Recovery of Continence Function following Simulated Birth Trauma Involves Repair of Muscle and Nerves in the Urethra in the Female Mouse

Background

The natural history and the mechanisms behind the alteration of vaginal distension (VD) in a mouse model are not clear.

Objective

We examined the temporal sequelae of VD and pudendal nerve transection (PNT) on leak-point pressure (LPP) and the muscular and nerve components of the urethra in mice.

Design, setting, and participants

Seventy-two virgin female C57BL/6 mice were equally distributed into three groups. The VD group underwent VD for 1 h. The PNT group received bilateral PNT. A control group underwent sham VD.

Intervention

Each group was divided into four subgroups of six mice for measurement of LPP at 0, 4, 10, and 20 d after VD or PNT.

Measurements

LPP was measured. Morphology and neurofilament-immunoreactive nerve of the urethra were assessed.

Results and limitations

LPP was decreased at 0, 4, and 10 d but not at 20 d after VD. Decreased LPP persisted to 20 d in the PNT group. The external urethral striated muscle appeared disrupted and/or wavy in two mice at 0 d, in three mice at 4 d, in one mouse at 10 d, and in one mouse in 20 d after VD. The density of neurofilament-immunoreactive nerve in the urethra was reduced at 4 and 10 d after VD, but not at 20 d, and at 4, 10, and 20 d after PNT compared with the corresponding values of the sham VD group. The limitation of this animal model is that the pelvic floor structure of the mouse is different from that of female humans. Therefore, results of this study should be carefully applied to human subjects.

Conclusions

VD causes reversible stress urinary incontinence in female mice. Recovery of continence function following VD is associated with repair of the external urethral sphincter and reinnervation of the urethra. This mouse model will be useful for mechanistic investigation and targeting of therapeutic intervention by taking advantage of genetic manipulation.     

Integrin-targeted nanocomplexes for tumour specific delivery and therapy by systemic administration

Nanoparticle formulations offer opportunities for tumour delivery of therapeutic reagents. The Receptor-Targeted Nanocomplex (RTN) formulation consists of a PEGylated, endosomally-cleavable lipid and an RGD integrin-targeting, endosomally-cleavable peptide. Nancomplexes self-assemble on mixing with plasmid DNA to produce nanoparticles of about 100 nm. The environmentally-sensitive linkers promote intracellular disassembly and release of the DNA. RTNs carrying luciferase genes were administered intravenously to mice carrying subcutaneous neuroblastoma tumours. Luciferase expression was much higher in tumours than in liver, spleen and lungs while plasmid biodistribution studies supported the expression data. Transfection in tumours was enhanced two-fold by integrin-targeting peptides compared to non-targeted nanocomplexes. RTNs containing the interleukin-2 (IL-2) and IL-12 genes were administered intravenously with seven doses at 48 h intervals and tumour growth monitored. Tumours from treated animals were approximately 75% smaller on day 11 compared with RTNs containing control plasmids with one third of treated mice surviving long-term. Extensive leukocyte infiltration, decreased vascularization and increased necrotic areas were observed in the tumours from IL2/IL12 treated animals. Splenocytes from re-challenged mice displayed enhanced IL-2 production following Neuro-2A co-culture, which, combined with infiltration studies, suggested a cytotoxic T cell-mediated9 tumour-rejection process. The integrin-targeted RTN formulation may have broader applications in the further development of cancer therapeutics.     

Differences in urinary incontinence between Hispanic and non-Hispanic white women: a population-based study

OBJECTIVE

To compare the prevalence of urinary incontinence (UI) between Hispanic and non‐Hispanic White women in a population‐based study.

SUBJECTS AND METHODS

The prevalence of moderate to severe UI, defined as Sandvik severity score of ≥3, was assessed in relation to ethnicity by stratification, age adjustment and logistic regression models among 250 Hispanic and 491 non‐Hispanic White women in Colorado, USA, who were participants in a breast cancer case‐control study.

RESULTS

Hispanic women reported more stress UI (odds ratio 1.7, P = 0.005) and mixed UI (odds ratio 1.8, P = 0.005) than did non‐Hispanic White women. These higher prevalences were largely associated with ethnic differences in parity, body mass index, diabetes, hysterectomy and bilateral oopherectomy.

