Metabolic regulation of calcium pumps in pancreatic cancer: role of phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3).

BACKGROUND: High glycolytic rate is a hallmark of cancer (Warburg effect). Glycolytic ATP is required for fuelling plasma membrane calcium ATPases (PMCAs), responsible for extrusion of cytosolic calcium, in pancreatic ductal adenocarcinoma (PDAC). Phosphofructokinase-fructose-bisphosphatase-3 (PFKFB3) is a glycolytic driver that activates key rate-limiting enzyme Phosphofructokinase-1; we investigated whether PFKFB3 is required for PMCA function in PDAC cells. METHODS: PDAC cell-lines, MIA PaCa-2, BxPC-3, PANC1 and non-cancerous human pancreatic stellate cells (HPSCs) were used. Cell growth, death and metabolism were assessed using sulforhodamine-B/tetrazolium-based assays, poly-ADP-ribose-polymerase (PARP1) cleavage and seahorse XF analysis, respectively. ATP was measured using a luciferase-based assay, membrane proteins were isolated using a kit and intracellular calcium concentration and PMCA activity were measured using Fura-2 fluorescence imaging. RESULTS: PFKFB3 was highly expressed in PDAC cells but not HPSCs. In MIA PaCa-2, a pool of PFKFB3 was identified at the plasma membrane. PFKFB3 inhibitor, PFK15, caused reduced cell growth and PMCA activity, leading to calcium overload and apoptosis in PDAC cells. PFK15 reduced glycolysis but had no effect on steady-state ATP concentration in MIA PaCa-2. CONCLUSIONS: PFKFB3 is important for maintaining PMCA function in PDAC, independently of cytosolic ATP levels and may be involved in providing a localised ATP supply at the plasma membrane.

Carotid sinus syndrome: a modifiable risk factor for nonaccidental falls in older adults (SAFE PACE).

OBJECTIVES: The aim of the study was to determine whether cardiac pacing reduces falls in older adults with cardioinhibitory carotid sinus hypersensitivity (CSH). BACKGROUND: Cardioinhibitory carotid sinus syndrome causes syncope, and symptoms respond to cardiac pacing. There is circumstantial evidence for an association between falls and the syndrome. METHODS: A randomized controlled trial was done of consecutive older patients (>50 years) attending an accident and emergency facility because of a non-accidental fall. Patients were randomized to dual-chamber pacemaker implant (paced patients) or standard treatment (controls). The primary outcome was the number of falls during one year of follow-up. RESULTS: One hundred seventy-five eligible patients (mean age 73 +/- 10 years; 60% women) were randomized to the trial: pacemaker 87; controls 88. Falls (without loss of consciousness) were reduced by two-thirds: controls reported 669 falls (mean 9.3; range 0 to 89), and paced patients 216 falls (mean 4.1; range 0 to 29). Thus, paced patients were significantly less likely to fall (odds ratio 0.42; 95% confidence interval: 0.23, 0.75) than were controls. Syncopal events were also reduced during the follow-up period, but there were much fewer syncopal events than falls-28 episodes in paced patients and 47 in controls. Injurious events were reduced by 70% (202 in controls compared to 61 in paced patients). CONCLUSIONS: There is a strong association between non-accidental falls and cardioinhibitory CSH. These patients would not usually be referred for cardiovascular assessment. Carotid sinus hypersensitivity should be considered in all older adults who have non-accidental falls.

Use of vaginal pressure measurements in urodynamic testing.

A study of 50 women using vaginal pressure measurements in urodynamic testing was performed. In the majority of patients, the vaginal pressure accurately reflects events occurring in the abdominal cavity. The elimination of abdominal pressure artifacts assists the physician in identifying patients with unstable bladders and assessing the voiding mechanisms. Vaginal placement of the pressure transducer is easier than rectal placement and better tolerated by patients.

Rapid assay--possible application in the diagnosis of premature rupture of the membranes.

Premature rupture of the membranes frequently presents a diagnostic dilemma to the clinician. The presence of alpha-fetoprotein (AFP) in amniotic fluid suggests a possible solution. A rapid, easy-to-use latex agglutination test for AFP was evaluated on 99 amniotic fluid samples of known AFP concentration. Body fluids (maternal serum, urine, vaginal secretions, and seminal fluid) that commonly interfere with other tests were also studied. The sensitivity for amniotic fluids from gestations less than 39 weeks was 93%, and specificity was 94%. The test is most accurate under 35 weeks, when diagnosis is critical. Equivocal results may be resolved by using radioimmunoassay. The results suggest that a rapid assay for AFP may be useful in the diagnosis of ruptured membranes. It has few interfering factors, is safe, and requires no elaborate equipment or training.

