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Biomedical subjects

C J Fowler

Publications and source records attributed to C J Fowler.

At least 91 records · Page 5Linked to original sources
PubMed1998

Characterization of the N-methyl-D-aspartate (NMDA) receptor in the embryonic chick brain.

Relatively little is known about the properties of the NMDA receptor in avian species. In the present study, NMDA receptor pharmacology and function has been studied in the embryonic chick brain. The competitive antagonist ligand [3H]CGP 39653 bound to telencephali membranes from 17-day-old chick embryos with KD and Bmax values of 6.6 nM and 3.3 pmol/mg protein, respectively. The binding was inhibited by CGS 19755, L-glutamate, R-CPP and D-AP5 with pI50 values of 7.57, 7.49, 7.28 and 7.08, respectively. L-glycine, S-AMPA, kainate and MK-801 only weakly affected the binding. The inhibitory potency of NMDA (pI50 value 6.98), however, was greater than seen in other species, suggesting a species difference in receptor structure. Such a possibility was investigated by use of two NMDA-R1 antibodies, AB 1516 and 69921 A, which recognize the C-terminal region and an intracellular domain of the rat receptor, respectively. Immunoreactive signals (approximately 116 kDa) were found for a rat brain homogenate, whereas only 69921A gave an immunoreactive signal in the chick. The functional status of the NMDA receptors was investigated in serum-free cultures of neurons from 8-day-old chick embryos. Glutamate and NMDA were found concentration-dependently, and in a manner that could be antagonized by CGS 19755 and MK-801, to produce cell death. Thus, the present study indicates that chick embryonic brain expresses functional NMDA receptors that are pharmacologically and possibly structurally different from their rodent counterparts.

2-Amino-5-phosphonovalerate↗
PubMed1998

The neurophysiology of urinary retention in young women and its treatment by neuromodulation.

Urinary retention occurring in young women as an isolated phenomenon was often thought to be psychogenic in origin. However, in 1988, Fowler et al. described a syndrome in young women in which urinary retention was the predominant feature and in which electromyography (EMG) of the striated urethral sphincter revealed a striking abnormality. This abnormality, it was postulated, would result in an inability of the sphincter to relax and retention would therefore result. Until recently there was no effective treatment for this disorder except management by clean intermittent self-catheterisation. However, preliminary results of neuromodulation using a Medtronic sacral nerve stimulator have been particularly promising in this group of patients. The response is often spectacular; a woman who has not passed urine per urethram for many months or years will frequently find that within a few hours of insertion of the percutaneous nerve evaluation (PNE) lead, she can void quite normally with little or no residual urine. The precise mechanism of action is yet to be defined, but measurements of the latency of anal sphincter contraction on S3 stimulation during PNE are so prolonged that they can only be the result of an afferent-mediated reflex.

Adult↗
PubMed1998

Electromotive drug administration of lidocaine to anesthetize the bladder before intravesical capsaicin.

PURPOSE: The discomfort caused by intravesical capsaicin during instillation may restrict its use in some patients. We studied the effectiveness of using electromotive drug administration (EMDA) of lidocaine to anesthetize the bladder before capsaicin. MATERIALS AND METHODS: EMDA of lidocaine and epinephrine was performed in 8 patients with detrusor hyperreflexia using catheters, electrodes and an electrical current generator (20 mA., 15 minutes) followed immediately by intravesical capsaicin (2 mmol./l.) for 30 minutes under urodynamic monitoring. The patients scored suprapubic pain at 5 minutes and at the end of the capsaicin instillations on a scale of 0 to 10. Of the 8 patients 5 had had previous capsaicin treatments and the scores were compared to previous scores when intravesical lidocaine without EMDA had been used as local anesthesia before capsaicin. RESULTS: The pain scores during capsaicin instillations after EMDA of lidocaine were much lower than those during capsaicin instillations after lidocaine alone. EMDA virtually eliminated the hyperreflexic contractions of the bladder occurring during capsaicin instillations, thus reducing the risk of urethral leakage, and prevented autonomic dysreflexia that had previously occurred in 1 patient. CONCLUSIONS: EMDA of lidocaine is an effective means of reducing pain during subsequent intravesical capsaicin, which makes the use of capsaicin in the treatment of detrusor hyperreflexia more acceptable.

