Larissa V. Rodríguez

Helicobacter pylori infection and gastric lymphoma

BACKGROUND Helicobacter pylori infection is a risk factor for gastric adenocarcinoma. We examined whether this infection is also a risk factor for primary gastric non-Hodgkins lymphoma. METHODS This nested case-control study involved two large cohorts (230,593 participants). Serum had been collected from cohort members and stored, and all subjects were followed for cancer. Thirty-three patients with gastric non-Hodgkins lymphoma were identified, and each was matched to four controls according to cohort, age, sex, and date of serum collection. For comparison, 31 patients with nongastric non-Hodgkins lymphoma from one of the cohorts were evaluated, each of whom had been previously matched to 2 controls. Pathological reports and specimens were reviewed to confirm the histologic type of the tumor. Serum samples from all subjects were tested for H. pylori IgG by an enzyme-linked immunosorbent assay. RESULTS Thirty-three cases of gastric non-Hodgkins lymphoma occurred a median of 14 years after serum collection. Patients with gastric lymphoma were significantly more likely than matched controls to have evidence of previous H. pylori infection (matched odds ratio, 6.3; 95 percent confidence interval, 2.0 to 19.9). The results were similar in both cohorts. Among the 31 patients with nongastric lymphoma, a median of six years had elapsed between serum collection and the development of disease. No association was found between nongastric non-Hodgkins lymphoma and previous H. pylori infection (matched odds ratio, 1.2; 95 percent confidence interval, 0.5 to 3.0). CONCLUSIONS Non-Hodgkins lymphoma affecting the stomach, but not other sites, is associated with previous H. pylori infection. A causative role for the organism is plausible, but remains unproved.

RISKS AND COMPLICATIONS OF TRANSRECTAL ULTRASOUND GUIDED PROSTATE NEEDLE BIOPSY: A PROSPECTIVE STUDY AND REVIEW OF THE LITERATURE

PURPOSE Transrectal ultrasound guided needle biopsy of the prostate is routinely performed to diagnose and stage prostate cancer. We prospectively evaluated the true incidence of complications and identified risk factors of needle biopsy. MATERIALS AND METHODS We prospectively studied 128 patients who underwent transrectal ultrasound guided needle biopsy. A pre-biopsy questionnaire provided demographic information. Immediate complications were recorded by the surgical team at the procedure. Information on delayed complications was obtained by telephone interview. Univariate and multivariate analyses were performed. RESULTS There was 1 major and 135 minor complications in 77 patients with at least 1 complication in 63.6%. Most patients tolerated the procedure with minimal discomfort regardless of the number and location of biopsies but younger patients had significantly more discomfort than older men (R = -0.26, p = 0.005). The most common complication was persistent hematuria in 47.1% of cases. None of the hemorrhagic complications was related to previous aspirin or nonsteroidal anti-inflammatory drug use, or the total number of biopsies performed. Infectious complications were rare with only a 1.7% incidence of fever. This rate was associated with the choice of antibiotic combination used (R = 0.25, p = 0.006). CONCLUSIONS Transrectal ultrasound guided needle biopsy is safe for diagnosing prostate cancer with few major but frequent minor complications. Patients are likely to have persistent hematuria for up to 3 to 7 days after the procedure. Recent use of aspirin or nonsteroidal anti-inflammatory drugs is not an absolute contraindication for this procedure. Additional analgesics are not required in patients who undergo anterior or multiple biopsies but they may be useful in younger patients.

Clonogenic multipotent stem cells in human adipose tissue differentiate into functional smooth muscle cells

Smooth muscle is a major component of human tissues and is essential for the normal function of a multitude of organs including the intestine, urinary tract and the vascular system. The use of stem cells for cell-based tissue engineering and regeneration strategies represents a promising alternative for smooth muscle repair. For such strategies to succeed, a reliable source of smooth muscle precursor cells must be identified. Adipose tissue provides an abundant source of multipotent cells. In this study, the capacity of processed lipoaspirate (PLA) and adipose-derived stem cells to differentiate into phenotypic and functional smooth muscle cells was evaluated. To induce differentiation, PLA cells were cultured in smooth muscle differentiation medium. Smooth muscle differentiation of PLA cells induced genetic expression of all smooth muscle markers and further confirmed by increased protein expression of smooth muscle cell-specific α actin (ASMA), calponin, caldesmon, SM22, myosin heavy chain (MHC), and smoothelin. Clonal studies of adipose derived multipotent cells demonstrated differentiation of these cells into smooth muscle cells in addition to trilineage differentiation capacity. Importantly, smooth muscle-differentiated cells, but not their precursors, exhibit the functional ability to contract and relax in direct response to pharmacologic agents. In conclusion, adipose-derived cells have the potential to differentiate into functional smooth muscle cells and, thus, adipose tissue can be a useful source of cells for treatment of injured tissues where smooth muscle plays an important role.

