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Biomedical subjects

G R Sant

Publications and source records attributed to G R Sant.

At least 19 recordsLinked to original sources
PubMed2000

Pentosanpolysulfate inhibits mast cell histamine secretion and intracellular calcium ion levels: an alternative explanation of its beneficial effect in interstitial cystitis.

PURPOSE: Mast cells are ubiquitous cells derived from the bone marrow and are responsible for allergic reactions as they release numerous vasodilatory, nociceptive and pro-inflammatory molecules in response to immunoglobulin E (IgE) and specific antigen. Mast cell secretion is also triggered by a number of peptides, such as bradykinin and substance P, and may also be involved in the development of inflammatory responses. An example is interstitial cystitis, which is a sterile painful bladder disorder that has been associated with a defective glycosaminoglycan bladder mucosal layer and an increased number of activated mast cells. Pentosanpolysulfate is a synthetic, sulfated polysaccharide that has been approved for the treatment of interstitial cystitis on the premise that it may replenish the defective glycosaminoglycan layer. We hypothesize that pentosanpolysulfate may also have an additional or alternate action on bladder mast cells. We report that pentosanpolysulfate has a powerful dose dependent inhibitory effect on mast cell release of histamine induced by the mast cell secretagogue compound 48/80. MATERIALS AND METHODS: Inhibition of mast cell secretion was documented by light and electron microscopy and extended to stimulation by substance P or IgE and antigen. RESULTS: The inhibition was more potent than that seen with the clinically available mast cell stabilizer disodium cromoglycate (cromolyn). Maximal inhibition by pentosanpolysulfate was apparent within 1 minute, was unaffected by the length of pre-incubation and persisted after the drug was washed off. In contrast, the effect of cromolyn was limited by rapid tachyphylaxis. In addition, while cromolyn has no effect on mucosal or rat basophilic leukemia cells, pentosanpolysulfate inhibited histamine secretion from both. Confocal microscopy using a calcium indicator dye showed that pentosanpolysulfate decreased intracellular calcium ion levels. CONCLUSIONS: Pentosanpolysulfate appears to be a potent inhibitor of allergic and nonimmune mast cell stimulation, which is an alternative explanation of its benefit in interstitial cystitis.

Animals↗
PubMed1999

Effect of a urinary control insert on quality of life in incontinent women.

The aim of the study was to evaluate the efficacy, safety and effect on quality of life of the Reliance urinary control insert (Uromed Corp., Needham, MA) in women with genuine stress incontinence. Efficacy was evaluated at baseline and at the end of the 12-month study period by standardized pad-weight studies and by rating scales measuring acceptability, incontinence symptom improvement, ease of learning, comfort and time to habituation, recorded in diaries at monthly intervals in 63 women. The SF-36 Health Survey questionnaire was used to assess quality of life status at baseline without the device and after 12 months of device use. A significant decrease in urine loss at 12 months compared with baseline was shown by standardized pad-weight studies, with and without the device in situ. Urine loss was reduced by more than 80% in 91% of the 63 patients, and 79% were completely dry. Patient diaries showed significant improvement in control of leakage, comfort, and ease of device use during the study period. Short-term-36 Health Status data also indicated significant improvement in the physical functioning score at 12 months. Urinary tract infection and hematuria were the most common adverse effects. The Reliance urinary control insert is an efficacious and safe means of controlling genuine stress incontinence in women. The device was perceived as easy to use and comfortable for these 63 women, and resulted in improved quality of life.

Adolescent↗
PubMed1999

Neurotensin mediates rat bladder mast cell degranulation triggered by acute psychological stress.

