Muscarinic M3 receptor stimulation increases cigarette smoke-induced IL-8 secretion by human airway smooth muscle cells.

Acetylcholine is the primary parasympathetic neurotransmitter in the airways and is known to cause bronchoconstriction and mucus secretion. Recent findings suggest that acetylcholine also regulates aspects of remodelling and inflammation through its action on muscarinic receptors. In the present study, we aimed to determine the effects of muscarinic receptor stimulation on cytokine production by human airway smooth muscle cells (primary and immortalised cell lines). The muscarinic receptor agonists carbachol and methacholine both induced modest effects on basal interleukin (IL)-8 and -6 secretion, whereas the secretion of RANTES, eotaxin, vascular endothelial growth factor-A and monocyte chemoattractant protein-1 was not affected. Secretion of IL-8 and -6 was only observed in immortalised airway smooth muscle cells that express muscarinic M3 receptors. In these cells, methacholine also significantly augmented IL-8 secretion in combination with cigarette smoke extract in a synergistic manner, whereas synergistic effects on IL-6 secretion were not significant. Muscarinic M3 receptors were the primary subtype involved in augmenting cigarette smoke extract-induced IL-8 secretion, as only tiotropium bromide and muscarinic M3 receptor subtype selective antagonists abrogated the effects of methacholine. Collectively, these results indicate that muscarinic M3 receptor stimulation augments cigarette smoke extract-induced cytokine production by airway smooth muscle. This interaction could be of importance in patients with chronic obstructive pulmonary disease.

Defined in situ enumeration of T6 and HLA-DR expressing epidermal Langerhans cells: morphologic and methodologic aspects.

An essential prerequisite for the in situ enumeration of epidermal Langerhans cells (LCs) is the unequivocal identification of the desired cell type. We have examined over 250 cryostat sections of normal human skin to analyze morphologic and methodologic problems underlying the quantification of epidermal LCs, defined by anti-T6 (OKT6) and anti-HLA-DR (OKIal) immunoperoxidase staining. Our findings show that OKT6 reactivity of dendritic processes in cross-sectioned epidermis yields microscopic images which are not easy to analyze objectively. The morphology that we find leads us to categorize dendritic cells into 3 arbitrary types of T6+ LC profiles. In addition we describe criteria for the assessment of OKT6 staining patterns relating to the dendritic state of epidermal LCs. Preliminary quantitative data on this issue are discussed in relation to: epidermal thickness; the thickness of skin tissue sections; and the discrepancy between the number of T6+ and HLA-DR+ LCs. We hope that the principles outlined in this report may serve to overcome potential methodologic problems with quantitation of T6+ epidermal LCs in skin sections.

Cystometry and periurethral striated muscle electromyography using cold and room temperature fluid.

In evlauating patients with neurologic lesions of the spinal cord and voiding abnormalities, it would appear from this study that distention is a more physiologic stimulus to bladder contraction than relatively smaller amounts of cold fluid. While the ice water test has speed and simplicity to recommend it, it should not be used as a sole means in determining whether or not a detrusor reflex is present. It may not uncover those patients with detrusor hyperreflexia or may fail to reveal a detrusor reflex. If iced contrast medium is to be used for voiding cystography, the volumes should approximate those used for regular cystometry.

Effect of autonomic hyperreflexia on plasma renin.

Four patients with paroxysmal hypertension related to spinal cord injury (autonomic hyperreflexia) were studied to determine if the plasma renin became elevated in relation to a sympathetic stimulus. Using bladder distention to produce the autonomic hyperreflexia, renin determinations were made during and after the hypertensive episode. None of the patients demonstrated elevation of the plasma renin after this event.

Use of stresscath for diagnosing stress incontinence.

The modified fluid bridge (flow) test (MFBT) is a simple procedure for detecting bladder neck incompetency using a fluid-filled catheter. The Stresscath (Hollister) female diagnostic catheter is an improved version of the MFBT. We evaluated the ability of the Stresscath to detect bladder neck incompetence in the first 66 female patients referred for urodynamics. The absence or presence of stress incontinence was based on the results from history and physical examinations. The results from the Stresscath correlated with the history showed that the Stresscath had a sensitivity of 0.73 and a specificity of 0.88 in determining stress incontinence due to bladder neck incompetency. The results from the Stresscath correlated with the physical examination (Marshall test) showed that the Stresscath had a sensitivity of 0.86 and a specificity of 0.87 in determining stress incontinence due to bladder neck incompetence. The Stresscath was at least as accurate as the urethral pressure profile in the diagnosis of stress incontinence, at less capital cost.

Pathophysiology and treatment of enuresis in adults.

Monosymptomatic nocturnal enuresis (MNE) in children is partly the result of inadequate reduction in the rate of urine output at night. This nocturnal polyuria is due to the lack of a rise in the anti-diuretic hormone, arginine vasopressin (AVP), and can be reduced or eliminated by treatment with desmopressin at bedtime. Since there is a 1% incidence of MNE among adults, this study investigated the circadian pattern of solute and water balance in nine young adult enuretics before and during desmopressin therapy and compared the results with nine-age- and sex-matched, healthy controls. Before treatment, enuretics and controls had similar total fluid intake, urine output, urine osmolality, plasma osmolality, plasma total protein, mean arterial pressure and plasma AVP. The circadian pattern of fluid intake was also normal in enuretics. This abnormality could not be attributed to a deficiency of plasma AVP or an increase in solute excretion, since both variables were similar to controls. Rather, their nocturnal polyuria appeared to be due to a marked nocturnal reduction in renal sensitivity to the antidiuretic effect of vasopressin. In seven enuretics, restudied during treatment with desmopressin (10-30 micrograms o.d.), circadian urine output was normal and enuresis was absent. These results indicate that: (i) The circadian pattern of urine output in healthy adults is largely due to a nocturnal decrease in solute excretion rather than a rise in plasma AVP; (ii) The subset of adults with persistent MNE also have nocturnal polyuria as a result of insensitivity to the antidiuretic action of AVP; (iii) These defects can be corrected by treatment with desmopressin.

