Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS.

We hypothesized that the suppression of uninvolved immunoglobulin in monoclonal gammopathy of undetermined significance (MGUS) as detected by suppression of the isotype-specific heavy and light chain (HLC-pair suppression) increases the risk of progression to malignancy. This approach required quantitation of individual heavy/light chains (for example, IgGλ in IgGκ MGUS patients). Of 1384 MGUS patients from Southeastern Minnesota seen at the Mayo Clinic from 1960 to 1994, baseline serum samples obtained within 30 days of diagnosis were available in 999 persons. We identified HLC-pair suppression in 27% of MGUS patient samples compared with 11% of patients with suppression of uninvolved IgG, IgA or IgM. HLC-pair suppression was a significant risk factor for progression (hazard ratio (HR), 2.3; 95% confidence interval (CI) 1.5-3.7; P<0.001). On multivariate analysis, HLC-pair suppression was an independent risk factor for progression to malignancy in combination with serum M-spike size, heavy chain isotype and free light chain ratio (HR, 1.8; 95% CI, 1.1-3.00; P=0.018). The finding that HLC-pair suppression predicts progression in MGUS and occurs several years before malignant transformation has implications for myeloma biology.

The natural history of non-alcoholic fatty liver disease in children: a follow-up study for up to 20 years.

OBJECTIVES: The long-term prognosis of non-alcoholic fatty liver disease (NAFLD) in children remains uncertain. We aimed at determining the long-term outcomes and survival of children with NAFLD. DESIGN: Retrospective longitudinal hospital-based cohort study. PATIENTS: Sixty-six children with NAFLD (mean age 13.9 (SD 3.9) years) were followed up for up to 20 years with a total of 409.6 person-years of follow-up. RESULTS: The metabolic syndrome was present in 19 (29%) children at the time of NAFLD diagnosis with 55 (83%) presenting with at least one feature of the metabolic syndrome including obesity, hypertension, dyslipidaemia and/or hyperglycaemia. Four children with baseline normal fasting glucose developed type 2 diabetes 4-11 years after NAFLD diagnosis. A total of 13 liver biopsies were obtained from five patients over a mean of 41.4 (SD 28.8) months showing progression of fibrosis stage in four children. During follow-up, two children died and two underwent liver transplantation for decompensated cirrhosis. The observed survival free of liver transplantation was significantly shorter in the NAFLD cohort as compared to the expected survival in the general United States population of the same age and sex (log-rank test, p<0.00001), with a standardised mortality ratio of 13.6 (95% confidence interval, 3.8 to 34.8). NAFLD recurred in the allograft in the two cases transplanted, with one patient progressing to cirrhosis and requiring re-transplantation. CONCLUSIONS: Children with NAFLD may develop end-stage liver disease with the consequent need for liver transplantation. NAFLD in children seen in a tertiary care centre may be associated with a significantly shorter survival as compared to the general population.

Effects of IGF-I gene therapy on the injured rat pudendal nerve.

Injured nerves and their motor units may undergo enhanced recovery when exposed to recombinant human insulin-like growth factor-I (rhIGF-I). The external anal sphincter muscle in the female rat was denervated to model incontinence. The treatment-group muscle was injected with rhIGF-1 plasmid, whereas in the control group the plasmid lacked the cDNA insert and the normal group received neither surgery nor treatment. Electromyography data at 56 days post surgery indicated more reinnervation without fibrillation potentials in the treatment group (2 of 6) than in the control group (0 of 6). The histology of the regenerated axons in the pudendal nerve distal to the crush site also suggested an improved recovery in the treatment group. The number of motor neurons retrogradely labeled with horseradish peroxidase was decreased by 50% following pudendal nerve crush in both experimental groups compared to the normal group. We conclude from these preliminary results that rhIGF-I gene therapy may improve the distal recovery of structure and function.

Monitoring pudendal nerve function during labor.