OBJECTIVES: An increased number of activated mast cells have been documented in interstitial cystitis (IC), a painful bladder disorder occurring primarily in women and exacerbated by stress. Mast cells in the bladder and in the intestine are often found in juxtaposition to neurons, where they are activated by neuropeptides and neurotransmitters as well as by acute psychological stress. This work was undertaken to investigate whether the neuropeptide neurotensin (NT) is involved in the activation of bladder mast cells by acute psychological stress. METHODS: Male 300-g Sprague-Dawley rats were either kept on the bench in a quiet procedure room or stressed by confining them one at a time for 30 minutes in a clear Plexiglas immobilizer and then killed with carbon dioxide. The bladder was removed and fixed with 4% paraformaldehyde. Frozen sections were either stained with acidified toluidine blue or processed for NT immunocytochemical analysis. An immunosorbent assay was used to also measure NT in bladder homogenate before and after stress. RESULTS: Bladder mast cell activation in control rats was 37.3 +/- 1.4%, as judged by extrusion of granule contents. Degranulation in stressed animals increased to 75.3 +/- 5.5% (P = 0.0003). Treatment of the animals neonatally with capsaicin decreased mast cell degranulation to 48.9 +/- 7.5% (P = 0.008), a 35.1% inhibition. Intraperitoneal administration of the nonpeptide NT receptor antagonist SR48692 sixty minutes before stress decreased bladder mast cell degranulation to 25.2 +/- 3.6% (P = 0.00007), a 66.5% inhibition. This value is 32.5% below control levels, indicating that NT is involved in basal mast cell degranulation. Stress also reduced the total bladder NT content. CONCLUSIONS: The present results indicate that NT mediates the effect of acute, nontraumatic psychological stress on bladder mast cell degranulation. They further suggest that NT receptor antagonists may be useful in subpopulations of patients with IC in whom symptoms worsen under stress.

Acute Disease↗
PubMed1999

Interstitial cystitis.

Interstitial cystitis is a complex inflammatory condition of the bladder. The pathophysiology of interstitial cystitis is incompletely understood, although altered epithelial permeability, mast cell activation and sensory afferent nerve upregulation play critical roles. A unified understanding of the pathogenesis of interstitial cystitis is emerging and this will hopefully lead to the introduction of novel therapies for pain and irritative voiding symptoms. Interstitial cystitis is a common disease among women and is frequently misdiagnosed as prostatitis and benign prostatic hyperplasia among men.

Animals↗
PubMed1998

Interstitial cystitis: a neuroimmunoendocrine disorder.

Interstitial cystitis (IC) is a sterile bladder condition occurring primarily in females. It is characterized by frequency, nocturia, and suprapubic pain. IC symptoms are exacerbated during ovulation and under stress, thus implicating neurohormonal processes. The most prevalent theories to explain the pathophysiology of IC appear to be altered bladder lining and increased number of activated bladder mast cells. A defective bladder glycosaminoglycan (GAG) layer could allow penetration of allergic triggers, as well as chemicals, food preservatives, drugs, toxins, and adherent bacteria, all of which can activate bladder mast cells. Vasoactive, nociceptive, and proinflammatory molecules released can lead to immune cell infiltration and can sensitize neurons to secrete neurotransmitters or neuropeptides that can further activate mast cells. Mast cell-derived proteases can directly cause tissue damage, and it is noteworthy that urine tryptase is elevated in IC. Bladder mast cells are located close to neuronal processes, which are increased in IC, and they can be activated in situ by acetylcholine (ACh) and substance P (SP). Such activation is augmented by estradiol, which acquires significance in view of the fact that human bladder mast cells express estrogen receptors, but few progesterone receptors, which may explain the worsening of IC symptoms during ovulation. Finally, acute psychological stress in rats leads to mast cell activation that can be reduced by depletion of SP or neutralization of peripheral immune corticotropin-releasing hormone (CRH). These findings suggest that IC could be a syndrome with neural, immune, and endocrine components, in which activated mast cells play a central role.

Animals↗
PubMed1998

Hydroxyzine inhibits neurogenic bladder mast cell activation.