CONCLUSIONS

The prevalence of moderate to severe UI in Colorado is higher among Hispanic women than among non‐Hispanic white women. This difference is largely compatible with differences in reproductive history, adiposity and diabetes.     

Lower urinary tract phenotype of experimental autoimmune cystitis in mouse: a potential animal model for interstitial cystitis

OBJECTIVE

To examine bladder function in a newly developed experimental autoimmune cystitis (EAC) model in female SWXJ strain mice, as a potential animal model for interstitial cystitis (IC).

MATERIALS AND METHODS

In all, 20 SWXJ female mice were divided into two groups: an EAC group immunized with mouse bladder homogenate in complete Freund’s adjuvant (CFA) and a control group immunized with CFA alone. At 4 months after injection, the bladder function of some mice (six) was studied with 24‐h micturition habits using metabolic cages and conscious cystometrography (CMG). The bladder and lung were harvested for histological examination and to assess interferon‐γ (IFN‐γ) mRNA expression.

RESULTS

Histology examination showed obviously thickened lamina propria, infiltration of lymphocytes, giant cells, and increased mast cells in the detrusor muscle of the EAC mice. The lungs of EAC mice showed normal histology. The IFN‐γ mRNA expression increased significantly in the bladder, but not in the lung of the EAC mice. The 24‐h micturition habits measurements showed increased frequency of urination in the EAC mice compared with the controls. Similarly, CMG showed decreased intercontraction intervals and voided volumes per micturition in the EAC mice compared with the controls. However, there were no significant differences in peak voiding pressure or total voiding volume between the EAC and control mice.

CONCLUSIONS

Our murine EAC model has comparable functional and histological alterations to those seen in human IC, and may provide a useful model for the study of the pathogenesis and treatment of IC.     

Long-term efficacy of a vaginal sling procedure in a rat model of stress urinary incontinence

PURPOSE: We examined the long-term efficacy of a newly created vaginal sling procedure for the restoration of leak point pressure (LPP) in a rat model of stress urinary incontinence (SUI). MATERIAL AND METHODS: A total of 20 female Sprague-Dawley rats were randomly assigned to 1 of 4 groups, namely normal control, SUI plus vaginal sling, SUI plus sham sling and SUI only. SUI was created in the latter 3 groups by bilateral pudendal nerve transection (PNT). In the sling procedure a 2 x 0.3 cm strip of polypropylene mesh was placed at the mid urethral level. Animals in the SUI plus sham sling group underwent vaginal dissection only. After 5 weeks LPP was measured 4 or 5 times in each rat and the mean was determined. The Kruskal-Wallis and Wilcoxon rank sum tests were used to evaluate whether levels of measurements differed across and between groups. RESULTS: Mean LPP +/- SD in control rats was 48.8 +/- 10.2 cm H2O. PNT decreased LPP to 23.5 +/- 7.4 cm H2O. Sling placement improved LPP at 5 weeks to 35.5 +/- 2.3 cm H2O, whereas LPP in the sham sling group was 29.1 +/- 4.9 cm H2O. LPP recovery in the sling group was significantly above levels for PNT (p = 0.037). LPP in the sling group did not differ statistically from that in the control group (p = 0.11). CONCLUSIONS: The newly created vaginal sling model restores the LPP in the rat model of SUI in the long term (5 weeks). This model could be used to address research questions related to the sling procedure.     

Diagnosis of Toxoplasma gondii infection in pregnant women using automated chemiluminescence and quantitative real time PCR

