FBS). Consistent with previous data for human glioblastoma cells, the tamoxifen sensitivity of the cells was increased as the FBS content of the culture medium was reduced from 10 to 0.4 and 0%. The cells expressed protein kinase C alpha and calmodulin (the concentration of which did not change significantly as the FBS concentration was reduced), but did not express estrogen receptors. Delta(9)-THC and cannabidiol, but not AEA, produced a modest reduction in cell viability after 6 days of incubation in serum-free medium, whereas no effects were seen in 10% FBS-containing medium. There was no observed synergy between the effects of tamoxifen and the cannabinoids upon cell viability.

Animals↗

PubMed2000

Long-term results of a multicenter study on sacral nerve stimulation for treatment of urinary urge incontinence, urgency-frequency, and retention.

Many patients have chronic, debilitating symptoms of voiding dysfunction that are refractory to conventional medical or surgical therapies. This multicenter, prospective study evaluated the long-term effectiveness of sacral nerve stimulation using the implantable Medtronic InterStim therapy for urinary control in patients with otherwise intractable complaints of urinary urge incontinence, urgency-frequency, or retention. Each patient first underwent temporary, percutaneous sacral nerve test stimulation. If at least a 50% reduction in target symptoms was documented for at least 3 days, patients received a permanent Medtronic InterStim sacral nerve stimulation system that includes a surgically implanted lead and neurostimulator. Regular follow-up was conducted with outcome data. We report here on patients who have been observed from 1.5 to 3 years postimplantation. The results demonstrate that after 3 years, 59% of 41 urinary urge incontinent patients showed greater than 50% reduction in leaking episodes per day with 46% of patients being completely dry. After 2 years, 56% of the urgency-frequency patients showed greater than 50% reduction in voids per day. After 1. 5 years, 70% of 42 retention patients showed greater than 50% reduction in catheter volume per catheterization. We conclude that the Medtronic InterStim therapy for urinary control system is an effective therapy with sustained clinical benefit for patients with intractable symptoms of urinary urge incontinence, urgency-frequency, or retention.

Adolescent↗

PubMed2000

Rapid inhibition by sodium azide of the phosphoinositide-mediated calcium response to serotonin stimulation in human platelets: preservation in Alzheimer's disease.

The effect of sodium azide (NaN(3)) upon platelet Ca(2+) signalling has been investigated. A 60 s preincubation with 1 mM NaN(3) reduced the Ca(2+) response to 1 microM serotonin without a corresponding reduction in the responses to 52 mU/ml thrombin or 70 microM beta-amyloid(25-35) (A beta(25-35)). The effect of NaN(3) upon the response to serotonin, which was not blocked by either glutathione ethyl ester (GTEE) or dithiothreitol (DTT), was similar in platelets obtained from patients with Alzheimer's disease and from age- and gender-matched controls. After a preincubation time of 5 min was used, the Ca(2+) response to thrombin was greatly reduced by 1 mM NaN(3), but not by 50 microM 4-hydroxynonenal (HNE, 50 microM). Platelet levels of HNE and malondialdehyde were not significantly affected by up to 30 min of incubation with NaN(3) at room temperature. It is concluded that the rapid effect of NaN(3) upon the Ca(2+) response to serotonin in human platelets is not mediated by an inhibition of cytochrome c oxidase, and is due to an action proximal to phosphoinositide-specific phospholipase C.

Adult↗

PubMed2000

Effects of sodium azide on the secretion of soluble amyloid-beta precursor protein and the accumulation of beta-amyloid(1-40) in cultured chick neurons.

Sodium azide has been reported in the literature to reduce the release of secreted amyloid beta-precursor protein (AbetaPPs) and to produce a large increase in the cellular level of an 11.5 kDa C-terminal AbetaPP derivative containing the beta-amyloid (Abeta) sequence. Here we report that 1 mM of sodium azide, reduced the constitutive AbetaPPs secretion from cultured embryonic chick neurons after 12 h of incubation. After 24 h of incubation there was a modest increase in lactate dehydrogenase (LDH) release and no change in MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) reduction, suggesting that the reduced AbetaPPs secretion was not due to the cell toxic effects of NaN(3). However, NaN(3) reduced the accumulation of Abeta(1-40) in the cell lysates and decreased the acetylcholine esterase activity both in cell culture media and in cell lysates. It is concluded that the effect of NaN(3) upon AbetaPP metabolism in the chick cultured neurons may be a rather non-specific effect.

Amyloid beta-Peptides↗

PubMed2000

Pressure-flow study as an evaluating method of neurogenic urethral relaxation failure.

