ABSTRACT
AIMS: Urodynamic studies (UDS) are generally recommended prior to surgical treatment for stress urinary incontinence (SUI), despite insufficient evidence that it impacts treatment plans or outcomes in patients with uncomplicated SUI. This analysis aimed to calculate the cost incurred when UDS was performed as a supplement to a basic office evaluation and to extrapolate the potential savings of not doing UDS in this patient population on a national basis. METHODS: This is a secondary analysis from the Value of Urodynamic Evaluation (ValUE) trial, a multicenter non-inferiority randomized trial to determine whether a basic office evaluation (OE) is non-inferior in terms of SUI surgery outcomes to office evaluation with addition of urodynamic studies (UDS). All participants underwent an OE; those patients who randomized to supplementary UDS underwent non-instrumented uroflowmetry, filling cystometry, and a pressure flow study. Costs associated with UDS were calculated using 2014 U.S. Medicare allowable fees. Models using various patient populations and payor mixes were created to obtain a range of potential costs of performing UDS in patients undergoing SUI surgery annually in the United States. RESULTS: Six hundred thirty women were randomized to OE or OE plus UDS. There was no difference in surgical outcomes between the two groups. The per patient cost of UDS varied from site to site, and included complex cystometrogram $314-$343 (CPT codes 51728-51729) plus complex uroflowmetry $16 (CPT code 51741). Extrapolating these costs for US women similar to our study population, 13-33 million US dollars could be saved annually by not performing preoperative urodynamics. CONCLUSION: For women with uncomplicated SUI and a confirmatory preoperative basic office evaluation, tens of millions of dollars US could be saved annually by not performing urodynamic testing. In the management of such women, eliminating this preoperative test has a major economic benefit.
Subject(s)
Diagnostic Techniques, Urological/economics , Health Care Costs , Preoperative Care/economics , Urinary Incontinence, Stress/economics , Urodynamics/physiology , Urologic Surgical Procedures/economics , Cost-Benefit Analysis , Female , Humans , Urinary Incontinence, Stress/physiopathology , Urinary Incontinence, Stress/surgeryABSTRACT
BACKGROUND: Midurethral slings are increasingly used for the treatment of stress incontinence, but there are limited data comparing types of slings and associated complications. METHODS: We performed a multicenter, randomized equivalence trial comparing outcomes with retropubic and transobturator midurethral slings in women with stress incontinence. The primary outcome was treatment success at 12 months according to both objective criteria (a negative stress test, a negative pad test, and no retreatment) and subjective criteria (self-reported absence of symptoms, no leakage episodes recorded, and no retreatment). The predetermined equivalence margin was +/-12 percentage points. RESULTS: A total of 597 women were randomly assigned to a study group; 565 (94.6%) completed the 12-month assessment. The rates of objectively assessed treatment success were 80.8% in the retropubic-sling group and 77.7% in the transobturator-sling group (3.0 percentage-point difference; 95% confidence interval [CI], -3.6 to 9.6). The rates of subjectively assessed success were 62.2% and 55.8%, respectively (6.4 percentage-point difference; 95% CI, -1.6 to 14.3). The rates of voiding dysfunction requiring surgery were 2.7% in those who received retropubic slings and 0% in those who received transobturator slings (P=0.004), and the respective rates of neurologic symptoms were 4.0% and 9.4% (P=0.01). There were no significant differences between groups in postoperative urge incontinence, satisfaction with the results of the procedure, or quality of life. CONCLUSIONS: The 12-month rates of objectively assessed success of treatment for stress incontinence with the retropubic and transobturator approaches met the prespecified criteria for equivalence; the rates of subjectively assessed success were similar between groups but did not meet the criteria for equivalence. Differences in the complications associated with the two procedures should be discussed with patients who are considering surgical treatment for incontinence. (ClinicalTrials.gov number, NCT00325039.)
Subject(s)
Suburethral Slings , Urinary Incontinence, Stress/surgery , Urologic Surgical Procedures/methods , Comparative Effectiveness Research , Female , Follow-Up Studies , Humans , Intention to Treat Analysis , Intraoperative Complications/epidemiology , Middle Aged , Patient Satisfaction , Postoperative Complications/epidemiology , Treatment Outcome , Urination Disorders/etiology , Urodynamics , Urologic Surgical Procedures/instrumentationABSTRACT
OBJECTIVES: A dysfunctional microcirculation is universal in shock and is often dissociated from global hemodynamic parameters. Persistent microcirculatory derangements reflect ongoing tissue hypoperfusion and organ injury. The initial microcirculatory dysfunction and subsequent resolution could potentially guide therapy and predict outcomes. We evaluated the microcirculation early in a heterogenous shocked population. Microcirculatory resolution was correlated with measures of tissue perfusion and global hemodynamics. The relationship between the microcirculation over 24âh and outcome were evaluated. DESIGN: We prospectively recruited patients with all forms of shock, based on global hemodynamics and evidence of organ hypoperfusion. SETTING: A 30-bed adult intensive care unit (ICU). PATIENTS: Eighty-two shocked patients. MEASUREMENTS AND MAIN RESULTS: Following the diagnosis of shock, patients underwent a sublingual microcirculation examination using Sidestream Dark Field Imaging. The median age of patients was 66 years old (interquartile range [IQR] 54-71), with an Acute Physiology and Chronic Health Evaluation II of 27 (IQR 20-32). Microcirculatory parameters included Percentage Perfused Vessels (PPV), De Backer Score, and a heterogeneity index in patients with septic shock, according to the second consensus guidelines Additional parameters collected: temperature, heart rate and arterial pressure, cumulative fluid balance, and vasopressor use. Arterial blood samples were taken at the time of microcirculatory assessments, providing HCO3, lactate concentrations, PaO2, and PaCO2 measurements. A statistically significant improvement in PPV and the heterogeneity index was demonstrated. This improvement was mirrored by biomarkers of perfusion; however, the global hemodynamic parameter changes were not significantly different over the 24-h period. The early microcirculatory improvement was not predictive of an improvement in acute kidney injury, length of stay, ICU, or hospital mortality. CONCLUSIONS: Early sequential evaluation of the microcirculation in shocked patients, demonstrated statistically significant improvement in the PPV and microvascular heterogeneity with standard care. These improvements were mirrored by biomarkers of organ perfusion; however, the changes in global hemodynamics were not as pronounced in this early phase. Early improvement in the microcirculation did not predict clinical outcome.