OBJECTIVES: Increased numbers of activated mast cells have been documented close to substance P (SP) containing nerve endings in the bladders of patients with interstitial cystitis (IC), a painful, sterile bladder disorder occurring primarily in females. Many of these patients also suffer from allergies, but common antihistamines do not help. In line with the fact that IC symptoms worsen under stress, we recently showed that bladder mast cells could be activated by the stable acetylcholine (Ach) analogue carbachol and by immobilization stress. Preliminary data from open label studies indicated that the heterocyclic histamine-1 receptor antagonist (H-1r alpha) hydroxyzine reduces IC symptoms. We, therefore, investigated whether hydroxyzine could inhibit carbachol-induced bladder mast cell activation. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with 10(-5) M carbachol, 10(-5) M SP, or 100 microg/ml compound 48/80 (C48/80), with or without preincubation with the designated concentrations of the H-1r alpha. Mast cell activation was assessed by release of exogenous 3H-serotonin and morphological evidence of secretion by light microscopy. RESULTS: Carbachol at 10(-5) M triggered rat bladder mast cell serotonin release which represented a 65% increase over control. Equimolar concentrations of SP caused a 32% increase, while C48/80 had no effect. The heterocyclic piperazine H-1r alpha hydroxyzine reduced carbachol-induced serotonin release by 25% at 10(-6) M and 34% at 10(-5) M, both of which were statistically significant (P < 0.05). On the contrary, the well known H-1r alpha diphenhydramine had no inhibitory effect, while the mixed H-1r alpha and 5-hydroxytryptamine-receptor antagonist (5-HTr alpha) azatadine actually caused an 11% increase. CONCLUSION: Hydroxyzine reduced carbachol-induced serotonin release from rat bladder in vitro through a mechanism which was unrelated to its H-1 receptor antagonistic properties. The ability of hydroxyzine to inhibit bladder mast cell activation by neurogenic stimuli along with its anticholinergic, anxiolytic and analgesic properties, may explain the clinical efficacy of this drug in reducing IC symptoms. Other, nonsedating, hydroxyzine analogues able to inhibit bladder mast cell activation may provide potentially new therapeutic approaches for IC.

Animals↗
PubMed1998

Increased expression of substance P receptor-encoding mRNA in bladder biopsies from patients with interstitial cystitis.

OBJECTIVES: To determine whether substance P (SP, also known as neurokinin 1, NK1) receptors are differentially expressed in bladder biopsies from patients with interstitial cystitis (IC) compared with matched controls. MATERIALS AND METHODS: Cold-cup biopsies were taken during routine diagnostic cystoscopy. NK1-receptor expression was assessed using a quantitative analysis of NK1-receptor-encoding mRNA in bladder biopsies from patients and controls using in situ hybridization histochemistry (ISHH) combined with autoradiographic image analysis. RESULTS: Autoradiographic signal indicating the presence of NK1-encoding mRNA was localized to detrusor muscle, urothelium and vascular structures. In the bladder vasculature, the signal was predominantly associated with endothelial cells. NK1 receptor-encoding mRNA within the vascular endothelium was increased in the biopsies obtained from patients with IC. CONCLUSION: Increased levels of NK1 receptor-encoding mRNA within the bladder vascular endothelium suggests the up-regulation of NK1 receptor as a putative factor in the pathogenesis of pain related to IC. Increased responsiveness to SP released from the perivascular sensory terminals may result in a local cascade of neurogenic inflammatory responses which trigger the pathophysiological changes, including pain, characteristic of IC.

Adult↗
PubMed1998

Acquired renal cystic disease and adenocarcinoma following renal transplantation--a current urologic perspective.

Two patients treated with chronic dialysis and renal transplantation developed acute hemorrhage from a native kidney. Bilateral native nephrectomy demonstrated acquired cystic disease and adenocarcinoma in each of the four kidneys. The etiology of acquired cystic kidney disease (ACKD) is unclear and its incidence increases with the duration of dialysis. ACKD patients have a propensity to develop adenomas and adenocarcinomas. The increased incidence of renal neoplasms in ACKD patients warrants careful radiologic monitoring of native end-stage kidneys in selected patients.