Medical treatment of urethral prolapse in children.

Urethral prolapse denotes the complete circular eversion of the urethral mucosa through the external meatus. Two different entities exist: premenarcheal and menopausal urethral prolapse. Premenarcheal prolapse is predominantly asymptomatic and is usually brought to medical attention by vaginal bleeding. Trauma and medical conditions predisposing a patient to increased abdominal pressure are associated with prolapse in children. The menopausal group seeks medical attention primary because of the severity of urinary symptoms, ie, nocturia, urgency, tenesmus, dysuria, and frequency. Therapy for both groups has been traditionally accomplished by surgical manipulation-excision, surgical ligation, cautery, fulguration, and cryosurgery. The authors treated 5 premenarcheal female children with antibiotics, estrogen cream, and sitz baths for 2 weeks. In all the patients prolapse was resolved. The results, with follow-up for 4 to 12 months without recurrence, suggest that urethral prolapse in children can be managed without surgical intervention.

Pelvic floor electrical stimulation for the treatment of urge and mixed urinary incontinence in women.

OBJECTIVES: To determine the efficacy of daily or every-other-day electrical stimulation in treating detrusor instability (urge) or urge plus genuine stress (mixed) urinary incontinence in women. METHODS: A multicenter, prospective, nonrandomized study enrolled subjects with urge and mixed urinary incontinence assigned to daily or every-other-day treatments (15 minutes twice daily) using pelvic floor stimulation. Outcome measures assessed were (1) leakage episodes, nocturnal episodes, voiding frequency, total voids, and pad count, and (2) patient subjective assessment and quality of life. RESULTS: Seventy-two subjects were enrolled. Sixty-eight subjects completed the 20-week protocol: 33 treated daily and 35 treated every other day. The entire study group (n = 68) experienced a significant decrease in total leaks (P < 0.001), nocturnal episodes (P = 0.001), pad count (P = 0.002), and total voids (P = 0.003) and on visual analog scales. Sixty-nine percent (n = 46) of subjects with urge or mixed incontinence were cured or improved by at least 50%, with 28% (n = 19) being cured. There were no significant differences between daily and every-other-day users. Nonresponse was correlated with number of previous therapies (P < 0.001) and number of vaginal deliveries (P = 0.007). Overall, subjects were 93% compliant with device use, and 72% (n = 47) were satisfied with the therapy. CONCLUSIONS: Twenty weeks of pelvic floor electrical stimulation therapy is effective in treating urge and mixed urinary incontinence, regardless of daily or every-other-day treatments.

Pelvic floor electrical stimulation: a comparison of daily and every-other-day therapy for genuine stress incontinence.

OBJECTIVES: To compare the effectiveness of daily and every-other-day electrical stimulation in treating genuine stress incontinence. METHODS: Subjects with genuine stress incontinence were enrolled in a multicenter, prospective, nonrandomized study and underwent daily or every-other-day pelvic floor stimulation treatments for 15 minutes twice a day. Outcome measures assessed were (1) leakage episodes and pad count; (2) leakage amount, and (3) subject subjective assessment and quality of life. Thirteen subjects treated daily and 15 treated every other day completed the 20-week protocol. One-year follow-up data were available for 21 subjects. RESULTS: No significant differences in primary outcome variables were found between the groups. Subjects treated every other day had significant decreases in total leakage episodes (P = 0.04), pad count (P = 0.04), total voids (P = 0.02), and visual analog scale scores, with stress incontinence cured or improved by 50% in 73% (n = 11). Subjects treated every day had significant decreases in urge episodes (P = 0.03), pad count (P = 0.05), and visual analog scale scores, with 62% (n = 8) cured or improved by 50%. Compliance was higher for subjects treated every other day (P = 0.05). Satisfaction with therapy was 75% (n = 10) for daily treatment and 77% (n = 12) for every-other-day treatment. At 1 year, 70% (n = 7) of subjects who continued device use maintained their cure or improvement status. CONCLUSIONS: Both daily and every-other-day therapy with pelvic floor electrical stimulation are effective in treating genuine stress incontinence. Subjects who continue device use maintain a higher curve or improvement rate.

Endometrial immunofluorescence associated with endometriosis and pelvic inflammatory disease.