Subject(s)
Microcirculation , Shock/physiopathology , Aged , Cohort Studies , Female , Humans , Male , Middle Aged , Prognosis , Prospective StudiesABSTRACT
Glutamatergic systems have been increasingly recognized as mediators of methamphetamine's (METH) pharmacological effects though little is known about the means by which METH interacts with glutamate receptors. The present studies examined effects of METH (0.1-100 microM) on [3H]MK-801 binding to membranes prepared from adult rat cortex, hippocampus and cerebellum, as well as the neurotoxicity produced by 24-h exposure to N-methyl-D-aspartate (5-10 microM; NMDA) employing organotypic hippocampal slice cultures of neonatal rat. Co-incubation of [3H]MK-801 with METH (0.1-100 microM) did not reduce dextromethorphan (1 mM)-displaceable ligand binding. Exposure of slice cultures to NMDA for 24-h produced increases in uptake of the non-vital fluorescent marker propidium iodide (PI) of 150-500% above control levels, most notably, in the CA1 region pyramidal cell layer. Co-exposure to METH (>1.0 microM) with NMDA (5 microM) reduced PI uptake by approximately 50% in each subregion, though the CA1 pyramidal cell layer was markedly more sensitive to the protective effects of METH exposure. In contrast, METH exposure did not reduce PI uptake stimulated by 24-h exposure to 10 microM NMDA. Co-exposure to the NMDA receptor antagonist D-2-amino-5-phosphonovaleric acid (20 microM) prevented toxicity produced by exposure to 5 or 10 microM NMDA. These findings indicate that the pharmacological effects of short-term METH exposure involve inhibition of NMDA receptor-mediated neuronal signaling, not reflective of direct channel inhibition at an MK-801-sensitive site.
Subject(s)
Hippocampus/drug effects , Methamphetamine/pharmacology , Neurons/drug effects , Neurotoxins/toxicity , Receptors, N-Methyl-D-Aspartate/drug effects , 2-Amino-5-phosphonovalerate/pharmacology , Animals , Animals, Newborn , Binding, Competitive/drug effects , Binding, Competitive/physiology , Central Nervous System Stimulants/toxicity , Dizocilpine Maleate/metabolism , Dose-Response Relationship, Drug , Drug Antagonism , Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/metabolism , Female , Glutamic Acid/metabolism , Hippocampus/metabolism , Hippocampus/physiopathology , Male , N-Methylaspartate/pharmacology , Neurons/metabolism , Organ Culture Techniques , Pyramidal Cells/drug effects , Pyramidal Cells/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Synaptic Transmission/drug effects , Synaptic Transmission/physiologyABSTRACT
OBJECTIVE: To determine the frequency of past psychological problems associated with the reproductive cycle in women seeking routine gynecological care. METHODS: Three hundred and sixty-eight women of menopausal age seen at a university medical center gynecology clinic were mailed a questionnaire requesting information about past mood or anxiety problems associated with specific reproductive cycle or hormone use times, such as the premenstruum, pregnancy, postpartum, perimenopause, following total hysterectomy with bilateral salpingo-oophorectomy, and during oral contraceptive or hormone replacement treatment. Chi-square analysis was done between groups categorized as with and without reproductively associated psychological problems (RAPP) and with or without non-reproductively related psychological problems (non-RAPP). Relative risk of women with RAPP having non-RAPP also was calculated. Results-One hundred thirteen women returned the questionnaire. Fifty percent of these women reported a past history of reproductive cycle-associated psychological problems (RAPP). Of these, 37% also reported psychological problems at times in their lives not associated with particular reproductive cycle (non-RAPP) times. However, of the 50% of women who reported no history of RAPP, only 14% reported non-RAPP. This was a significant difference between the groups (p = .0064). There was also a 2.7 times greater risk of women with RAPP also having non-RAPP (RR 2.7). CONCLUSIONS: Women with reproductively associated psychological problems have a greater risk of also having psychological problems at non-reproductively associated times.