Administration, Intravesical↗
PubMed1998

Comparison of the effects of hydrogen peroxide, 4-hydroxy-2-nonenal and beta-amyloid (25-35) upon calcium signalling.

The neurotoxic beta-amyloid (Abeta) peptide fragment Abeta(25-35) has been suggested to exert its deleterious effects on cells via production of hydrogen peroxide. In human platelets and in the presence of DMSO to prevent production of hydroxyl radicals from hydrogen peroxide, both Abeta(25-35) and hydrogen peroxide were found to increase intracellular calcium levels. Hydrogen peroxide in addition reduced the calcium response to thrombin, whereas this was not seen with Abeta(25-35). A similar pattern of effects to those seen with hydrogen peroxide were also seen with the neurotoxic aldehyde lipid peroxidation product 4-hydroxy-2-nonenal (HNE). The initial increase in calcium produced by hydrogen peroxide was not affected by EGTA, but was partially prevented by dithiothreitol. The calcium response to Abeta(25-35) [which was also seen with Abeta(1-40) and Abeta(1-42) but not with the inactive peptide Abeta(40-1)] consisted of an EGTA-sensitive and an EGTA-resistant component, of which the latter was also sensitive to DTT. Hydrogen peroxide increased basal phosphoinositide breakdown in rat brain miniprisms and decreased the responses to noradrenaline, carbachol and veratrine. The specific binding of [3H]inositol-1,4,5-trisphosphate ([3H]Ins(1,4,5)P3) to its receptor recognition site in human platelet membranes was increased by Abeta(25-35) but remained unchanged following hydrogen peroxide treatment. It is concluded that under conditions where production of hydroxyl radicals from hydrogen peroxide is blocked, hydrogen peroxide and Abeta(25-35) produce their effects on calcium by affecting the mobilisation of intracellular calcium. The qualitative differences in the calcium responses of these two agents can be explained (a) by an additional effect of Abeta(25-35) upon calcium entry and (b) by differences in their effects upon the Ins(1,4,5)P3 receptor.

Aldehydes↗
PubMed1998

The sulphydryl oxidizing reagent diamide affects phosphoinositide-mediated signal transduction: implications for the pathogenesis of Alzheimer's disease.

In fura-2-labelled human platelets, the thiol oxidising agent diamide decreases the intracellular calcium response to thrombin and serotonin without affecting the basal calcium levels. The effect of diamide on the thrombin response could be prevented by pre-treatment with dithiothreitol (DTT) and reduced when DTT was added 60 s after diamide. The effects of diamide and hydrogen peroxide on the thrombin response were additive. Hydrogen peroxide also produced a calcium response per se, but this response was not affected by diamide. Hydrogen peroxide increased rat brain phosphoinositide hydrolysis and reduced the response to carbachol and noradrenaline, whereas diamide was without effect. The binding of [3H]inositol-1,4,5-trisphosphate to human platelet membranes was inhibited by diamide but not by hydrogen peroxide. Thus diamide affects the phosphoinositide signal transduction pathway in a qualitatively different manner from that found with hydrogen peroxide. It is suggested that oxidative stress may contribute to the disturbances in the phosphoinositide transduction pathway that are found in Alzheimer's disease.

Alzheimer Disease↗
PubMed1998

Serotonin-stimulated calcium responses in human platelets: assay buffer dependency.