Anti-immunoglobulin G (anti-IgG) staining in the endometrium by immunofluorescence has been associated with endometriosis. To investigate this phenomenon further, we took endometrial samples from 42 patients who underwent laparoscopy or laparotomy, which were tested for immunofluorescence. Fluorescein-labeled anti-IgG was incubated with tissue samples. Of 18 patients with documented endometriosis, 16 had positive immunofluorescence (89% sensitivity). Of 24 patients with no evidence of endometriosis, 9 had false-positive immunofluorescence and 15 had negative immunofluorescence. Of the 9 false-positive samples, 8 had evidence of old pelvic inflammatory disease. In the absence of this condition, there was only one false-positive study for immunofluorescence. The implications of these findings in terms of the pathophysiology of endometriosis-associated infertility is that it may be an immune-mediated process. With regard to diagnosis, the high predictive value of endometrial immunofluorescent IgG may be a useful tool in indicating early laparoscopic examination of the infertile period.

Gynecologic disorders in women with Ehlers-Danlos syndrome.

OBJECTIVE: We characterized the population with Ehlers-Danlos syndrome with regard to genital prolapse, urinary incontinence, and other gynecologic disorders. METHODS: Forty-one adult women who had registered for a first-ever Ehlers-Danlos multidisciplinary clinic participated in the study. Each had a comprehensive standardized evaluation, including gynecologic history, physical examination, urodynamic testing, and physical therapy evaluation. Qualitative and quantitative data were analyzed to determine means for various gynecologic disorders of Ehlers-Danlos syndrome. RESULTS: The frequencies of incontinence complaints (59%), endometriosis (27%), dyspareunia (57%), and previous hysterectomy (44%) were higher than expected for a population with a mean age of 41 years. Incontinence could not be demonstrated objectively. Prolapse was diagnosed in 12 (29.3%). CONCLUSIONS: Careful attention should be paid to women with Ehlers-Danlos syndrome because of an association with many gynecologic complaints. Women with Ehlers-Danlos syndrome should be questioned regarding incontinence, genital prolapse, endometriosis, and dyspareunia.

Assessing medical students' perceptions of mistreatment in their second and third years.

PURPOSE: To study medical students' perceptions of mistreatment in their second and third years of training. METHOD: A questionnaire was distributed at Wayne State University School of Medicine to the class of 1993 at the end of its third year and to the class of 1994 at the end of its second and third years. The students were asked if they had been subjected to various forms of mistreatment; the third-year students were asked to rate their perceptions of each clinical department's response to them on the basis of gender and race-ethnicity, as well as their overall treatment. The students also completed demographic information about age, gender, and marital status, number of children, and race-ethnicity. Results were analyzed using chi-square statistics, multivariate statistical analyses, analyses of variance, and Duncan's post-hoc comparisons. RESULTS: The response rate for the class of 1993 was 71.5%; response for the class of 1994 were 66.9% in their second year and 75.2% in their third year; 41.7% were women, and the racial-ethnic breakdown was 71.2% white/Caucasian, 11.7% black/African American and 16.8% other. There was a significant difference between the percentages of second-year and third-year students reporting any experience of mistreatment (37.2% vs 75.8%, p < .001). Canonical correlation analysis revealed bias in the third year based on gender (p < .0001) and race-ethnicity (p < .0002); both variates were related to sexual humor. The students' perceptions of mistreatment were lowest for family medicine and highest for obstetrics-gynecology and surgery. Perceptions of mistreatment in departments varied significantly by gender and race-ethnicity. The nonwhite males reported the least favorable treatment in most departments. CONCLUSION: Marked variability in the students' perceptions of mistreatment within departments suggest that a variety of approaches will be required to improve the medical training environment.

Cystourethroscopy in urogynecology.

Cystourethroscopy has become a basic tool in the investigation of female genitourinary problems. It provides the gynecologist with essential information regarding the presence of bladder or urethral pathology and documents ureteral patency.

Dysuria and urinary tract infections.

It has been estimated that up to 25% of American women may experience acute dysuria yearly. Many physicians commonly equate dysuria with urinary tract infection and will treat empirically without adequate evaluation. This therapeutic trial of antibiotics represents undertreatment for many patients and inappropriate treatment for others. It is important that physicians understand that dysuria is only a symptom that can be produced by many different clinical entities.

A practical approach to the painful bladder syndrome.

The painful bladder syndrome (PBS) is a progressive and painful disease of the bladder that may lead to fibrosis, contracture and reduction of bladder capacity. The usual symptoms are urinary urgency, frequency, nocturia, chronic pelvic pain and lower abdominal pain upon filling of the bladder. A retrospective analysis was performed on 21 women with PBS between March 1987 and March 1988. The patients were treated weekly with a bladder pillar block, bladder distention and dimethyl sulfoxide instillation. Symptomatic relief was observed in 80% of the patients so treated. The maximum bladder volume increased from 185 to 475 mL (P less than .01). The side effects were minimal.