BACKGROUND: To determine methodology and feasibility of pudendal nerve monitoring during labor and delivery. METHODS: With Institutional Review Board approval, 13 low-risk, singleton pregnant women were recruited. The latency and amplitude of the perineal branch of the pudendal nerve compound muscle action potential were recorded during the second stage of labor and after delivery. With the first two patients, a wire electrode was used to stimulate the pudendal nerve continuously at the ischial spine. For the remaining 11 patients, a St. Mark's electrode was used to stimulate transvaginally. Aurethral ring electrode on a 14 French foley catheter monitored the response from the urethral sphincter. All patients received prophylactic antibiotics. EXPERIENCE: Twelve patients delivered vaginally, and one by cesarean. In two patients, continuous wire stimulation showed a gradual decrease in amplitude. Changes were minimal over 15-minute intervals. Wire electrode placement was technically difficult and dislodged easily. With the remaining 11 patients, all had data available for interpretation, and of the 85 potential perineal branch of the pudendal nerve compound muscle action potentials, 53 were obtained. No patients developed cystitis. CONCLUSION: Intrapartum assessment of pudendal nerve function is feasible. Continuous wire stimulation is technically more difficult and does not provide additional information beyond that available from intermittent stimulation.

New therapeutic options for urge incontinence.

A critical evaluation of the literature published over the past year reveals several therapeutic options for urge incontinence. Basic science advances in understanding the pathophysiology of bladder instability are paramount in the development of new therapeutic options, chief of which is sacral neuromodulation. Epidemiologic studies from around the world impact the therapies and diagnosis. Therapies include hormone delivery systems, pharmaceutical, combined behavioral and drug, botulinum, surgery, magnetic stimulation, and sacral neuromodulation.

Detrusor biopsy as a potential clinical tool.

Previous published work suggests that electron microscopic findings in bladder biopsies correlate with urodynamic diagnoses of bladder dysfunction in geriatric patients. Our goal was to determine the reproducibility of this previous work and to evaluate the use of detrusor biopsy as a clinical tool in the diagnosis and management in a urogynecology referral population. All patients underwent an initial evaluation, including history, physical examination and urodynamics. Urodynamic evaluation included uroflowmetry, provocative cystometry, instrumented voiding study, urethral profilometry, pressure-flow studies, and evaluation of postvoid residual urine. A cystoscopic-guided detrusor muscle biopsy was obtained from all patients. Each patient was assigned one of four urodynamic diagnoses: detrusor overactivity, obstructed voiding, both overactivity and obstruction, or neither. Each was given a subgroup of normal or ineffective contractility. All detrusor biopsies were evaluated by electron microscopy. Each biopsy was assigned one of four pathologic diagnoses: dysjunction, hypertrophy, both dysjunction and hypertrophy, or neither. Each was given a subgroup of the presence or absence of degeneration. All diagnoses were assigned in a double-blind fashion. All urodynamic and pathologic diagnoses were then compared to determine the percentage agreement. Twenty-six women participated, mean age 52.7 years, range 29-77. Overall agreement among diagnoses was 30% (95% CI 11%-50%). Comparison of each category revealed the following percentage agreements: detrusor overactivity/dysjunction, 52% (95% CI 32%-73%); obstructed voiding/hypertrophy, 78% (95% CI 61%-95%); ineffective contractility/degeneration, 65% (95% CI 45%-85%). The use of detrusor biopsy as a clinical tool was not supported in this population, as demonstrated by the low percentage agreement between urodynamic and pathologic diagnoses. The etiology of bladder dysfunction should be investigated by looking beyond organ-specific structural changes.

A revised natural history model for primary sclerosing cholangitis.

OBJECTIVE: To describe a natural history model for primary sclerosing cholangitis (PSC) that is based on routine clinical findings and test results and eliminates the need for liver biopsy. PATIENTS AND METHODS: Using the Cox proportional hazards analysis, we created a survival model based on 405 patients with PSC from 5 clinical centers. Independent validation of the model was undertaken by applying it to 124 patients who were not included in the model creation. RESULTS: Based on the multivariate analysis of 405 patients, a risk score was defined by the following formula: R = 0.03 (age [y]) + 0.54 loge (bilirubin [mg/dL]) + 0.54 loge (aspartate aminotransferase [U/L]) + 1.24 (variceal bleeding [0/1]) - 0.84 (albumin [g/dL]). The risk score was used to obtain survival estimates up to 4 years of follow-up. Application of this model to an independent group of 124 patients showed good correlation between estimated and actual survival. CONCLUSIONS: A new model to estimate patient survival in PSC includes more reproducible variables (age, bilirubin, albumin, aspartate aminotransferase, and history of variceal bleeding), has accuracy comparable to previous models, and obviates the need for a liver biopsy.

