Post-injury atomoxetine treatment improves cognition following experimental traumatic brain injury.

Catecholaminergic neurotransmission is regionally altered following injury, and drugs aimed at these systems offer promising avenues for post-traumatic brain injury (TBI) pharmacotherapies. Atomoxetine is a selective norepinephrine transporter (NET) inhibitor currently indicated for treatment of attention-deficit hyperactivity disorder (ADHD). The current study was designed to test the efficacy of atomoxetine in treating cognitive deficits following experimental TBI in animals and to determine an optimal dose and therapeutic window for drug treatment. Sprague-Dawley rats were subjected to lateral fluid-percussion injury (L-FPI) of moderate severity (2.08 atm +/- 0.05). Two experiments were performed. In the first study, atomoxetine (0.3, 1, 3, or 9 mg/kg) or vehicle was administered daily on post-injury days (PID) 1-15. Cognitive assessment was performed using the Morris water maze on PID 11-15. L-FPI resulted in significant cognitive impairment when compared to Sham-Injury. Treatment with lower doses of atomoxetine (0.3, 1, and 3 mg/kg) significantly attenuated the cognitive deficits in injured animals. Treatment with the higher dosage (9 mg/kg) of atomoxetine resulted in animals that were not significantly different than injured-vehicle treated animals. The optimal response was achieved using 1 mg/kg atomoxetine. In the second study, treatment with atomoxetine (1 mg/kg) or vehicle was delayed for 11 days post-injury. Rats were administered atomoxetine daily for 15 days, and cognitive assessment was performed on PID 25-29. In this study, treatment with atomoxetine (1 mg/kg) did not result in improved cognitive performance. In conclusion, this is the first study to show low-dose atomoxetine initiated early after experimental TBI results in improved cognition.

Is localized, provoked vulvodynia an inflammatory condition?

OBJECTIVE: To perform a pilot study to investigate the relationship between localized, provoked vulvodynia of the vestibule and inflammatory cytokine expression. STUDY DESIGN: Women with a diagnosis of localized, provoked vulvodynia had tissue samples taken for vulvar expression of Interleukin 1alpha and 1beta and tumor necrosis factor alpha and compared to those of a control group. RESULTS: The study group did not show a significant increase in expression of inflammatory markers. CONCLUSION: There was no evidence in this study that localized, provoked vulvodynia is an inflammatory condition, as previously thought. This may be helpful in explaining why some women are resistant to medical or antiinflammatory treatment and may allow treatment to be prescribed more effectively.

Insulin-like growth factor-1 gene splice variants as markers of muscle damage in levator ani muscle after the first vaginal delivery.

OBJECTIVE: Studies in animals and human muscle have demonstrated differential splicing of the insulin-like growth factor-1 gene in response to mechanical strain and damage. We conducted a study on the expression of insulin-like growth factor-1 splice variants in the levator ani muscle after the first vaginal delivery. STUDY DESIGN: Ten women were recruited after the first vaginal delivery. Biopsy specimens were taken vaginally of the pubovisceral component of the levator ani muscle. Five nonpregnant women were recruited as control subjects. Samples were processed with real-time quantitative polymerase chain reaction, with specific primers for the insulin-like growth factor-1 splice variants. RESULTS: Insulin-like growth factor splice variants mechano growth factor and insulin-like growth factor-1Ea were significantly up-regulated (100- and 1000-fold) in the delivery population, compared with control subjects (P=.012 and .04, respectively). Statistical analysis indicated a correlation between the expression of the insulin-like growth factor-1 splice variants and the length of the second stage. CONCLUSION: These results show that damaged levator ani muscle results from stretch and overload after the first vaginal delivery.

Achieving compliance with the European Working Time Directive in a large teaching hospital: a strategic approach.