Angiography↗
PubMed1997

Intravesical dimethyl sulfoxide (DMSO) for interstitial cystitis--a practical approach.

OBJECTIVES: To provide a brief overview of intravesical dimethly sulfoxide (DMSO) therapy for interstitial cystitis and offer a practical approach to patient treatment. METHODS: A review of the literature and a summation of the experience with treatment of > 300 patients with DMSO at the Interstitial Cystitis Clinic, New England Medical Center. RESULTS: DMSO is helpful in a significant number of patients and it has acceptable morbidity and an excellent safety profile. CONCLUSIONS: Intravesical DMSO (singly or in combination) is one of the mainstays in the pharmacologic treatment of interstitial cystitis.

Administration, Intravesical↗
PubMed1997

Hydroxyzine therapy for interstitial cystitis.

OBJECTIVES: To determine the usefulness of oral hydroxyzine for the treatment of symptomatic interstitial cystitis. METHODS: This study was an open-label, nonconsecutive case series of patients treated by their local physicians, in consultation with the authors. A case-report form using visual analog scales was used to assess outcomes. RESULTS: Out of 140 patients, 90 (65%) returned the case-report forms. A 40% reduction in symptom scores was reported. This rose to 55% in patients with a history of allergies. CONCLUSIONS: Hydroxyzine is a useful drug for the symptomatic treatment of IC, especially in patients with documented allergies and/or evidence of bladder mast cell activation.

Cystitis, Interstitial↗
PubMed1997

The interstitial cystitis symptom index and problem index.

OBJECTIVES: To develop 2 brief self-administered indices for measuring lower urinary tract symptoms and their impact in patients with interstitial cystitis (IC). METHODS: An initial set of questions was developed and evaluated in focus groups. The index was revised, shortened, and validated with patients diagnosed in 3 large urologic practices with experience in interstitial cystitis (N = 45). Controls were recruited from a group of healthy volunteers in a gynecology clinic (N = 67). Internal consistency, construct validity, and test-retest reliability were evaluated. RESULTS: The IC symptom index and the IC problem index measure urinary and pain symptoms and assesses how problematic symptoms are for patients with interstitial cystitis. Psychometric performance of both instruments is good, with the symptom index demonstrating excellent ability to discriminate characteristics between patients and controls. CONCLUSION: Both indices should be useful in the evaluation and management of patients with IC and should be particularly useful in clinical trials of new therapies for this condition, where reliable, validated, and reproducible outcome measures are critically important.

Cystitis, Interstitial↗
PubMed1997

Histological evidence of an inflammatory reaction to suture material in the dog vas deferens.

OBJECTIVE: To evaluate changes in histology and semen variables after using an elastomeric-hydrogel matrix plug as a reversible vasectomy device in dogs, and to determine the potential applications for improving fertility after vasectomy reversal. MATERIALS AND METHODS: Semen samples from six adult male dogs were obtained after left vasal ligation, placement of the plug in the right vas deferens, and subsequent removal of the plug. The vasa, epididymides and testes were evaluated histologically in four of the dogs after removal of the implant. RESULTS: No sperm were present in the ejaculate after the plug was removed. Histological sections showed intraluminal spermatids in areas where the plug had been placed. The lumen was occluded, secondary to foreign-body giant-cell reaction, at the vasotomy suture site, but other areas of the was previously containing the implant remained patent after it was removed. CONCLUSIONS: There were no sperm in the ejaculate after the plug was removed because the vasal lumen was occluded as a result of an inflammatory reaction to the suture material. In contrast, areas that had contained the implant but without a vasotomy suture were not inflamed. We suggest that further trials comparing various suture materials are carried out to determine if patency rates can be improved during vasotomy closure or vasovasotomy.

Animals↗
PubMed1997

Interstitial cystitis and bladder mastocytosis in a woman with chronic urticaria.