Urethral collagen morphologic characteristics among women with genuine stress incontinence.

OBJECTIVE: This was a study of the morphologic characteristics of urethral collagen in women with stress incontinence and continent control women. STUDY DESIGN: Urethral needle biopsy specimens were obtained from 31 women. Fifteen women were continent, and the other 16 had undergone full urogynecologic assessment for symptoms of urinary incontinence. Biopsy specimens were assessed under electron microscopy. Mean collagen fibril diameter was measured and collagen morphologic characteristics were assessed. RESULTS: The biopsy specimens from 30 women were included in the analysis. Collagen fibril diameter did not vary with continence status, the presence of pelvic organ prolapse, age, race or hormonal status. Alterations in collagen fibril morphologic characteristics were evident in the biopsy specimens from nine patients with incontinence. The alterations in collagen morphologic characteristics fell into three patterns, which for convenience were referred to as the obscured pattern, the dense pattern, and the degenerative pattern. CONCLUSION: Altered collagen morphologic characteristics are found in some patients with stress incontinence, and possible causes for those alterations are suggested by their appearances.

Ultrastructure of detrusor and urethral smooth muscle in women with urinary incontinence.

OBJECTIVE: We performed a quantitative study to determine whether mixed urinary incontinence was associated with any ultrastructural changes in detrusor and urethral smooth muscle. STUDY DESIGN: Detrusor and urethral smooth muscle biopsy specimens were obtained at the time of laparotomy from 5 women aged 35 to 65 years with mixed urinary incontinence and from a control group of 5 continent women. Smooth muscle morphologic characteristics were assessed from a systematic random sample of electron micrographs. A further 16 urethral biopsy specimens were similarly analyzed to confirm the findings of the initial study. RESULTS: The electron-dense portion of the sarcolemma was smaller in urethral biopsy specimens taken from patients with intrinsic sphincter deficiency than in those from control subjects (chi(2)((1)) = 4.9; P =.027). No other morphologic characteristics were unique to patients with incontinence. CONCLUSIONS: Our study suggests that focal adhesion architecture is decreased in urethral smooth muscle of patients with intrinsic sphincter deficiency.

Female pelvic organ prolapse: a comparison of triphasic dynamic MR imaging and triphasic fluoroscopic cystocolpoproctography.

OBJECTIVE: This study compared dynamic MR imaging with fluoroscopic cystocolpoproctography for the detection and measurement of prolapse of pelvic organs. SUBJECTS AND METHODS: Ten patients underwent triphasic dynamic MR imaging and triphasic fluoroscopic cystocolpoproctography with identical amounts of contrast material to opacify the bladder, vagina, and rectum. The dynamic MR imaging procedure included cine-loop presentation. Each examination was analyzed to determine the presence and extent of prolapse of pelvic organs based on specific measurements. RESULTS: Both dynamic MR imaging and fluoroscopic cystocolpoproctography revealed 10 rectoceles (mean extents, 2.85 and 2.45 cm, respectively). Nine cystoceles were revealed by both dynamic MR imaging (mean extent, 4.05 cm) and fluoroscopy (mean extent, 4.55 cm). Seven enteroceles were revealed, one of which was initially not seen on dynamic MR imaging. Two sigmoidoceles were revealed, one of which was not seen on fluoroscopy. The mean extent of the enteroceles and sigmoidoceles on dynamic MR imaging was 3.50 cm, and the mean extent on fluoroscopy was 4.25 cm. Nine of the 10 patients were able to defecate in the supine position on the MR imaging table. Patients were divided equally in their preference for dynamic MR imaging or fluoroscopic cystocolpoproctography. CONCLUSION: Triphasic dynamic MR imaging and triphasic fluoroscopic cystocolpoproctograpy show similar detection rates for prolapse of pelvic organs. Although dynamic MR imaging underestimates the extent of cystoceles and enteroceles, it has the advantage of revealing all pelvic organs and the pelvic floor musculature in a multiplanar cine-loop presentation.