This paper describes the strategy which achieved European Working Time Directive (EWTD) compliance at the Royal Free Hampstead NHS Trust in medicine and surgery. Compliance with EWTD regulations was assessed by diary card exercise, clinical care assessed through critical incident reports, electronic handover documents and nursing reports, training opportunities assessed by unit training directors, cost controls assessed by finance department analysis, and workload assessed by staff attendance on wards, in casualty and in theatres. There was a change in focus of care to a consultant-led, specialist registrar- (SpR-)driven service extending into evenings and on weekends, coupled with a move to a multi-skilled team for night cover, and to a move from traditional on-call shifts to a full shift system across both medicine and surgery. Compliance with the EWTD was achieved whilst maintaining good standards of clinical care, ensuring training opportunities for doctors in training, controlling payroll costs, removing the need for locums, and reducing workload for both junior doctors and consultants.

Clinical examination and dynamic magnetic resonance imaging in vaginal vault prolapse.

OBJECTIVE: To estimate the role of dynamic magnetic resonance imaging (MRI) as a diagnostic tool in the evaluation of vaginal apex prolapse in women with previous hysterectomy. METHODS: Clinical examinations were performed on 51 women presenting with symptoms of prolapse. A preoperative dynamic MRI assessment was performed. The mid pubic line was the reference level used for prolapse grading. The parameters of analysis included 1). correlation by compartments of clinical and MRI grading of prolapse, 2). assessment of the accuracy of clinical examination of the middle compartment, and 3). identification of any additional information provided by MRI. All MRI films were analyzed and validated by the same two observers. RESULTS: Analysis of each compartment separately revealed poor correlation between clinical and MRI assessment. Of the 51 cases with clinical vault prolapse, 27 (52.9%) cases were clinically overdiagnosed, 3 (6%) were underdiagnosed, and there was agreement in 21 (41.1%) when compared with MRI findings. Postoperative follow-up of the 18 (85%) patients who underwent colposacropexy after intraoperative assessment revealed the presence of cystocele in 4 (26.6%) occasions and rectocele in 3 (20%), which had been detected on MRI but not confirmed intraoperatively. CONCLUSION: There is poor correlation between clinical and MRI findings when assessing vaginal apex prolapse. Magnetic resonance imaging allows the identification of other prolapsing compartments and may be a complementary diagnostic tool for the diagnosis of complex vaginal apex prolapse.

Estrogen receptor expression in vulvar vestibulitis syndrome.

OBJECTIVE: A pilot study was performed to investigate the relationship between vulvar vestibulitis syndrome and estrogen receptor expression. STUDY DESIGN: Women with a diagnosis of vulvar vestibulitis syndrome had tissue samples taken for vulvar estrogen receptor-alpha expression and this was compared with a control group. RESULTS: The study group showed a significant decrease in estrogen receptor expression, and 50% of the samples did not exhibit any receptor expression. CONCLUSION: There appears to be a subgroup of women with vulvar vestibulitis syndrome who exhibit abnormal estrogen receptor-alpha expression. This may be helpful in explaining why some women are resistant to medical treatment and may allow treatment to be prescribed more effectively.

Three-dimensional magnetic resonance imaging assessment of levator ani morphologic features in different grades of prolapse.