Subject(s)
Anxiety/epidemiology , Genital Diseases, Female/epidemiology , Menopause/psychology , Reproductive History , Stress, Psychological/epidemiology , Women's Health , Adult , Aged , Comorbidity , Female , Genital Diseases, Female/psychology , Humans , Incidence , Middle Aged , Surveys and Questionnaires , United States/epidemiologyABSTRACT
Long-term ethanol exposure produces multiple neuroadaptations that likely contribute to dysregulation of Ca(2+) balance and neurotoxicity during ethanol withdrawal. Conversely, nicotine exposure may reduce the neurotoxic consequences of Ca(2+) dysregulation, putatively through up-regulation of the Ca(2+)-buffering protein calbindin-D(28k). The current studies were designed to examine the extent to which 10-day ethanol exposure and withdrawal altered calbindin-D(28k) expression in rat hippocampus. Further, in these studies, we examined the ability of nicotine, through action at alpha(7)(*)-bearing nicotinic acetylcholine receptors (nAChRs), to antagonize the effects of ethanol exposure on calbindin-D(28k) expression. Organotypic cultures of rat hippocampus were exposed to ethanol (50-100 mM) for 10 days. Additional cultures were exposed to 500 nM (-)-nicotine with or without the addition of 50 mM ethanol, 100 nM methyllycaconitine (an alpha(7)*-bearing nAChR antagonist), or both. Prolonged exposure to ethanol (>/=50 mM) produced significant reductions of calbindin-D(28k) immunolabeling in all regions of the hippocampal formation, even at nontoxic concentrations of ethanol. Calbindin-D(28k) expression levels returned to near-control levels after 72 h of withdrawal from 10-day ethanol exposure. Extended (-)-nicotine exposure produced significant elevations in calbindin-D(28k) expression levels that were prevented by methyllycaconitine co-exposure. Co-exposure of cultures to (-)-nicotine with ethanol resulted in an attenuation of ethanol-induced reductions in calbindin-D(28k) expression levels. These findings support the suggestion that long-term ethanol exposure reduces the neuronal capacity to buffer accumulated Ca(2+) in a reversible manner, an effect that likely contributes to withdrawal-induced neurotoxicity. Further, long-term exposure to (-)-nicotine enhances calbindin-D(28k) expression in an alpha(7)* nAChR-dependent manner and antagonizes the effects of ethanol on calbindin-D(28k) expression.
Subject(s)
Ethanol/pharmacology , Gene Expression Regulation/drug effects , Hippocampus/drug effects , Nicotine/pharmacology , S100 Calcium Binding Protein G/biosynthesis , Animals , Calbindin 1 , Calbindins , Dose-Response Relationship, Drug , Female , Gene Expression Regulation/physiology , Hippocampus/chemistry , Hippocampus/metabolism , Male , Rats , Rats, Sprague-Dawley , S100 Calcium Binding Protein G/analysis , Substance Withdrawal Syndrome/metabolismABSTRACT
Relapse and neurodegeneration are two of the major therapeutic targets in alcoholism. Fortuitously, the roles of glutamate/NMDA receptors (NMDARs) in withdrawal, conditioning and neurotoxicity mean that NMDAR inhibitors are potentially valuable for both targets. Preclinical studies further suggest that inhibitory modulators that specifically reduce the co-agonist effects of polyamines on NMDARs are potential non-toxic medications. Using agmatine as a lead compound, over 1000 novel compounds based loosely on this structure were synthesized using feedback from a molecular screen. A novel series of aryliminoguanidines with appropriate NMDAR activity in the molecular screen were discovered (US patent application filed 2007). The most potent and selective aryliminoguanidine, JR 220 [4- (chlorobenzylidenamino)- guanidine hydrochloride], has now been tested in a screening hierarchy for anti-relapse and neuroprotective activity, ranging from cell-based assay, through tissue culture to animal behavior. This hierarchy has been validated using drugs with known, or potential, clinical value at these targets (acamprosate (N-acetyl homotaurine), memantine and topiramate). JR220 was non-toxic and showed excellent activity in every screen with a potency 5-200x that of the FDA-approved anti-relapse agent, acamprosate. This chapter will present a review of the background and rationale for this approach and some of the findings garnered from this approach as well as patents targeting the glutamatergic system especially the NMDAR.