Labial adhesions secondary to postpartum vulvar edema. A report of two cases.

Labial adhesions have been found commonly in children. Two patients developed thick labial adhesions secondary to massive postpartum vulvar edema.

Carotid sinus syndrome and falls in older adults.

Retrospective and circumstantial evidence supports an overlap between symptoms of falls and syncope in older adults. Because of this overlap, we undertook a prospective, explanatory, single-center study of cardiac pacing for falls in patients with carotid sinus syndrome in a consecutive series of over 56,000 adult visitors to an emergency department. One third attended because of a fall; one in five fallers had unexplained falls, and one third of these had carotid sinus hypersensitivity, of whom one half had a cardioinhibitory or mixed response that may be expected to respond to cardiac pacing. In a randomized, controlled trial of a subset of these patients, cardiac pacing was shown to significantly reduce subsequent fall rates by two thirds and syncopal rates during 1-year follow-up. The current pacing rate for carotid sinus syndrome is much higher in our practice than in other series because our facility is dedicated to falls and syncope in older subjects who have direct access to referring physicians and family practitioners. Of the implants in our region, 24% are for carotid sinus syndrome, compared with 43% for atrioventricular block, 20% for sick sinus syndrome, and 12% for atrial fibrillation. These rates do not include pacing in patients who fall, but rather reflect pacing rates consistent with American College of Cardiology guidelines for carotid sinus syndrome, such as recurrent syncope. These preliminary results from a local explanatory study are now being tested in a multicenter study entitled Syncope and Falls in the Elderly: Pacing and Carotid Sinus Evaluation (SAFE-PACE II).

Delayed reaction to the Dacron buttress used in urethropexy.

Eleven patients developed a delayed reaction to the Dacron buttress used in Stamey urethropexy. The reaction was characterized by pain, dyspareunia, vaginal discharge and/or bleeding, induration of the abdominal incision, vaginal granulation tissue and draining abdominal or vaginal sinus tracts. This complication occurred in 5% of the 163 patients we treated with the Stamey procedure for stress urinary incontinence. Treatment consisted of removal of the nylon suture and Dacron buttress. None of the 11 patients developed recurrent incontinence. The subjective cure rate for stress urinary incontinence was 92% using the Stamey procedure.

Complications from permanent suture in surgery for stress urinary incontinence. A report of two cases.

Two cases reports are used to illustrate potential complications of permanent suture in vaginal and abdominal surgical procedures for urinary incontinence. The first case used permanent suture for an abdominal retropubic urethropexy. A portion of a glove finger remained attached to the suture and was not recognized until the patient developed a retropubic abscess two years later. In the second case, permanent suture used in a vaginal retropubic urethropexy eroded through the vagina. The patient presented with lower abdominal pain 18 months after the procedure; the pain was relieved with removal of the suture. Complications of using permanent suture in abdominal retropubic urethropexy have not been reported, but the attachment of a foreign body, such as a glove finger, can create an adverse outcome. The use of permanent suture in vaginal procedures should be used with the awareness that there are potential complications.

A proposed scoring system for the management of female urinary incontinence.

The management of urinary incontinence is frequently ineffective. Inappropriate surgical intervention can convert medically treatable incontinence into a more serious and less remediable condition. To allow a more scientific approach to management, we have developed a scoring system for female incontinence based on three primary controlling factors: (1) the direction of the urethra, (2) the urethral vesical angle and (3) the urethral pressure profile. For each factor a score of 1 to 3 was assigned according to the deviation from normal anatomy or function. Scores ranged from 3 to 9. Patients scoring 6 to 9 were treated surgically, by ventral suspension of the bladder neck and urethra. Patients scoring 3 to 5 were treated medically and underwent surgery only if indicated for other pathology. Thirty-three patients were evaluated and treated with this approach, with a one- to two-year follow-up. This system appears to provide an objective method of choosing between surgical and medical therapy for urinary incontinence.

Surgical management of uterine prolapse in young women.

A new procedure was developed for the management of uterine prolapse in young women. Transvaginal sacrospinous uterine fixation was employed successfully in five patients. The advantages of the procedure are that it avoids surgical trauma to the cervix, can be accomplished entirely vaginally, maintains the normal vaginal axis and obliterates the space for potential enterocele.

Urethral stones in women. A case report.

Urethral stones are encountered rarely in the urethra in women. We report the clinical and urodynamic findings and the management of 17 stones in a urethral diverticulum.