Some aspects of striated urethral sphincter structure and function.

During the last 2 decades various routes of investigation have enhanced our knowledge of the striated urethral sphincter. Anatomic and neurophysiological studies as well as clinical evaluation in the form of urodynamic studies have demonstrated the components of the sphincter and its function. This information has provided the urologist with greater understanding of problems related to striated sphincter function.

Experience with measurement of bladder electrical activity.

A series of patients is presented in whom the recording of bladder electrical activity was performed. There was a significant difference in frequency of the spike activity between patients with upper and lower motor neuron injury. This technique would seem to offer greater clinical application in areas of bladder dysfunction and evaluation of drugs on the bladder.

Augmentation of bladder contractility after beta-adrenergic blockade in spinal cord injured patients.

Six spinal cord injured patients were evaluated with cystometry, bladder electromyography, and external urethal spincter pressure profiles before and after propranolol hydrochloride administration. Bladder contractility was significantly augmented, and therefore was associated with decreased beta-sympathetic bladder stimulation. The results of these clinical neurophysiological investigations suggest inhibitory influences upon the smooth muscle of the human urinary bladder via beta-sympathetic receptors.

Reduction of bladder contractility after alpha-adrenergic blockade and after ganglionic blockade.

Seven spinal cord injured patients were evaluated with cystometry bladder, electromyography, and pressure profiles of the external urethral sphincter before and after phenoxybenzamine administration. Seven more patients were evaluated before and after mecamylamine administration. Both drugs reduced the contractility of the bladder. The reduction of bladder contractility may reflect decreased sympathetic stimulation to the bladder. Bladder electric potentials reflect the intrinsic tone of the detrusor muscle.

Urethral sphincter activity following acute spinal cord injury.

We studied 44 patients with spinal cord injury during the first 72 hours after injury to determine the functional status of the bladder and external urethral sphincter. The studies included determination of the bulbocavernosus reflex, cystometry and sphincter electromyogram. In patients with lesions above the sacral cord the bulbocavernosus reflex was present. In nearly all of these patients the external sphincter activity increased with bladder filling. In all but 1 patient with injury to the sacral cord the bulbocavernosus reflex could not be elicited and the sphincter electromyogram did not increase with bladder filling.

The effect of sacral nerve stimulation for bladder control during pregnancy: a case report.

Neural stimulation was used to reduce bladder hyperreflexia and incontinence in a woman with myelodysplasia. The stimulation was delivered via an electrode placed in a sacral foramen and attached to a stimulator placed subcutaneously. The patient activated the device to inhibit the bladder and deactivated it to allow voiding. The device proved to be helpful in reducing bladder hyperreflexia and its use during pregnancy did not seem to have any adverse effect.

Inhibition of the external urethral sphincter and sacral reflex by anal stretch in spinal cord injured patients.

Relaxation of both detrusor and external sphincter muscles by mechanical stretch instead of cutaneous stimulation of the anal sphincter has been recognized and applied clinically for bladder emptying and for aiding catheterization in patients with spastic urethral sphincter. In a three-year study anal stretch was included as part of urodynamic examination in patients who could potentially use this method for bladder management. Anal stretch was found to inhibit the bulbocavernosus reflex and to be a useful alternative technique for bladder emptying in patients having complete paraplegia with normal hand function and with detrusor-sphincter dyssynergia. It is recommended that anal stretch combined with Credé or Valsalva maneuvers be a part of the urodynamic study of such patients to determine whether or not these techniques can be utilized for bladder management.

Effect of intrathecal baclofen on bladder and sphincter function.

A programmable baclofen pump was implanted in 7 patients for relief of severe spasticity. The patients experienced improvement in bladder and sphincter function. This system would seem to be of value in improving lower urinary tract function in patients with diseases that produce marked spasticity.

Effect of phentolamine on perineal muscle EMG activity in paraplegia.

The effect of the alpha-adrenergic blocking agent, phentolamine, was studied on the perineal muscle EMG in 3 paraplegic patients. The drug reduced the EMG activity in these patients. This suggests that the normal suppression of external sphincter activity during micturition might be related to a reduction in the external sphincter activity supplied by the sympathetic system.

The use of tetrazolium to determine hydronephrotic damage in human kidneys.

A study detailing an assay for evaluating hydronephrotic damage is presented. We used nitroblue tetrazolium, which is reduced by intact renal tissue. When marked hydronephrotic damage has occurred little evidence of tetrazolium reducing activity is present. The clinical application has been helpful in determining the extent of damage and the subsequent need for removal of the kidney in question. When the test indicated functioning renal tissue a repair of the obstruction was performed with subsequent improvement in function.