Subject(s)
Alcoholism/drug therapy , Guanidines/pharmacology , Polyamines/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/agonists , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Animals , Disease Models, Animal , Drug Evaluation, Preclinical/methods , Drug Evaluation, Preclinical/psychology , Female , Fetal Alcohol Spectrum Disorders/drug therapy , Guanidines/chemical synthesis , Guanidines/therapeutic use , Molecular Targeted Therapy , Neuroprotective Agents/pharmacology , Patents as Topic , PregnancyABSTRACT
OBJECTIVE: To determine symptom-specific distress and quality-of-life impact outcomes among women who had undergone transvaginal repair of symptomatic rectocele. METHODS: Women who underwent transvaginal repair of symptomatic rectocele at the University of Alabama at Birmingham, USA, between April 2006 and June 2009 were included in a retrospective case series. Minimum follow-up was 1 year post-surgery. Women who underwent concomitant surgery, other than perineoplasty and/or midurethral sling, were excluded. End points were assessed using the Pelvic Floor Distress Inventory (PFDI-20) and the Pelvic Floor Impact Questionnaire (PFIQ-7). RESULTS: Overall, 113 women underwent repair of symptomatic rectocele, of whom 69 (61.1%) completed preoperative questionnaires and 66 (58.4%) responded to follow-up questionnaires. Mean time from surgery was 31.2±11.2 months. PFDI-20 and PFIQ-7 scores were significantly improved following surgery, with a median pre- and post-surgery difference of 35.4 (P<0.001) and 31.0 (P=0.002), respectively. CONCLUSION: Patients who underwent transvaginal repair of symptomatic rectocele reported improvements in symptom-specific distress and impact on quality of life.
Subject(s)
Pelvic Floor Disorders/surgery , Quality of Life , Rectocele/surgery , Aged , Fecal Incontinence/etiology , Female , Frustration , Humans , Middle Aged , Motor Activity , Pelvic Floor Disorders/complications , Pelvic Floor Disorders/psychology , Perineum/surgery , Quality of Life/psychology , Rectocele/complications , Rectocele/psychology , Retrospective Studies , Suburethral Slings , Surveys and Questionnaires , Vagina/surgeryABSTRACT
OBJECTIVE: To estimate whether the use of a low-cost cystoscopy model effectively trains residents in cystourethroscopy and to validate the model as a teaching tool. METHODS: A randomized, controlled, and evaluator-blinded study was performed. Twenty-nine obstetrician-gynecologist residents had access to fresh-frozen cadavers on which baseline cystoscopic skills were assessed using the validated Objective Structured Assessment of Technical Skills checklists for cystourethroscopy. Subsequently, residents were randomized to one of two arms, a didactic study arm using the cystoscopy model and a control arm. Repeated technical skills testing was performed. RESULTS: The study group demonstrated statistically significant decreases in cystoscope assembly time (128.8 seconds at baseline to 54.9 seconds postintervention; P=.005), and increases in task-specific checklist scores (from 59.3 at baseline to 92.9 postintervention; P<.001) and in global rating scale scores (from 61.0 at baseline to 87.8 postintervention; P<.001). Further, there was a significant improvement in task-specific checklist (P<.001), global rating scale (P=.002), and knowledge quiz scores (P=.011) in the study arm compared with the control arm. CONCLUSION: Use of the bladder model exhibited validity in enhancing performance and knowledge of cystourethroscopy among ob-gyn residents. LEVEL OF EVIDENCE: I.
Subject(s)
Cystoscopy , Obstetrics/education , Teaching Materials , Female , Gynecology/education , Humans , Internship and Residency , Teaching Materials/economicsABSTRACT
INTRODUCTION AND HYPOTHESIS: This study reports 1-year outcomes in women who underwent transvaginal pelvic organ prolapse (POP) surgery with Prolift transvaginal mesh. METHODS: Pre- and postoperative objective vaginal Pelvic Organ Prolapse Quantification (POP-Q) and subjective symptom and impact assessments (Pelvic Floor Distress Inventory (PFDI)-20 and Pelvic Floor Impact Questionnaire (PFIQ)-7, respectively) were performed. Postoperative vaginal tenderness, stricture, and patient satisfaction were also obtained. Paired t tests were utilized for analysis. RESULTS: Mean age was 61.8 +/- 9.8 years; mean follow-up interval was 425.0 +/- 80.0 days (range, 237-717). POP-Q measurements of Ba, Bp, and C were significantly improved (all p values Subject(s)
Gynecologic Surgical Procedures/methods
, Suburethral Slings
, Surgical Mesh
, Uterine Prolapse/surgery
, Aged
, Female
, Follow-Up Studies
, Gynecologic Surgical Procedures/instrumentation
, Health Surveys
, Humans
, Middle Aged
, Patient Satisfaction
, Quality of Life
, Retrospective Studies
, Suburethral Slings/adverse effects
, Surgical Mesh/adverse effects
, Treatment Outcome
ABSTRACT