Urinary Bladder Smooth Muscle Engineered from Adipose Stem Cells and a Three Dimensional Synthetic Composite

Human adipose stem cells were cultured in smooth muscle inductive media and seeded into synthetic bladder composites to tissue engineer bladder smooth muscle. 85:15 Poly-lactic-glycolic acid bladder dome composites were cast using an electropulled microfiber luminal surface combined with an outer porous sponge. Cell-seeded bladders expressed smooth muscle actin, myosin heavy chain, calponinin, and caldesmon via RT-PCR and immunoflourescence. Nude rats (n=45) underwent removal of half their bladder and repair using: (i) augmentation with the adipose stem cell-seeded composites, (ii) augmentation with a matched acellular composite, or (iii) suture closure. Animals were followed for 12 weeks post-implantation and bladders were explanted serially. Results showed that bladder capacity and compliance were maintained in the cell-seeded group throughout the 12 weeks, but deteriorated in the acellular scaffold group sequentially with time. Control animals repaired with sutures regained their baseline bladder capacities by week 12, demonstrating a long-term limitation of this model. Histological analysis of explanted materials demonstrated viable adipose stem cells and increasing smooth muscle mass in the cell-seeded scaffolds with time. Tissue bath stimulation demonstrated smooth muscle contraction of the seeded implants but not the acellular implants after 12 weeks in vivo. Our study demonstrates the feasibility and short term physical properties of bladder tissue engineered from adipose stem cells.

Discrepancy in patient and physician perception of patient’s quality of life related to urinary symptoms

OBJECTIVES To investigate the relationship between physician-assessed quality-of-life (QOL) parameters obtained from patient interview and patient self-report of QOL by using the short form of the Urogenital Distress Inventory (UDI-6). METHODS Female patients presenting for the first time at our clinic at two different academic institutions were consecutively evaluated. All patients were asked to fill out the UDI-6 while in the waiting area before their appointment. One additional global QOL question specific to the patients overall urinary condition was included in the questionnaire. A physician who was unaware of the patients responses then interviewed all patients. The physicians then filled out the UDI-6 on the basis of their impression of the patients symptoms from the patients responses during the medical interview. A statistician unaware of the patients diagnosis and presenting symptoms compared the physician and patient symptom bother assessments. RESULTS Seventy-nine patients were analyzed. Statistical analysis with weighted kappas revealed poor concordance between the physician and patient responses. Overall, the physicians at both institutions underestimated the patients degree of bother 25% to 37% of the time. CONCLUSIONS Reports of outcomes after treatment of urinary incontinence should always include independent patient self-administered questionnaires. Because of interviewer bias, physician assessment of QOL tends to underestimate a patients bother from urinary symptoms.

The MAPP research network: a novel study of urologic chronic pelvic pain syndromes