In Fura-2 labelled human platelets, the observed calcium response to serotonin stimulation is increased if the assay is conducted in a Krebs buffer compared with the HEPES buffer system usually used. The serotonin response in the Krebs buffer system was concentration dependent with an EC50 value of approximately 0.3 microM and was blocked by nanomolar concentrations of the serotonin2-receptor antagonist methiothepin. In a series of samples collected from 11 persons, a reasonable correlation was seen between the response to 1 microM serotonin and the serotonin2A-receptor density measured in corresponding membrane preparations. The calcium response to serotonin was reduced by treatment with hydrogen peroxide. It is concluded that the use of the Krebs buffer gives a more sensitive response of the Fura-2 loaded human platelets to serotonin stimulation than does the use of HEPES buffer and that the increased sensitivity is achieved without affecting the pharmacological properties of the response. For the response to thrombin, the response intensity is affected by the pH of the buffer used but is not sensitive to the buffer composition.

Blood Platelets↗
PubMed1998

Use of intravesical capsaicin for urge urinary incontinence and irritative voiding syndromes.

Intravesical capsaicin has been used in the management of selected patients with urge urinary incontinence throughout this decade, but the past 12 months has seen considerable interest in this and related compounds. It is no coincidence that during the same period the capsaicin receptor was cloned and named the vanilloid receptor subtype 1 and the European dual centre study of intravesical capsaicin reported that overall 80% of patients derived some clinical benefit. In spite of this, ultrapotent capsaicin analogues such as resiniferatoxin, which also interact with the vanilloid receptor subtype 1, are being studied. Preliminary reports of the potential advantages of intravesical resiniferatoxin are beginning to emerge, and in the future drugs that manipulate the vanilloid receptor may become universally important in the management of neurogenic overactive bladders.

Journal Article↗
PubMed1998

Evaluation of interventions to prevent injuries: an overview.

Overview of issues involved in evaluating the effectiveness of injury interventions is presented. An intervention should be evaluated to show it prevents injuries in the target population, to identify unintended consequences, to correct problems that limit effectiveness, to justify current and future resources from funding agencies, and to guide its replication elsewhere. Problems in conducting evaluations include obtaining sufficient resources, coping with rare events, establishing reliability and validity of measurement instruments, separating effects of multiple simultaneous events, and adjusting for the time lag between an intervention and its effects. When feasible, changes in injury rates (documented by medical records) should be used. These are more convincing for demonstrating intervention effectiveness than changes in observed or reported behaviors or in knowledge and attitudes (documented by surveys). Quasiexperimental evaluation designs are often useful, such as measuring injury rates before and after an intervention in a time series design, or intervening in one of two comparable communities in a nonequivalent control group design. Evaluations using true experimental designs, in which individuals or groups are randomized to receive or not receive an intervention, are highly desirable but are often difficult due to logistical or ethical considerations. An evaluation component should be integral to the introduction of any new injury intervention.

Accident Prevention↗
PubMed1998

Evidence of CNS impairment in HIV infection: clinical, neuropsychological, EEG, and MRI/MRS study.

OBJECTIVES: To identify by clinical examination, EEG, MRI, and proton spectroscopy, and neuropsychological assessment the prevalence of signs of CNS involvement in patients infected with HIV, and to relate such findings to the evidence of immunosuppression. METHODS: The design was a cross sectional analysis of a cohort of male patients with infected HIV with an AIDS defining diagnosis or low CD4 count (<350), and seropositive asymptomatic subjects, both groups being followed up in a longitudinal study. Control groups consisted of seronegative subjects from the same genitourinary medicine clinics. RESULTS: This report sets out the cross sectional findings at the seventh visit in the longitudinal study. Patients with AIDS had more signs of neurological dysfunction, poorer performance on a neuropsychological test battery, were more likely to have an abnormal EEG, and to have abnormalities on MRI. They more often had cerebral atrophy, abnormal appearing white matter, and abnormal relaxometry and spectroscopy. There was little evidence of abnormality in seropositive people who had a CD4 count >350 compared with seronegative people from a similar background. CONCLUSIONS: Detailed testing failed to disclose significant CNS impairment without immunosuppression in men infected with HIV. Findings from MRI and magnetic resonance spectroscopy (MRS) correlated with those of the neurological examination and neuropsychological assessment. A combination of such assessments offers a simple surrogate for studies of CNS involvement in HIV disease.