Voiding difficulty is a common feature in neurological diseases, which can be attributed to dysfunction of the urethral sphincter and the detrusor. Electromyography (EMG)-cystometry can reveal the presence of detrusor-external sphincter dyssynergia (DESD), however, internal sphincter function on voiding is not easily evaluated. Pressure-flow study is widely used to diagnose benign outlet obstruction due to prostatic hypertrophy. We applied pressure-flow study in neurological patients in order to evaluate neurogenic urethral relaxation failure. We recruited 71 patients with neurological diseases. All were men under 60 years, with mean age of 44 years, ranging from 18 to 59 years. None had abnormal finding of digital examination or ultrasound echography of the prostate. Standard cystometry showed detrusor hyperreflexia in 33 patients and residual urine was noted in 36. DESD was noted in seven of 43 patients. Pressure-flow relation curve and a detrusor pressure (P(det)) at the point of maximum flow rate (Q(max)) (i.e., P(det)Q(max)) were obtained by urodynamic computers. The Abram-Griffiths (AG) number (P(det)Q(max)-2Q(max)), showing outlet obstruction particularly over 40, was also obtained. The points of P(det)Q(max) of the patients fell into three categories of the AG nomogram, showing obstruction in 19.7%, equivocal in 52.1% and unobstructed in 28.2%. Patients with DESD had AG number over 40 more commonly (57.1%) than those without DESD (8.4%) (p<0.05). The mean AG number was 46.4 in patients with DESD, which was larger than 17.1 in patients without DESD (p<0.01). Patients with detrusor hyperreflexia had AG number over 40 more commonly (42.4%) than those with normal cystometric curve (0%) (p<0.01). The mean AG number was 30.6 in patients with detrusor hyperreflexia, which was larger than 13.6 in patients with normal cystometric curve (p<0.01). The results showed that 19.7% of patients with neurological diseases had obstructive pattern (high pressure voiding), evidence of urethral relaxation failure with relatively preserved detrusor contraction. DESD is a factor contributing to the urethral relaxation failure of the patients. The results also indicated a relationship between detrusor hyperreflexia and obstructed pattern, probably reflecting co-occurrence of detrusor hyperreflexia with DESD or detrusor-internal sphincter dyssynergia.

Adolescent↗

PubMed2000

Pharmacological properties of rat brain fatty acid amidohydrolase in different subcellular fractions using palmitoylethanolamide as substrate.

In the present study, the pharmacological properties of fatty acid amide hydrolase (FAAH) in subcellular fractions of rat brain were investigated using palmitoylethanolamide (PEA) and arachidonyl ethanolamide (anandamide, AEA) as substrates. FAAH hydrolysed [(3)H]PEA in crude homogenates with median K(m) and V(max) values of 2.9 microM and 2.14 nmol.(mg protein)(-1).min(-1), respectively. [(3)H]PEA hydrolysis was inhibited both by non-radioactive AEA (with a K(i) value very similar to the K(m) value for [(3)H]AEA as substrate using the same assay) and by R(-)ibuprofen (mixed-type inhibition K(i) and K'(i) values 88 and 720 microM, respectively). FAAH activity towards both [(3)H]PEA and [(3) myelin = cytosol, but there were no differences between the relative activities towards the two substrates in any of the fractions. [(3)H]PEA hydrolysis in mitochondrial, myelin, microsomal, and synaptosomal fractions was inhibited by oleyl trifluoromethylketone, phenylmethylsulphonyl fluoride, and the R(-)- and S(+)-enantiomers of the nonsteroidal anti-inflammatory drug ibuprofen, with mean IC(50) values in the ranges 0.028-0.041, 0.37-0.52, 67-110, and 130-260 microM, respectively. It is concluded that the pharmacological properties of FAAH in the different subcellular fractions are very similar.

Amides↗

PubMed2000

Neurotoxicity of glutamate in chick telencephalon neurons: reduction of toxicity by preincubation with carbachol, but not by the endogenous fatty acid amides anandamide and palmitoylethanolamide.

Exposure of chick telencephalon neurons in serum-free primary culture to glutamate produced a concentration-dependent cell toxicity as seen by an increase in lactate dehydrogenase (LDH) release that was blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine and was reduced by preincubation with the cholinergic agonist carbachol. Preincubation with a threshold concentration of NMDA did not prevent glutamate toxicity, suggesting that chick NMDA receptors do not desensitize in the manner reported for their rodent counterparts. Neither anandamide (arachidonyl ethanolamide, AEA) nor palmitoylethanolamide (PEA) was able to prevent the neurotoxicity produced by prolonged glutamate incubation, even under conditions in which the metabolism of the compounds by fatty acid amide hydrolase or AEA cellular uptake was blocked. It is concluded that treatments reported as granting neuroprotection towards glutamate toxicity in rodent primary neuronal cultures do not necessarily show the same properties in the chick.

Amides↗

PubMed2000

Intravesical treatment of overactive bladder.