BACKGROUND: Previous studies have shown that withdrawal from ethanol (EtOH) exposure induces neuronal damage, as indicated by propidium iodide (PI) uptake, in organotypic hippocampal slice cultures. This is prevented by MK801, suggesting that damage is "excitotoxic," resulting from activation of N-methyl-d-aspartate (NMDA) receptors by endogenous glutamate. To avoid reliance on a single indicator, and to enable assessment of recovery from the EtOH withdrawal (EWD) insult, we assessed changes in cell markers for neurons and glia, as well as cell division, following either EWD or NMDA challenge (as a positive control). METHODS: Organotypic cultures from postnatal day (PND) 8 rats were cultured for 5 days before exposure to EtOH (mean concentration approximately 65 mM) for 10 days before EWD. Cultures of the same "days in vitro" age (DIV16) were exposed to NMDA (200 microM) for 1 hour. Neuronal injury was visualized using PI and indices of neurons, glia, or cell division were measured at intervals up to 10 days following the neurotoxic insults. Each time point and measurement used separate slice cultures, and these were treated as separate experiments with paired controls. Regional neuronal content was assessed by neuronal nuclear protein (NeuN) and calbindin D28k (Calb), glial content by glial fibrillary acidic protein (GFAP), and cell division by bromodeoxyuridine (BrdU) incorporation, all measured immunohistochemically. RESULTS: Chronic exposure to EtOH was associated with a dramatic reduction in BrdU incorporation in all regions of cultures. Propidium iodide fluorescence in the CA1 region was elevated significantly after EWD and more so after NMDA challenge. Reduced immunoreactivity (IR) of NeuN and Calb suggested that loss of neurons resulted from the EWD insult. Bromodeoxyuridine incorporation was initially depressed even further by EWD, but had returned to control levels after 3 days. In contrast, following NMDA insult, BrdU incorporation was significantly and persistently elevated above control levels after 3 days. Glial fibrillary acidic protein was reduced immediately after both EWD and NMDA challenge. Several days after EWD, expression of neuronal and glial markers, although variable, had generally returned to control levels. In contrast, NeuN IR remained significantly reduced after NMDA challenge. CONCLUSIONS: In general, the use of additional markers supports data obtained with PI uptake alone and suggests that neurons (and glia) are lost from the culture following EWD or NMDA challenge. These cell markers recover several days after EWD, but it is unclear whether functional recovery accompanies these changes. If the dramatic effect of EtOH exposure and EWD on BrdU incorporation reflects reduced neuro- and gliogenesis, it is likely that this adversely affects long-term recovery from EWD. Finally, some markers showed significant and consistent changes after EWD, whereas others did not. This information may facilitate the use of this model in evaluation of potential medications that protect against and/or promote recovery from neurotoxicity.
Subject(s)
Central Nervous System Depressants/pharmacology , Ethanol/pharmacology , Excitatory Amino Acid Agonists/pharmacology , Hippocampus/drug effects , N-Methylaspartate/pharmacology , Substance Withdrawal Syndrome/metabolism , Animals , Antigens, Nuclear/metabolism , Biomarkers/metabolism , Calbindin 1 , Calbindins , Cell Division/drug effects , Disease Models, Animal , Female , Glial Fibrillary Acidic Protein/metabolism , Hippocampus/cytology , Hippocampus/metabolism , Male , Nerve Tissue Proteins/metabolism , Neurons/cytology , Neurons/metabolism , Organ Culture Techniques , Propidium/pharmacokinetics , Rats , Rats, Sprague-Dawley , S100 Calcium Binding Protein G/metabolismABSTRACT
OBJECTIVE: The objective of this study was to assess the risk profile for chronic pelvic pain (CPP) after pelvic inflammatory disease (PID). STUDY: Multivariate logistic regression was used to assess risk factors for CPP in a longitudinal study of 780 predominately black, urban women with clinically suspected PID: complaints of acute pain (<30 days); a clinical finding of pelvic tenderness; and leukorrhea, mucopurulent cervicitis, or untreated gonococcal or chlamydial cervicitis. CPP was defined as pain reported at >or=2 consecutive interviews conducted every 3 to 4 months for 2 to 5 years. RESULTS: Nonblack race (odds ratio [OR], 2.17; 95% confidence interval [CI], 1.31-3.58), being married (OR, 2.06; 95% CI, 1.02-4.18), a low SF-36 mental health composite score (OR, 2.71; 95% CI, 1.69-4.34), >or=2 prior PID episodes (OR, 2.84; 95% CI, 1.07-7.54), and smoking (OR, 1.65; 95% CI, 1.01-2.71) independently predicted CPP. Histologic endometritis or evidence of endometrial Neisseria gonorrhoeae or Chlamydia trachomatis infection was negatively associated with CPP (OR, 0.69; 95% CI, 0.44-1.10). CONCLUSIONS: A range of demographic, clinical, historical, and behavioral factors predict CPP after PID.
Subject(s)
Pelvic Inflammatory Disease/epidemiology , Pelvic Pain/etiology , Adolescent , Adult , Black People/statistics & numerical data , Female , Humans , Logistic Models , Longitudinal Studies , Pain Measurement , Pelvic Inflammatory Disease/complications , Pelvic Inflammatory Disease/ethnology , Pelvic Inflammatory Disease/pathology , Pelvic Inflammatory Disease/prevention & control , Randomized Controlled Trials as Topic , Risk Factors , United States/epidemiology , Urban Health , White People/statistics & numerical data , Women's HealthABSTRACT
BACKGROUND AND OBJECTIVES: Vaginal acidification has been suggested as a means of normalizing the vaginal flora. GOAL: The purpose of this study was to determine the effectiveness of an acetic acid-based vaginal gel in the treatment of bacterial vaginosis (BV). STUDY DESIGN: Forty-four patients with BV were enrolled in a randomized, double-blind clinic trial. Of these, 29 were evaluable. Patients were randomized to receive either 5 mL acetic acid gel (n = 14) or placebo gel (n = 15) intravaginally twice daily for 7 days. Clinical criteria and vaginal Gram stain scores were compared between the initial visit and at 2 weeks after initiating therapy. RESULTS: No significant differences were noted when comparing drug and placebo in terms of subjective or clinical improvement or improvement in Gram stain smears for bacterial vaginosis. CONCLUSION: Vaginal acidification with an acetic acid gel formulated to pH 3.9 to 4.1 was ineffective therapy for bacterial vaginosis.