AIDS Dementia Complex↗
PubMed1998

Desmopressin in the treatment of daytime urinary frequency in patients with multiple sclerosis.

Twenty two patients with multiple sclerosis, complaining of frequency of day time micturition, completed a double blind crossover trial of desmopressin (DDAVP nasal spray) versus placebo. There was a significant decrease in micturition frequency in the 6 hour post-treatment period from 3.1 voids after placebo to 2.4 voids and a significant reduction in urinary volume after desmopressin. Eighty per cent of patients preferred the active treatment phase. Mean 24 hour urinary volume did not differ between active and placebo treatments and patients did not complain of increased night time frequency. Transient symptoms of hyponatraemia occurred in one patient but these resolved within 48 hours of stopping desmopressin. There were otherwise no side effects and mean serum sodium concentrations of the group remained unchanged throughout the study. The clinical indications for prescribing daytime desmopressin are discussed and the importance of patient compliance stressed.

Adolescent↗
PubMed1998

Treating the human bladder with capsaicin: is it safe?

OBJECTIVES: Although human contact with capsaicin has occurred over thousands of years, some uncertainty surrounds its status as a possible carcinogen. This is the first report of bladder biopsies from patients who have been treated with capsaicin over a 5-year period. METHODS: Between 1991 and 1996, 20 patients (9 males, 11 females; mean age 52.5 years, range 40-70 years) with intractable detrusor hyperreflexia have had repeated instillations of intravesical capsaicin (1-2 mmol/l). The number of treatments per patient varied between 1 and 17 (total = 82; average 6/patient). The surveillance programme involved repeated flexible cystoscopy and bladder biopsies before and after capsaicin. Cryostat sections were stained with haematoxylin-eosin and examined by light microscopy. RESULTS: None of the bladder biopsies have shown metaplasia, dysplasia, flat carcinoma in situ, papillary or solid invasive cancer. CONCLUSIONS: No pre-malignant of malignant change has been found in biopsies of patients who had repeated capsaicin instillations for up to 5 years. However, as the morphological effects of chemical carcinogens may not be apparent for 10 years, further surveillance is being continued.

Adult↗
PubMed1998

Investigational techniques.

There are various clinical neurophysiological techniques which have been applied to the investigation of the pelvic floor and neurogenic bladder. Sphincter electromyography (EMG) has proved to be particularly valuable in identifying patients with parkinsonism who have multiple system atrophy. EMG of the striated muscle of the urethral sphincter is essential in recognizing the abnormal spontaneous activity which causes urinary retention in young women. Tests which examine aspects of nerve conduction velocity have proved to be of lesser value both because such investigations test conduction of nerve fibres rather than levels of innervation, and furthermore examine large myelinated fibre conduction rather than that of the unmyelinated fibres which comprise the autonomic innervation.

Adult↗
PubMed1998

The secretion of soluble amyloid beta precursor protein (A beta PPs) by chick neurons in serum-free primary culture is not regulated by protein kinase C.

The metabolism of amyloid precursor protein (A beta PP) in chick neurons cultured in serum-free medium is described. A beta PP immunoreactivity, detected with the 22C11 antibody, was seen at approximately 135 and approximately 120 kDa. A beta PPs (approximately 120 kDa) was released from the cells and could be detected in the culture medium without the need of a purification step. The content of A beta PPs increased with time after medium change, but was not affected by either carbachol (100 microM), glutamate (50 microM), veratrine (20 microM), oleic acid (200 microM), A23187 (5 microM), phorbol 12, 13-dibutyrate (PDBu, 1 microM), staurosporine (1 microM), Gö 6976 (1 microM) or okadaic acid (50 nM) although the combination of PDBu and okadaic acid reduced the secretion. Addition of the muscarinic receptor agonist carbachol to the neurons increased the rate of phosphoinositide breakdown. In Western blot experiments using antibodies to the alpha, beta II and epsilon isoforms of protein kinase C and conditions whereby robust signals could be seen with rat brain lysates, no immunoreactive bands that could be inhibited by appropriate positive control peptides were seen. It is concluded A beta PPs production by chick neurons in culture is mainly constitutive in nature.