OBJECTIVE: The study was undertaken to identify the morphologic changes in the levator ani in different grades of prolapse by using reconstructed three-dimensional models of magnetic resonance images (MRI) and to subclassify prolapse into different categories on the basis of their levator ani morphologic characteristics. STUDY DESIGN: Sixty-one women were studied, 8 women in stage I, 15 women in stage II, 22 women in stage III, 7 women in stage IV prolapse, and 9 asymptomatic volunteers with stage 0 prolapse. Axial, sagittal, and coronal T2-weighted pelvic magnetic resonance scans were obtained with the patient in the supine position. The three-dimensional models were reconstructed from the source images by using manual segmentation and surface modeling. The morphologic characteristics of the puborectalis were assessed on these reconstructed models by measuring (1). the levator symphysis gap, (2). the width of the levator hiatus, and (3). the length of the levator hiatus. To assess the iliococcygeus, we measured (1). the maximum width of the iliococcygeus, (2). the direction of its fibers that was assessed by measuring the iliococcygeal angle, and (3) the levator plate angle. Nine nulliparous asymptomatic women were studied as controls. RESULTS: Alterations in levator ani morphologic features are not dependent on the grade of the prolapse, and not all women with pelvic floor prolapse have abnormal morphologic features. In healthy control subjects, the iliococcygeal width measured less than 40 mm and the iliococcygeal angle measured less than 20 degrees. On the basis of the MRI findings, four patterns of changes in the levator ani have been identified. Both the levator symphysis gap and the levator hiatus, which is dependent on the puborectalis function, widen with increasing grade of prolapse. CONCLUSION: It is possible to subclassify prolapse on the basis of morphologic changes in the levator ani by using MRI. This may be a very useful predictor as to which patients have recurrent prolapse develop after surgery.

The role of angiogenesis in vulvar cancer, vulvar intraepithelial neoplasia, and vulvar lichen sclerosus as determined by microvessel density analysis.

OBJECTIVES: We compared microvessel density (MVD) in normal, benign, preneoplastic, and neoplastic (squamous cell carcinoma (SCC)) vulvar disease to ascertain if this parameter could identify cases with lichen sclerosus (LS) and high-grade vulvar intraepithelial neoplasia (VIN3) at risk of developing malignancy. METHODS: Microvessels were immunohistochemically stained in paraffin wax-embedded vulvar tissue sections with anti-von Willebrand factor (vWF) antibody using the streptavidin-biotin-horseradish peroxidase complex technique. Three "hot spots" with the greatest MVD were identified within 200 microm of the subepithelial dermis under low magnification (x 40 and x 100). The highest (HVD) and average (AVD) MVDs were quantified for each sample under high magnification (x 200) using an image analysis system. RESULTS: HVD and AVD showed similar significant differences. SCC had significantly the highest MVD followed by VIN3, normal vulva, and LS. LS had significantly the lowest MVD, even lower than that of normal vulva. Two cases of VIN3 had much higher HVD (9.16 and 9.61) and AVD (6.89 and 7.71) compared with the main cluster of cases. CONCLUSION: In vulvar LS, MVD, as assessed by HVD/AVD, is not a useful parameter in determining potential malignant progression, while in VIN3 this parameter could be valuable in identifying cases at greatest risk of progression to invasive disease.

The role of vascular endothelial growth factor-A (VEGF-A) and platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) in Paget's disease of the vulva and breast.

BACKGROUND: Paget's disease of the vulva and the breast are uncommon conditions. The pathogenesis underlying these diseases is still unclear. Vascular endothelial growth factor-A (VEGF-A), a potent angiogenic factor, has been demonstrated in a variety of tumour cell types and is thought to be involved in tumour expansion. Platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP) has also been shown to stimulate angiogenesis. MATERIALS AND METHODS: Fifty-four cases of Paget's disease of the vulva, including 10 with an associated invasive adenocarcinoma, and 38 cases of Paget's disease of the breast, including 26 with available associated ductal carcinoma in situ (DCIS) and/or invasive carcinoma of the breast, were evaluated immunohistochemically for the expression of VEGF-A and PD-ECGF/TP. RESULTS: VEGF-A was not expressed in Paget's disease of the vulva or breast. PD-ECGF/TP was expressed in 22 out of 54 (41%) cases of Paget's disease of the vulva. Four of the cases associated with invasive disease (40%) expressed PD-ECGF/TP. Twenty-one out of 38 (55%) cases of Paget's disease of the breast were positive for PD-ECGF/TP. CONCLUSION: Our data suggest that PD-ECGF/TP may have a role to play in the pathogenesis of Paget's disease of the vulva and the breast. The role of VEGF-A in Paget's disease of the vulva and the breast remains to be fully elucidated.