Intravesical agents for overactive bladder have mostly been used in patients with neurogenic bladder disorders. The patients have usually had severe detrusor hyperreflexia (DH) plus a disorder of bladder emptying, and because of residual urine have been performing intermittent self-catheterization. Intravesical medication has therefore been appropriate. Strategies for treating DH have been either to lessen the parasympathetic efferent activity or to de-afferent the bladder. Two types of treatment have been used: intravesical medications that block pelvic nerve-detrusor smooth muscle cholinergic transmission, or agents that block the afferent arm of the reflex that causes detrusor contraction. Intravesical oxybutynin is thought to have some local anesthetic effect, although its main mode of action is to block cholinergic transmission. It has been demonstrated to be effective in resistant DH. Intravesical atropine has been demonstrated to increase bladder capacity but its usefulness in the clinical management of DH has yet to be demonstrated. Local anesthetics can increase bladder capacity, but the effect is short-lived. Longer-acting agents may have a selective neurotoxic effect on capsaicin-sensitive bladder afferents. Many patients worldwide have now been treated with intravesical capsaicin. Resiniferatoxin (RTX) is an ultrapotent capsaicin analog that has the significant advantage of being a nonirritant. Intravesical agents appear to be attractive alternatives to oral medication and hold the exciting possibility of selectively targeting end organs implicated in pathophysiologic responses.

Administration, Intravesical↗

PubMed2000

Differences in the pharmacological properties of rat and chicken brain fatty acid amidohydrolase.

The pharmacological properties of fatty acid amidohydrolase (FAAH) were investigated in brains of 35-day-old chickens, since nothing is known about the enzyme in avian species. FAAH activity towards both [(3)H]-palmitoylethanolamide (PEA) [K(M)=1.5 microM] and [(3)H]-anandamide (AEA) [K(M)=5.4 microM] was demonstrated in the chicken brains. The chicken FAAH was inhibited by the substrate analogues oleyl trifluoromethylketone (OTMK) and diazomethylarachidonyl ketone (DAK) with similar potencies to the rat FAAH. However, in contrast to the rat brain, phenylmethylsulphonyl fluoride (PMSF) and the enantiomers of ibuprofen had very weak effects on chicken brain FAAH. Indomethacin and niflumic acid were found to inhibit rat brain AEA hydrolysis. The inhibition by indomethacin was reversible and competitive, with a K(i) value of 120 microM. Chicken FAAH was less sensitive to indomethacin than its rodent counterpart, but the inhibition was also competitive (K(i)). It is concluded that chicken FAAH activity has different pharmacological properties to its rodent counterpart.

Amidohydrolases↗

PubMed2000

The value of the Kurtzke Functional Systems Scales in predicting incomplete bladder emptying.

STUDY DESIGN: A field study was conducted in 40 patients with multiple sclerosis (MS) by comparing their residual urine volumes with the Kurtzke Functional Systems Scales for pyramidal (PFS) or bladder functions (BFS). OBJECTIVES: To determine whether raised residual urine volumes necessitating intermittent self catheterisation can be predicted by the PFS or BFS. SETTING: Department of Uro-Neurology, The National Hospital for Neurology and Neurosurgery, University College London Hospitals Trust, London, UK. METHODS: In 40 patients with MS, post micturition residual volumes were measured with ultrasound prior to any treatment of bladder dysfunction. The patients' symptoms were assessed using PFS and BFS. Correlation between PFS, BFS and post micturition residual volumes were calculated as were sensitivity and specificity of PFS and BFS in predicting incomplete bladder emptying with residuals above 100 ml. RESULTS: None of the patients with a PFS or BFS of 0 or 1 had a residual of more than 100 ml. There was a linear progression of maximal residuals with PFS and BFS. Correlation between PFS (BFS) and the post micturition residual volumes was 0.37 (0.71). CONCLUSION: Unless a patient with MS has a PFS or BFS of greater than 1 they are unlikely to have incomplete bladder emptying with post micturition residual volumes above 100 ml. With PFS of BFS greater than 1 measurement of the post voiding residual volume is mandatory.

Adult↗

PubMed2000

The effect of intravesical capsaicin on the suburothelial innervation in patients with detrusor hyper-reflexia.