A patient with chronic urticaria and angioedema developed endoscopically confirmed interstitial cystitis. Bladder biopsy revealed bladder mastocytosis with > 60 mast cells/mm2 (normal < 10) in the detrusor and submucosa. Most of the mast cells were activated and degranulated. The occurrence of IC in a patient with urticaria and angioedema, diseases both associated with mast cell pathophysiology, supports the role of mast cells in interstitial cystitis.

Adult↗
PubMed1997

Stress-induced bladder mast cell activation: implications for interstitial cystitis.

PURPOSE: To investigate whether acute psychological stress may activate bladder mast cells which appear to play a significant role in the pathophysiology of interstitial cystitis, a syndrome that occurs primarily in females and is characterized by urinary urgency, frequency and suprapubic pain, all of which often worsen with stress. MATERIALS AND METHODS: Non-traumatic immobilization stress was used as a model of acute emotional stress by placing a rat in a plexiglass immobilizer, after first bringing each rat in the laboratory daily for 4 days to reduce the stress of handling. The rat was then anesthetized, decapitated and the bladder removed and fixed for light and electron microscopy. RESULTS: This type of stress resulted in activation of over 70% of bladder mast cells within 30 minutes, as evidenced by light and electron microscopy. Pretreatment of the animals with intraperitoneal administration of polyclonal antiserum to corticotropin releasing hormone had no effect on bladder mast cell activation and no nerve fibers positive for this hormone were identified in the bladder. Stress-induced bladder mast cell activation was, however, substantially reduced in animals treated neonatally with capsaicin suggesting that sensory neuropeptides, such as substance P, of which increased positive nerve fibers have been localized close to bladder mast cells, are involved in this response. CONCLUSIONS: This is the first time that psychological stress is shown to activate bladder mast cells, apparently via the action of at least some sensory neuropeptides. These findings have implications for the pathophysiology and possible therapy of interstitial cystitis.

Animals↗
PubMed1997

Interstitial cystitis.

Interstitial cystitis is a urologic disorder with protean pelvic manifestations (urologic, gynecologic, gastroenterologic) and variable prevalence. Although current research indicates a non-bacteriologic etiology, interstitial cystitis has features suggestive of autoimmunity, a deficient bladder wall lining, activated bladder sensory neuropeptides and bladder mastocytosis. Pentosan polysulfate sodium is a recently approved oral treatment for interstitial cystitis. Further research into the gynecologic and pain aspects of interstitial cystitis is clearly needed.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1996

Carbachol-induced bladder mast cell activation: augmentation by estradiol and implications for interstitial cystitis.

OBJECTIVES: Interstitial cystitis (IC) is a painful, sterile bladder disorder that occurs primarily in women, many of whom also experience allergies with symptoms that worsen perimenstrually. Increased numbers of activated bladder mast cells have recently been implicated in the pathophysiology of IC. These mast cells express high-affinity estrogen receptors and are located close to increased bladder nerves, many of which contain the neuropeptide substance P (SP). We therefore investigated whether the neurotransmitter acetylcholine (ACh) and SP could activate bladder mast cells and whether estradiol could influence this effect. METHODS: Bladder pieces from male Sprague-Dawley rats were perfused with carbachol (the stable analogue of ACh), SP, or the mast cell secretagogue compound 48/80 (C48/80) with or without preincubation with beta-estradiol. The effect of carbachol was also investigated after pretreatment with the muscarinic antagonist atropine. Mast cell activation was assessed by release of 3H-serotonin and morphologic evidence of secretion by light and electron microscopy. RESULTS: Carbachol triggered rat bladder mast cell serotonin release in a dose-dependent manner, an effect increased by tissue pretreatment with estradiol and blocked by atropine. The effect of carbachol was accompanied by ultrastructural evidence of mast cell activation and was stronger than that obtained by either C48/ 80 or SP. CONCLUSIONS: Bladder mast cell activation is neurogenically mediated and augmented by estradiol, findings that could possibly explain the painful symptoms of IC and its prevalence in women, as well as the worsening of symptoms perimenstrually.

Acetylcholine↗