Urologic chronic pelvic pain syndrome (UCPPS) may be defined to include interstitial cystitis/bladder pain syndrome (IC/BPS) and chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). The hallmark symptom of UCPPS is chronic pain in the pelvis, urogenital floor, or external genitalia often accompanied by lower urinary tract symptoms. Despite numerous past basic and clinical research studies there is no broadly identifiable organ-specific pathology or understanding of etiology or risk factors for UCPPS, and diagnosis relies primarily on patient reported symptoms. In addition, there are no generally effective therapies. Recent findings have, however, revealed associations between UCPPS and “centralized” chronic pain disorders, suggesting UCPPS may represent a local manifestation of more widespread pathology in some patients. Here, we describe a new and novel effort initiated by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) of the U.S. National Institutes of Health (NIH) to address the many long standing questions regarding UCPPS, the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network. The MAPP Network approaches UCPPS in a systemic manner, in which the interplay between the genitourinary system and other physiological systems is emphasized. The network’s study design expands beyond previous research, which has primarily focused on urologic organs and tissues, to utilize integrated approaches to define patient phenotypes, identify clinically-relevant subgroups, and better understand treated natural history and pathophysiology. Thus, the MAPP Network provides an unprecedented, multi-layered characterization of UCPPS. Knowledge gained is expected to provide important insights into underlying pathophysiology, a foundation for better segmenting patients for future clinical trials, and ultimately translation into improved clinical management. In addition, the MAPP Network’s integrated multi-disciplinary research approach may serve as a model for studies of urologic and non-urologic disorders that have proven refractory to past basic and clinical study.Trial registrationClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”.

Complications of sling surgery among female Medicare beneficiaries.

OBJECTIVE: To analyze Medicare claims data to determine short-term complications after sling surgery among female beneficiaries aged 65 years and over. METHODS: We analyzed the 1999–2001 Medicare Public Use Files provided by the Centers for Medicare and Medicaid Services on a 5% national random sample of beneficiaries. Women undergoing sling procedures between January 1, 1999, and July 31, 2000, (the index period) were identified by Physicians Current Procedural Terminology Coding System (4th edition) and tracked for 12 months. Main outcome measures were complications as identified by International Classification of Diseases (9th revision) (ICD-9) diagnosis codes and Current Procedural Terminology procedure codes in the first postoperative year. RESULTS: A total of 1,356 sling procedures were performed during the index period. In the 3 months after the procedure, 12.5% of women developed surgical or urologic complications, and 33.6% were diagnosed with urinary tract infections. Within 1 year of the procedure, 6.9% of subjects had a new diagnosis of outlet obstruction, and 8.0% underwent treatments to manage outlet obstruction. There was a high incidence of new diagnoses of urge incontinence (15.2%) and treatment of pelvic prolapse (23.2%). Both cystoscopy and urodynamic testing, which may serve as indicators of possible complications, were performed frequently during the first year after surgery (32.4% and 30.5%, respectively). Patient race, age, and comorbidity each had a significant influence on outcomes. CONCLUSION: Complication rates within 1 year after sling surgery among Medicare beneficiaries were found to be higher than those reported in the clinical literature. The high rates of postoperative urinary tract infections, prolapse, and outlet obstruction suggest the need for quality improvement measures in the management of women with incontinence and pelvic prolapse. LEVEL OF EVIDENCE: III

The MAPP research network: design, patient characterization and operations

BackgroundThe “Multidisciplinary Approach to the Study of Chronic Pelvic Pain” (MAPP) Research Network was established by the NIDDK to better understand the pathophysiology of urologic chronic pelvic pain syndromes (UCPPS), to inform future clinical trials and improve clinical care. The evolution, organization, and scientific scope of the MAPP Research Network, and the unique approach of the network’s central study and common data elements are described.MethodsThe primary scientific protocol for the Trans-MAPP Epidemiology/Phenotyping (EP) Study comprises a multi-site, longitudinal observational study, including bi-weekly internet-based symptom assessments, following a comprehensive in-clinic deep-phenotyping array of urological symptoms, non-urological symptoms and psychosocial factors to evaluate men and women with UCPPS. Healthy controls, matched on sex and age, as well as “positive” controls meeting the non-urologic associated syndromes (NUAS) criteria for one or more of the target conditions of Fibromyalgia (FM), Chronic Fatigue Syndrome (CFS) or Irritable Bowel Syndrome (IBS), were also evaluated. Additional, complementary studies addressing diverse hypotheses are integrated into the Trans-MAPP EP Study to provide a systemic characterization of study participants, including biomarker discovery studies of infectious agents, quantitative sensory testing, and structural and resting state neuroimaging and functional neurobiology studies. A highly novel effort to develop and assess clinically relevant animal models of UCPPS was also undertaken to allow improved translation between clinical and mechanistic studies. Recruitment into the central study occurred at six Discovery Sites in the United States, resulting in a total of 1,039 enrolled participants, exceeding the original targets. The biospecimen collection rate at baseline visits reached nearly 100%, and 279 participants underwent common neuroimaging through a standardized protocol. An extended follow-up study for 161 of the UCPPS participants is ongoing.DiscussionThe MAPP Research Network represents a novel, comprehensive approach to the study of UCPPS, as well as other concomitant NUAS. Findings are expected to provide significant advances in understanding UCPPS pathophysiology that will ultimately inform future clinical trials and lead to improvements in patient care. Furthermore, the structure and methodologies developed by the MAPP Network provide the foundation upon which future studies of other urologic or non-urologic disorders can be based.Trial registrationClinicalTrials.gov identifier: NCT01098279 “Chronic Pelvic Pain Study of Individuals with Diagnoses or Symptoms of Interstitial Cystitis and/or Chronic Prostatitis (MAPP-EP)”. http://clinicaltrials.gov/show/NCT01098279