Female pelvic organ prolapse: diagnostic contribution of dynamic cystoproctography and comparison with physical examination.

OBJECTIVE: The aim of this study was to assess the contribution of dynamic cystoproctography to the evaluation of female pelvic organ prolapse and to compare this contribution with that of physical examination. MATERIALS AND METHODS: The presence or absence of rectocele, enterocele, sigmoidocele, and cystocele on physical examination and on cystoproctography was retrospectively analyzed in 170 consecutive patients. For each of these diagnostic methods, organ prolapse was graded as small, moderate, or large on the basis of specific, defined measurements. RESULTS: A rectocele was detected by proctography in 155 patients (91%); 119 (77%) of these rectoceles were also found on physical examination. Barium trapping at proctography was related to rectocele size. Proctography showed an enterocele in 47 patients (28%); 24 (51%) of these enteroceles were also found on physical examination. Physical examination also found 44 enteroceles that could not be corroborated radiologically. At proctography, the enteroceles were relatively large, extending an average of 7.3 cm below the vaginal apex. Eight patients had sigmoidoceles, none of which were found on physical examination. A cystocele was shown by cystoproctography in 159 patients (94%); 132 (83%) of these cystoceles were also found on physical examination. CONCLUSION: The correlation between finding prolapsed pelvic organs on dynamic cystoproctography and finding them on physical examination varies. Most radiographically detected rectoceles and cystoceles are found on physical examination, whereas the correlation for enteroceles and sigmoidoceles is poor. Dynamic cystoproctography provides direct visualization and quantification of female pelvic organ prolapse, information that usually can only be inferred by physical examination.

Hepatic retransplantation in cholestatic liver disease: impact of the interval to retransplantation on survival and resource utilization.

The aim of our study was to quantitatively assess the impact of hepatic retransplantation on patient and graft survival and resource utilization. We studied patients undergoing hepatic retransplantation among 447 transplant recipients with primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) at 3 transplantation centers. Cox proportional hazards regression analysis was used for survival analysis. Measures of resource utilization included the duration of hospitalization, length of stay in the intensive care unit, and the duration of transplantation surgery. Forty-six (10.3%) patients received 2 or more grafts during the follow-up period (median, 2.8 years). Patients who underwent retransplantation had a 3.8-fold increase in the risk of death compared with those without retransplantation (P <.01). Retransplantation after an interval of greater than 30 days from the primary graft was associated with a 6.7-fold increase in the risk of death (P <.01). The survival following retransplantations performed 30 days or earlier was similar to primary transplantations. Resource utilization was higher in patients who underwent multiple consecutive transplantations, even after adjustment for the number of grafts during the hospitalization. Among cholestatic liver disease patients, poor survival following hepatic retransplantation is attributed to late retransplantations, namely those performed more than 30 days after the initial transplantation. While efforts must be made to improve the outcome following retransplantation, a more critical evaluation may be warranted for late retransplantation candidates.

Relationship between surgically induced neuropathy and outcome of pelvic organ prolapse surgery.

The aim of the study was to determine whether surgically induced perineal neuropathy relates to the outcome of surgery for the correction of pelvic organ prolapse. Perineal nerve terminal motor latencies (PeNTML) were obtained in 31 women prior to and following transvaginal surgery for the correction of pelvic organ prolapse consisting of bilateral sacrospinous ligament vault suspension and bilateral paravaginal cystocele repair. Mean follow-up was 32 months (range 12-60). Surgical outcome was defined as optimal (asymptomatic, with the apex of the vagina above the levator plate with no tissue protruding beyond the hymen in the upright position with maximum Valsalva), or suboptimal (apical descent of > 50%, or any vaginal wall protrusion beyond the hymen in the upright position with maximum Valsalva). Surgically induced neuropathy was defined as an increase of 0.6 ms or more in the averaged right and left PeNTML measurements following the surgery. All women had preoperative symptomatic prolapse and the mean preoperative PeNTML was prolonged compared to established normals. Using strict definitions, 11 women had optimal outcome and 20 had suboptimal outcome. The outcome groups were similar with respect to age, weight, parity, degree of preoperative prolapse and preoperative perineal neuropathy. Eleven women had surgically induced perineal neuropathy. This was associated with suboptimal outcome compared to optimal outcome (P = 0.03). The relative risk of suboptimal outcome with surgically induced neuropathy was 1.82 (95% CI 1.13-2.93). It was concluded that a relationship exists between the outcome of organ prolapse surgery and surgically induced perineal neuropathy as measured by PeNTML. Such neuropathy may play a role in failed pelvic reconstructive surgery.