Amyloid beta-Protein Precursor↗
PubMed1997

Calibration of Fura-2 signals introduces errors into measurement of thrombin-stimulated calcium mobilisation in human platelets.

The intracellular calcium indicator dye Fura-2 has been widely used for the study of human platelet thrombin receptor-mediated calcium mobilisation in disease states. In general, authors (a) use a Fura-2/AM concentration of 2-3 mumol/l and (b) calibrate fluorescence signals on the basis of maximum and minimum ratios of fluorescence (Rmax and Rmin) and the ratio of the calcium-free and calcium-bound fluorescence at an excitation wavelength of 380 nm ("C2/B2"). In the present study, it is found (a) that a greater peak response to thrombin is seen when 1 mumol/l Fura-2/AM rather than 2 or 3 mumol/l is used; and (b) that calibration leads to a poorer test-retest reliability and in general a greater variability of the obtained calcium signal than when the simple measurement of the 340 nm/380 nm fluorescence ratio is used. It is suggested that this poor variability is due to the presence of an extracellular factor that can quench the Fura-2 signal once the platelets have been permeabilised by detergent treatment. Consistent with this, addition of bovine serum albumin to the assay medium has no significant effect on the fluorescence ratio response to thrombin, but greatly increases the observed calibrated calcium signal.

Blood Platelets↗
PubMed1997

Value of sphincter electromyography in the diagnosis of multiple system atrophy.

It is clinically important, to distinguish between idiopathic Parkinson's disease (IPD) and multiple system atrophy (MSA) not only because of the implications for prognosis but also because urinary incontinence is often an early troublesome feature of MSA and by making the correct neurological diagnosis inappropriate urological surgery may be avoided. Onuf's nucleus in the sacral cord is the location of the anterior horn cells innervating the sphincters, and it is among central nervous system sites affected by neuronal cell loss in MSA but not in IPD. A systematic analysis of motor units recorded from the sphincter looking for changes of chronic reinnervation has therefore been used to distinguish between these conditions. Sphincter electromyography (EMG) was carried out in 126 patients with suspected MSA with review of their case notes up to 2 years later. Of those in whom a diagnosis of MSA was made, 82% had had an abnormal sphincter EMG.

Adult↗
PubMed1997

Cerebellar presentation of multiple system atrophy.

Early diagnosis of multiple-system atrophy (MSA) is important in patients presenting with late-onset cerebellar ataxia because it has a less favourable prognosis than other degenerative ataxic disorders. We report cerebellar presentation of MSA in a series of 16 patients, 3 of whom later developed parkinsonism. Two-thirds of them had early evidence of impaired postural reflexes with a history of recurrent falls. Some of these had a narrow-based, unsteady gait, unlike the more classic broad-based gait ataxia of cerebellar disease. On review of the patients' histories, genitourinary dysfunction (particularly impotence) was present at the onset of, or preceding, cerebellar ataxia in 60% of patients, but this had often been attributed to age, or to urological or gynaecological causes. External striated anal or urethral sphincter electromyography (EMG) demonstrated features of chronic denervation and reinnervation in 14 (93%) of 15 patients, consistent with degeneration in Onuf's nucleus as occurs in MSA. Autonomic function tests were abnormal in 9 (64%) of 14 patients. Our data suggest that close enquiry into genitourinary function and analysis of the gait disorder can be useful pointers to a diagnosis of MSA in patients with an unexplained adult-onset progressive cerebellar syndrome, and that sphincter EMG is the most useful investigation in this context.

Adult↗