Trends in surgical mesh use for pelvic organ prolapse from 2000 to 2010.

OBJECTIVE: To describe trends in and predictors of surgical mesh use for pelvic organ prolapse (POP) repair and to estimate the influence of safety advisories on mesh use. METHODS: Analysis of women aged 18 years and older recorded in a health care quality and resource utilization database who underwent POP repair from 2000 to 2010, identified by International Classification of Diseases, 9th Revision, Clinical Modification procedure codes, and stratified by mesh use. Odds ratios were calculated with adjustments for patient, physician, and hospital-level characteristics. RESULTS: Among 273,275 women in the cohort, 64,968 (23.8%) underwent a mesh-augmented repair. Concurrent incontinence surgery was a strong predictor of mesh use (odds ratio [OR] 9.95; 95% confidence interval [CI] 9.70–10.21). Mesh use increased from 7.9% in 2000 to a peak of 32.1% in 2006, and declined slightly to 27.5% in 2010. Among women without incontinence, mesh use increased from 3.3% in 2000 to 13.5% in 2006, and remained stable at 12.8% in 2010. Intermediate-volume (OR 1.53; 95% CI 1.44–1.62) and high-volume (OR 2.74; 95% CI 2.58–2.92) surgeons were more likely to use mesh than low-volume surgeons. Compared with women who underwent operation by gynecologists, those treated by urologists were more than three times more likely to undergo mesh-augmented prolapse repair (OR 3.36; 95% CI 3.09–3.66). Black women were 27% less likely to undergo mesh repair (OR 0.73; 95% CI 0.66–0.82). CONCLUSIONS: Mesh-augmented prolapse repairs increased substantially over the past decade, and this increase was most pronounced in the years before the publication of safety advisories. Physician specialty and surgical volume are important factors underlying mesh use. Additional measures must ensure evidence-based use of mesh for pelvic reconstruction. LEVEL OF EVIDENCE: II

The Effects of Acute and Chronic Psychological Stress on Bladder Function in a Rodent Model

OBJECTIVE Psychological stress plays a role in the exacerbation of functional lower urinary tract disorders, such as painful bladder syndrome and overactive bladder. To better understand the mechanism underlying this relationship, we characterized changes in micturition, anxiety-related behavior, and bladder pathology in rats exposed to repeated water avoidance (WA) stress. METHODS Twenty-four Wistar rats were subjected to WA stress or sham. Immediately after acute (day 1) and chronic (day 10) stress or sham, rats were placed in a metabolic cage for a 2-hour voiding behavior assessment. Voiding parameters were compared with baseline values obtained before stress. Four animals from each group were sacrificed on day 10 and bladders harvested for histologic and gene expression studies. The remaining 8 animals per group underwent repeated voiding assessment every 3 days for 1 month followed by 10 days of repeat WA stress or sham. Bladder histology and gene expression were studied. RESULTS Rats exposed to WA stress developed a significant increase in micturition frequency and decrease in latency to void, voiding interval, and volume of first void compared with sham and baseline. Alterations in micturition persisted for approximately 1 month. Stressed rats showed increased fecal pellet excretion and anxiety-like behavior. In addition, bladder specimens from stressed animals revealed increased angiogenesis, and increased total and activated mast cells. CONCLUSION In rats, repeated psychological stress results in lasting alterations in micturition frequency, interval, and volume. This rodent model may represent a valid tool for studying syndromes characterized by increased urinary frequency.