Association of compartment defects in pelvic floor dysfunction.

OBJECTIVE: Dynamic cystoproctography was used to determine the frequency of associated urinary, genital, and anorectal abnormalities in women with pelvic floor dysfunction. SUBJECTS AND METHODS: We categorized, by pelvic floor compartments, the symptoms at presentation of 100 consecutive female patients who had been referred for dynamic cystoproctography. We then analyzed the compartment defects seen on dynamic cystoproctography relative to those detected on clinical presentation. RESULTS: Of the 20 patients with symptoms of anterior compartment (urinary) defect, dynamic cystoproctography revealed that 45% had vaginal vault prolapse of more than 50% and that 90% had rectoceles. Of the 45 patients with symptoms of middle compartment (genital) defect, dynamic cystoproctography revealed that 91% had cystoceles, 56% had a hypermobile bladder neck, 82% had rectoceles, 58% had enteroceles, 11% had sigmoidoceles, 20% had rectoanal intussusception, and 16% had anal incontinence. Of the 17 patients with symptoms of posterior compartment (anorectal) defect, dynamic cystoproctography showed that 71% had cystoceles, 65% had a hypermobile bladder neck, and 35% had vaginal vault prolapse of more than 50%. Of the 18 patients with symptoms of defects from a combination of compartments, dynamic cystoproctography revealed that 89% had cystoceles, 56% had a hypermobile bladder neck, 39% had vaginal vault prolapse exceeding 50%, 100% had rectoceles (of which 45% were large), 6% had enteroceles, 6% had sigmoidoceles, 22% had rectoanal intussusception, and 6% had anal incontinence. CONCLUSION: Although patients may present with symptoms that involve only one compartment, a multicompartment prolapse is usually revealed on dynamic cystoproctography. Of the patients with pelvic floor dysfunction, 95% had abnormalities in all three compartments.

Histologic analysis of needle biopsy of urethral sphincter from women with normal and stress incontinence with comparison of electromyographic findings.

OBJECTIVE: Our goal was to compare urethral sphincter biopsy and needle electromyography between women who had genuine stress incontinence and those who did not. STUDY DESIGN: Seventeen continent women and 10 women with stress incontinence had urethral sphincter needle electromyography and urethral biopsy specimens blindly processed for light and electron microscopy. RESULTS: The continent group had greater skeletal muscle content and percentage in each muscle fascicle and each urethral sphincter. The group with genuine stress incontinence had higher connective tissue content. All urethral skeletal muscle was type 1. The smooth muscle was "multiunit" type and was morphologically indistinguishable between the 2 groups. On electromyography, patients with genuine stress incontinence had significantly more fibrillation potentials, fewer motor unit action potentials, a higher percentage of polyphasia, and less maximum voluntary electrical activity than control subjects. CONCLUSIONS: Women with stress incontinence differ from continent women in skeletal muscle volume, amount of fibrosis, and electromyographic parameters; these differences support a neurogenic contribution to genuine stress incontinence. Urethral sphincter has only type 1 skeletal muscle and "multiunit" type smooth muscle.

Transvaginal electrical stimulation for female urinary incontinence.