Subject(s)
Acetic Acid/therapeutic use , Anti-Infective Agents/therapeutic use , Vaginosis, Bacterial/drug therapy , Acetic Acid/administration & dosage , Administration, Intravaginal , Adult , Anti-Infective Agents/administration & dosage , Double-Blind Method , Female , Humans , Hydrogen-Ion Concentration , Treatment Outcome , Vaginal Creams, Foams, and Jellies/administration & dosage , Vaginal Creams, Foams, and Jellies/therapeutic useABSTRACT
BACKGROUND: It has been suggested that the antirelapse drug acamprosate can inhibit or potentiate glutamate/NMDA receptor-mediated responses via a polyamine site. Additionally, subchronic exposure to acamprosate increases expression of some NMDA receptor subunits. These effects on NMDA receptors imply that the drug may have neurotoxic or neuroprotective actions under different conditions, and these studies were undertaken to evaluate this possibility in hippocampal neuronal cultures. METHODS: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in medium for 28 days. The effects of acamprosate (100 microM) alone or on neurotoxic challenges induced by either 50 microM NMDA or 100 microM spermidine were studied. Neurotoxicity was assessed by uptake of propidium iodide 24 hr after challenge. Calcium entry was measured by uptake of 45Ca2+ into the culture during the challenge. RESULTS: Acamprosate produced no neurotoxicity in these cultures after acute or subchronic exposure. In contrast, the presence of acamprosate significantly reduced "basal" propidium iodide uptake caused by the medium change procedure; similar effects were obtained with dizocilpine (MK-801; 30 microM) and, to a lesser extent, with ifenprodil (50 microM). Acamprosate did not significantly potentiate or inhibit NMDA-induced neurotoxicity, but the presence of acamprosate significantly reduced spermidine-induced neurotoxicity. CONCLUSION: No evidence was obtained that the putative agonist or coagonist effects of acamprosate on the NMDA receptor are able to cause neurotoxicity. Similarly, no evidence for inhibitory effects of acamprosate on NMDA-induced toxicity was observed under any of these conditions. However, acamprosate significantly inhibited the toxicity associated with changing medium and the toxicity induced by spermidine in these hippocampal cultures. The mechanism is unknown but is compatible with previously reported inhibition of polyamine-mediated effects.
Subject(s)
Hippocampus/drug effects , N-Methylaspartate/toxicity , Spermidine/antagonists & inhibitors , Spermidine/toxicity , Taurine/pharmacology , Acamprosate , Animals , Animals, Newborn , Culture Media/pharmacology , Female , Hippocampus/metabolism , Male , Organ Culture Techniques/statistics & numerical data , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/metabolism , Taurine/analogs & derivativesABSTRACT
BACKGROUND: The antirelapse drug acamprosate has previously been reported to inhibit activating effects of polyamines on -methyl-D-aspartic acid receptor (NMDAR) function. Because increased synthesis of polyamines has been suggested as a mechanism for potentiation of NMDAR function during ethanol withdrawal, we evaluated the effects of acamprosate, MK-801, and ifenprodil in a cell culture model of ethanol withdrawal-induced neurotoxicity. METHODS: Organotypic hippocampal cultures from 8-day-old neonatal rats were maintained in vitro for 23 days before experimental use. The ethanol withdrawal model consisted of exposing cultures to ethanol (70-100 mM) for 4 days before being "withdrawn" into Calcium-Locke's buffer for 1 hr and then into minimal medium for 23 hr. Uptake of (45)CaCl(2) and propidium iodide by damaged cells was assessed 1 hr and 24 hr after the start of ethanol withdrawal, respectively. Additional studies examined effects of exposure to NMDA (50 microM) or spermidine (100 microM) on withdrawal-induced hippocampal damage. Last, these studies examined the ability of the sodium salt of acamprosate (Na-acamprosate, 200 microM), ifenprodil (50 microM), or MK-801 (30 microM) to inhibit neurotoxicity and (45)Ca(2+) entry produced by these insults. RESULTS: Ethanol withdrawal was associated with significantly greater toxicity and (45)Ca(2+) entry, relative to controls. Exposure to spermidine and NMDA during ethanol withdrawal further increased neurotoxicity and (45)Ca(2+) entry. Acamprosate, ifenprodil, and MK-801 almost completely prevented ethanol withdrawal-induced toxicity and (45)Ca(2+) entry. Acamprosate also reduced spermidine-induced neurotoxicity during ethanol withdrawal but was ineffective against NMDA-induced toxicity or (45)Ca(2+) entry at this time. CONCLUSIONS: The results support the contention that acamprosate, like ifenprodil, interacts with polyamines and that these compounds may be effective in reducing consequences of ethanol withdrawal. NMDAR activation is also strongly implicated in ethanol withdrawal neurotoxicity, but whether acamprosate causes any of these effects in this preparation directly via the NMDAR remains uncertain.