OBJECTIVE: To determine the effect of intravesical capsaicin on the suburothelial innervation in patients with detrusor hyper-reflexia, in whom a single dose of intravesical capsaicin (1-2 mmol/L) increases the bladder capacity for 3-6 months. PATIENTS AND METHODS: Thirteen patients with detrusor hyper-reflexia underwent cystometry and had flexible cystoscopic biopsies taken before and 6 weeks after receiving instillations of intravesical capsaicin (1 mmol/L). Similar biopsies were also obtained from a control group of 12 neurologically normal patients with microscopic haematuria and normal bladders. Frozen sections were stained using antibodies to S100 and PGP 9.5. Using computerized analysis, the mean nerve density scores were expressed as nerves/mm2 for S100-positive structures and 'red%' and 'red in frame' for PGP 9.5. RESULTS: The mean (SEM) functional bladder capacity increased from 193.2 (28.17) mL before to 396.3 (41.96) mL at 6 weeks after treatment with capsaicin, in nine of the 13 patients. The mean nerve density of S100-positive structures in the control group was 83 (3.18) nerves/mm2. In hyper-reflexic patients who responded to capsaicin by improved bladder capacity, the mean nerve density of S100-positive structures was reduced from 100 (12.2) before to 66 (9.4) nerves/mm2 6 weeks after treatment. In those who did not respond to capsaicin there was no significant difference in these scores. Similarly the 'red%' and 'red in frame' reduced from 3.41 (1.06) to 1.15 (0.32) and 824.7 (246.3) to 297.9 (83.5) units, respectively, before and 6 weeks after capsaicin treatment. The difference in those not responding was not significant. CONCLUSIONS: Intravesical capsaicin causes a reduction in suburothelial nerve densities in the bladder of patients with detrusor hyper-reflexia. This may explain its prolonged beneficial effect in these patients.

Administration, Intravesical↗

PubMed2000

Sacral neuromodulation for women with Fowler's syndrome.

Neuromodulation of the sacral nerves has been found to be an effective therapy for a variety of lower urinary tract dysfunctions. The reported success rate for the period of trial stimulation (peripheral nerve evaluation test) prior to permanent implantation of a sacral nerve stimulator is variable, but generally reported to be in the region of 30-50%. We present here the results of the peripheral nerve evaluation test in 38 patients with urinary retention. 34 of the 38 had been found to have an abnormality of their striated urethral sphincter on electromyography using a concentric needle electrode, i.e., they had the disorder which was described by Fowler and coworkers in 1988. The overall success rate in this group was 68%. We believe that our relatively high success rate is due to sacral neuromodulation working via a mechanism which involves the urethral sphincter, an abnormality which had been demonstrated in 89% of these patients. Twelve of the patients subsequently underwent permanent implantation of a sacral nerve stimulator, and all of them have experienced a return of voiding. However, in 2 patients, there is a persisting need for self-catheterization. There is, however, a high reoperation rate.

Adolescent↗

PubMed2000

beta-Amyloid(25-35) inhibits the activity of inositol(1,4,5)-trisphosphate-5-phosphatase.

beta-amyloid (A beta) peptides are known to disrupt calcium homeostasis in cells. In the present study, the effects of A beta(25-35) upon the activity of soluble Ins(1,4,5)P3-5-phosphatase have been investigated. A beta(25-35) inhibited, and dithiothreitol (DTT) increased the activity of soluble rat cerebellar Ins(1,4,5)P3-5-phosphatase. The change in activity was not accompanied by an obvious change in the sensitivity of the Ins(1,4,5)P3-5-phosphatase to inhibition by glucose-6-phosphate or phytic acid. A beta(35-25) also inhibited soluble Ins(1,4,5)P3-5-phosphatase activity, but at a lower potency than A beta(25-35). It is concluded that A beta(25-35) affects the metabolism of Ins(1,4,5)P3 although the potency is not sufficiently high to contribute to any significant extent to the effects of this peptide upon calcium homeostasis.

Amyloid beta-Peptides↗

PubMed2000

Studies of the latency of pelvic floor contraction during peripheral nerve evaluation show that the muscle response is reflexly mediated.

PURPOSE: Whether neuromodulation using an implanted sacral nerve stimulator acts by its effects on pelvic afferent or efferent nerves remains to be determined. However, it has been observed that eliciting an "anal wink" is helpful in the optimal siting of the foraminal stimulating electrode. This observation has been interpreted as indicating that a direct effect on efferent pelvic innervation is an important functional component of the technique. We studied the latency of this motor response to determine whether it is consistent with neuromodulation working via a direct efferent mechanism. MATERIALS AND METHODS: We studied 9 women with urinary retention undergoing the first stage of a stimulator implant (peripheral nerve evaluation). Stimulation was applied to an electrode placed in the S3 foramen and the latency of the response of the striated anal sphincter, a contraction which gives rise to the "anal wink," was measured using a concentric needle electrode placed in the striated part of the anal sphincter. RESULTS: Mean latency of response was 98 milliseconds (range 52 to 140), which is approximately 10 times longer than would be expected from that resulting from direct motor nerve stimulation. CONCLUSIONS: Our results indicate that anal sphincter contraction observed during peripheral nerve evaluation is the result of an afferent mediated response.

Adult↗