Objective: To identify serodiagnosis and quantification of Toxoplasma gondii(T. gondii) infection among pregnant women in Salmas, northwest of Iran. Methods: In this crosssectional study, 276 blood samples were collected from pregnant women referred to the health care centers in Salmas city. The demographic variables were also recorded. Titers of antiToxoplasma IgM and IgG antibodies(Ab) were determined using the chemiluminescence immunoassay. Quantitative real-time PCR targeting the T. gondii repeated element gene was also performed on the blood sample. Results: Out of all, 19.92%(55/276) and 2.17%(6/276) patients were seropositive for anti-Toxoplasma IgG and IgM Ab, respectively. Moreover, the presence of T. gondii DNA was observed in 12.31%(34/276) blood samples. A significant relationship was observed between the IgG Ab seropositivity and contact with the cat as a risk factor(P=0.022). Conclusions: The seroprevalence rate of T. gondii infection in pregnant women is relatively low. Consequently, the seronegative pregnant women are at risk, and a considerable rate of positive blood samples for the presence of parasite's DNA should not be ignored. Besides, quantitative real-time PCR could be considered as an accurate method for diagnosis of acute toxoplasmosis especially when the precise results are of the most importance in pregnancy. Limiting contact with cats is also suggested for pregnant women.     

Recent advances in assisted reproductive technologies

Assisted reproductive technologies (ART) have received considerable attention, both clinically and empirically. Drs. Steptoe and Edwards removed one oocyte surgically from a woman with infertility related to tubal disease. They fertilized this oocyte in vitro and transferred the formed embryo to the woman’s uterus and achieved pregnancy and delivery. The technique of in vitro fertilization (IVF) and embryo transfer (ET) quickly became widely utilized for other causes of infertility as well as for tubal disease. In the last 5 years there has been a number of new developments that are reviewed in this article. The most important and now widely practiced technology has been direct intracytoplasmic injection (ICSI) of the husband’s sperm into the wife’s oocyte. This was developed for treatment of infertility related to low sperm count. Subsequently it was shown that sperm can be aspirated from epididymis or found in testicular biopsy in obstructive azoospermia. Another promising development is in vitro maturation (IVM) of immature oocytes. This has the potential of avoiding ovarian hyperstimulation, which can be uncomfortable and occasionally dangerous. Some oocytes are unable to fertilize and/or develop into normal embryos. It may be possible that the problem is with the machinery of cytoplasm of the oocyte. Therefore cytoplasmic transfer from a normal oocyte to an abnormal oocyte may overcome the problem. Infertile couples may be faced with many psychological problems that become even more complex with various treatments. Whereas donation of oocytes or embryos can be technically quite simple, there are many psychological issues involved. As can be gathered from aforementioned discussions, the treatments developed for infertility appear to be somewhat illogical and in the style of “shot gun therapy.” In the field of infertility, as in other areas of medicine, it is of paramount importance to know the details of disease mechanisms. This in turn will allow specific and logical treatments to be developed.     

Cushing's syndrome associated with ectopic corticotropin production and small-cell lung cancer.

PURPOSE: This study was undertaken to review the clinical and laboratory features and response to treatment of patients with Cushing's syndrome associated with ectopic corticotropin (adrenocorticotropic hormone; ACTH) production and small-cell lung cancer (SCLC). PATIENTS AND METHODS: We undertook a retrospective chart review of 545 patients with SCLC seen at Toronto General Hospital between 1980 and 1990 and identified 23 patients (4.5%) with Cushing's syndrome and ectopic ACTH production. RESULTS: There were 17 male and six female patients, with a median age of 60 years. The syndrome was diagnosed at the time of initial presentation of SCLC in 13 patients and at relapse in 10 patients. Seven patients had limited disease and 16 had extensive disease at their initial diagnosis of SCLC, but 20 of 23 had extensive disease at the time of diagnosis of Cushing's syndrome. Ten patients had bone marrow involvement. The most frequent physical findings included edema (83%) and proximal myopathy (61%). All patients had elevated plasma and urinary free cortisol levels; 22 had a hypokalemic alkalosis, and 13 had hyperglycemia. Only one patient had a normal ACTH level. The response rate (complete plus partial) to chemotherapy for patients who had the syndrome diagnosed at initial presentation of SCLC was only 46%, and their median survival was only 3.57 months. Only two patients achieved complete normalization of all hormone parameters, and neither experienced hormone relapse at the time of SCLC relapse. Complications of therapy included gastrointestinal (GI) ulceration (six patients), GI bleeding (four), perforation of a duodenal ulcer (one), pneumonia (10), septic shock (three), and fungal infections (five). CONCLUSION: Ectopic ACTH production is associated with a low response to chemotherapy, short survival, and a high rate of complication to therapy.