Subject(s)
Calcium Signaling/drug effects , Dizocilpine Maleate/pharmacology , Ethanol/toxicity , Hippocampus/drug effects , Piperidines/pharmacology , Taurine/analogs & derivatives , Taurine/pharmacology , Acamprosate , Animals , Animals, Newborn , Calcium Signaling/physiology , Dizocilpine Maleate/therapeutic use , Female , Hippocampus/metabolism , Hippocampus/pathology , Male , Organ Culture Techniques , Piperidines/therapeutic use , Rats , Rats, Sprague-Dawley , Substance Withdrawal Syndrome/drug therapy , Substance Withdrawal Syndrome/metabolism , Substance Withdrawal Syndrome/pathology , Taurine/therapeutic useABSTRACT
OBJECTIVE: The purpose of this study was to describe the effects of full-length cadaveric fascia lata (CFL) sling on quality-of-life outcomes. STUDY DESIGN: Patients were 102 women (aged 29 to 87 years) who underwent the sling procedure for stress incontinence associated with intrinsic sphincter deficiency. They were followed up at 12, 24, 36, and 48 months with the Incontinence Impact Questionnaire (IIQ-7), Urogenital Distress Inventory (UDI-6), and a patient satisfaction questionnaire. RESULTS: Mean IIQ score declined from 55.1 before surgery to 11.0 at 12 months (P<.001). Mean UDI score declined from 67.1 to 28.0 at 12 months (P<.01). At 12 months, 79.7% of patients reported that leakage was better or much better, and 90.2% reported that they were somewhat or completely satisfied with their progress. Results were maintained throughout the 48-month follow-up period. CONCLUSION: The CFL sling procedure has an enduring beneficial effect on lower urinary tract symptoms and quality of life.
Subject(s)
Fascia Lata/transplantation , Quality of Life , Urinary Incontinence, Stress/surgery , Urologic Surgical Procedures/methods , Adult , Aged , Aged, 80 and over , Cadaver , Cohort Studies , Female , Humans , Middle Aged , Patient Satisfaction , Probability , Prospective Studies , Recovery of Function , Risk Assessment , Tissue Donors , Treatment Outcome , Urinary Incontinence, Stress/diagnosisABSTRACT
BACKGROUND: Several reports demonstrate that withdrawal from long-term ethanol exposure is associated with significant central nervous system neurotoxicity, produced at least in part by increased activity of N-methyl-d-aspartate receptors (NMDARs). Recent evidence suggests that elevations in the synthesis and release of the polyamines spermidine and spermine, which are known modulators of NMDARs, contribute to the increased activity of the receptor during ethanol withdrawal. Therefore, the goal of this investigation was to examine what role, if any, spermidine and spermine have in the generation of ethanol withdrawal-induced neurotoxicity. METHODS: Neurotoxicity (measured as fluorescence of the cell death indicator propidium iodide, PI), glutamate release (measured by high-performance liquid chromatography analysis), and polyamine concentrations (by high-performance liquid chromatography) were measured in rat hippocampal slice cultures undergoing withdrawal from chronic (10 day) ethanol exposure (100 mM). In addition, the effects of the polyamine synthesis inhibitor di-fluoro-methyl-ornithine (DFMO, 0.1-100 nM) and NMDAR polyamine-site antagonists ifenprodil, arcaine, and agmatine (1 nM-100 microM) on ethanol withdrawal- and NMDA-induced neurotoxicity were measured. RESULTS: Ethanol withdrawal significantly increased glutamate release (peaking at 18 hr with a 53% increase), increased concentrations of putrescine and spermidine (136% and 139% increases, respectively, at 18 hr), and produced significant cytotoxicity in the CA1 hippocampal region (56% increase in PI staining relative to controls) of the cultures. The cell death produced by ethanol withdrawal was significantly inhibited by ifenprodil (IC(50) = 14.9 nM), arcaine (IC(50) = 37.9 nM), agmatine (IC(50) = 41.5 nM), and DFMO (IC(50) = 0.6 nM). NMDA (5 microM) significantly increased PI staining in the CA1 region of the hippocampal cultures (365% relative to controls), but ifenprodil, arcaine, agmatine, and DFMO all failed to significantly affect this type of toxicity. CONCLUSIONS: These data implicate a role for polyamines in ethanol withdrawal-induced neurotoxicity and suggest that inhibiting the actions of polyamines on NMDARs may be neuroprotective under these conditions.