OBJECTIVE: Our purpose was to determine the objective and subjective efficacy of transvaginal electrical stimulation for treatment of common forms of urinary incontinence in women. STUDY DESIGN: A prospective, double-blind, randomized clinical trial included 121 women with either urinary incontinence caused by detrusor instability or genuine stress incontinence, or both (mixed incontinence). Participants used the assigned device for 8 weeks. Identical preintervention and postintervention assessment included multichannel urodynamic testing, quality-of-life scale, and urinary diaries. RESULTS: A total of 121 women completed this study at four North American urogynecology centers. Detrusor instability was cured (stable on provocative cystometry) in 49% of women with detrusor instability who used an active electrical device (p = 0.0004, McNemar's test), whereas there was no statistically significant change in the percentage with detrusor instability in the sham device group. There was no statistically significant difference between the preintervention and postintervention rates of genuine stress incontinence for either the active device group or the sham device group. CONCLUSION: This form of transvaginal electrical stimulation may be effective for treatment of detrusor overactivity, with or without genuine stress incontinence.

A prognostic model for the outcome of liver transplantation in patients with cholestatic liver disease.

We studied the outcome of 436 patients with primary biliary cirrhosis (PBC) or primary sclerosing cholangitis (PSC) who underwent orthotopic liver transplant (OLT) at three major liver transplant centers. Univariate predictors of outcome included age, Karnofsky score, Child's class, Mayo risk score, United Network for Organ Sharing (UNOS) status, nutritional status, serum albumin, serum bilirubin, international normalized ratio, and the presence of ascites, encephalopathy, renal failure (serum creatinine > 2 mg/dL), and edema refractory to diuretics. Using these predictors, we developed a four variable mathematical prognostic model to help the liver transplant physician predict the following: 1) the amount of intraoperative blood loss; 2) the number of days in the intensive care unit (ICU); and 3) severe complications after surgery. The model uses age, renal failure, Child's class, and United Network for Organ Sharing status. This study is the first to model the outcome of liver transplant in patients with a specific etiology of chronic liver disease (PBC or PSC). The model may be used to help select patients for OLT and to plan the timing of their transplantation.

Vaginal versus abdominal reconstructive surgery for the treatment of pelvic support defects: a prospective randomized study with long-term outcome evaluation.

OBJECTIVES: Our purpose was to determine whether a vaginal or abdominal approach is more effective in correcting uterovaginal prolapse. STUDY DESIGN: Eighty-eight women with cervical prolapse to or beyond the hymen or with vaginal vault inversion > 50% of its length and anterior vaginal wall descent to or beyond the hymen were randomized to a vaginal versus abdominal surgical approach. Forty-eight women underwent a vaginal approach with bilateral sacrospinous vault suspension and paravaginal repair, and 40 women underwent an abdominal approach with colposacral suspension and paravaginal repair. Ancillary procedures were performed as indicated. Detailed pelvic examination was performed postoperatively by the nonsurgeon coauthor yearly up to 5 years. The women were examined while standing during maximum strain. Surgery was classified as optimally effective if the woman remained asymptomatic, the vaginal apex was supported above the levator plate, and no protrusion of any vaginal tissue beyond the hymen occurred. Surgical effectiveness was considered unsatisfactory if the woman was symptomatic, the apex descended > 50% of its length, or the vaginal wall protruded beyond the hymen. RESULTS: Eighty women (vaginal 42, abdominal 38) were available for evaluation at 1 to 5.5 years (mean 2.5 years). The groups were similar in age, weight, parity, and estrogen status, and 56% had undergone prior pelvic surgery. There was no significant difference between the groups in morbidity, complications, hemoglobin change, dyspareunia, pain, or hospital stay. The vaginal group had longer catheter use, more urinary tract infections, more incontinence, decreased operative time, and lower hospital charge. Surgical effectiveness was optimal in 29% of the vaginal group and 58% of the abdominal group and was unsatisfactory leading to reoperation in 33% of the vaginal group and 16% of the abdominal group. The reoperations included procedures for recurrent incontinence in 12% of the vaginal and 2% of the abdominal groups. The relative risk of optimal effectiveness by the abdominal route is 2.03 (95% confidence interval 1.22 to 9.83), and the relative risk of unsatisfactory outcome using the vaginal route is 2.11 (95% confidence interval 0.90 to 4.94). CONCLUSIONS: Reconstructive pelvic surgery for correction of significant pelvic support defects was more effective with an abdominal approach.