Subject(s)
Biogenic Polyamines/metabolism , Ethanol/toxicity , Hippocampus/drug effects , Receptors, N-Methyl-D-Aspartate/metabolism , Substance Withdrawal Syndrome/metabolism , Animals , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/pharmacology , Female , Hippocampus/metabolism , Male , Organ Culture Techniques , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitorsABSTRACT
BACKGROUND: Several reported effects of acamprosate within the glutamatergic system could result from interactions with metabotropic glutamate receptors (mGluRs). The following experiments were performed to determine whether acamprosate could compete with trnas-ACPD (+/--1-aminocyclopentane-trans-1,3-dicarboxylic acid, an equimolecular mixture of 1S, 3R and 1R, 3S-ACPD and an agonist at both group I and group II mGluRs) sensitive binding sites and protect against trans-ACPD-induced neurotoxicity in organotypic hippocampal slice cultures. METHODS: A P2 membrane preparation of cortices, cerebellums, and hippocampi of adult, male Sprague Dawley rats was used to determine the abilities of N-methyl-D-aspartic acid (NMDA) and trans-ACPD to displace [3H]glutamate in both the absence and the presence of the sodium salt of acamprosate (sodium mono N-acetyl homotaurine or Na-acamprosate). A comparison of the effects of 100 microM guanosine 5'-triphosphate on unlabeled glutamate, trans-ACPD, and Na-acamprosate was performed in the same paradigm. For the neurotoxicity studies, organotypic hippocampal slice cultures from male and female 8-day-old neonatal rats were exposed to either 500 microM -ACPD or 50 microM NMDA for 24 hr in normal culture medium containing serum on day 20 in vitro. The effects of Na-acamprosate and 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at metabotropic type 5 receptors (mGluR5s), were assessed by determining differences in propidium iodide uptake as compared with neurotoxic challenges alone. RESULTS: Na-acamprosate displaced 31% of [3H]glutamate but did not compete with NMDA for [3H]glutamate binding sites. Na-acamprosate displayed total competition with trans-ACPD. The presence of 100 microM guanosine 5'-triphosphate differentially altered the displacing capabilities of the two mGluR agonists, unlabeled glutamate and trans-ACPD, as compared with Na-acamprosate. Na-acamprosate (200-1000 microM) and SIB-1893 (20-500 microM) both were neuroprotective against trans-ACPD induced neurotoxicity that likely results from mGluR potentiation of NMDARs. In turn, Na-acamprosate and SIB-1893 had no direct effects on NMDA-induced neurotoxicity. CONCLUSIONS: Na-acamprosate demonstrates the binding and functional characteristics that are consistent with a group I mGluR antagonist. The functional similarities between Na-acamprosate and SIB-1893 support an interaction of Na-acamprosate at mGluR5s. The neuroprotective properties of acamprosate and possibly its ability to reduce craving in alcohol-dependent patients may result from its alterations in glutamatergic transmission through mGluRs.
Subject(s)
Cycloleucine/analogs & derivatives , Cycloleucine/antagonists & inhibitors , Cycloleucine/toxicity , Receptors, Metabotropic Glutamate/metabolism , Taurine/pharmacology , Acamprosate , Animals , Binding Sites/drug effects , Binding Sites/physiology , Cycloleucine/metabolism , Dose-Response Relationship, Drug , Excitatory Amino Acid Antagonists/metabolism , Excitatory Amino Acid Antagonists/pharmacology , Male , Protein Binding/drug effects , Protein Binding/physiology , Rats , Rats, Sprague-Dawley , Receptors, Metabotropic Glutamate/antagonists & inhibitors , Taurine/analogs & derivatives , Taurine/metabolismABSTRACT
BACKGROUND: We recently reported that the sodium salt of acamprosate (Na-acamprosate) demonstrates the characteristics of an antagonist at metabotropic glutamate type 5 receptors (mGluR5s) rather than at N-methyl-d-aspartate receptors (NMDARs). Because mGluR5s are able to enhance the function of NMDARs, this interplay may be involved in the dysregulation of glutamatergic transmission during ethanol withdrawal. The following studies use organotypic hippocampal slice cultures at a mature age to investigate the potential for this interplay in the neurotoxicity associated with withdrawal from long-term ethanol exposure. METHODS: At 25 days in vitro, organotypic hippocampal slice cultures prepared from male and female 8-day-old rats were exposed to an initial concentration of 100 mM ethanol for 10 days before undergoing a 24-hr period of withdrawal. The effects of Na-acamprosate; 2-methyl-6-(2-phenylethenyl)pyridine (SIB-1893), a noncompetitive antagonist at mGluR5s; 7-(hydroxyimino)cyclopropa[b]chromen-1a-carboxylate ethyl ester, a noncompetitive antagonist at mGluR1s; dizocilpine (MK-801), a noncompetitive NMDAR antagonist; and staurosporine on the neurotoxicity induced by ethanol withdrawal were assessed by determining differences in propidium iodide uptake. Polypeptide levels of mGluR5s and the NR1 and NR2B subunits of NMDARs were also determined via Western blot analyses after 10 days of ethanol exposure. RESULTS: Significant neurotoxicity was always evident in the CA1 hippocampal region after a 24-hr withdrawal period. This spontaneous neurotoxicity resulted from intrinsic changes induced by the long-term presence of ethanol. Na-acamprosate (200-1000 microM), SIB-1893 (200-500 microM), MK-801 (20 microM), and staurosporine (200 nM) were all neuroprotective. The polypeptide levels of mGluR5s and NR1 and NR2B subunits of NMDARs were all increased after ethanol exposure; however, the increase in mGluR5s did not achieve statistical significance. CONCLUSIONS: From this model of long-term ethanol exposure and withdrawal, the functional interplay between mGluR5s and NMDARs might represent a novel target for the prevention of neurotoxicity associated with ethanol withdrawal.