Bo Blomgren

Influence of different sling materials on connective tissue metabolism in stress urinary incontinent women.

Abstract: The aim of this study was to investigate the influence on the paraurethral connective tissue of different sling materials used in incontinence surgery. Biopsies from the paraurethral connective tissue were obtained intraoperatively from 16 women with stress urinary incontinence; all were operated on with the TVT procedure, 6 with Mersilene as the sling material and 10 with Prolene. Biopsies from 4 continent women with uterine bleeding irregularities, matched for age and parity, served as controls. New biopsies were obtained from all women after 2 years. The biopsies were examined histologically and analyzed for collagen concentration and solubility. An obvious inflammatory reaction with a significant increase in collagen extractability by pepsin was identified in patients where Mersilene was used as the sling material. A minimal inflammatory reaction without a significant change in collagen solubility was found in the Prolene group. In the control group no inflammatory reaction was seen. Mersilene gave rise to a significant foreign-body reaction in the paraurethral connective tissue after surgery. Such a reaction was not found with Prolene.

Increased blood flow and erythema in the posterior vestibular mucosa in vulvar vestibulitis

OBJECTIVE To evaluate vascular changes as a possible underlying cause of mucosal erythema in women with vulvar vestibulitis. METHODS Laser Doppler perfusion imaging was used to map the superficial blood flow in the vestibular mucosa in 20 women with vestibulitis and in 21 healthy control subjects. A possible correlation between perfusion values and graded erythema (1–5) around the vaginal introitus was analyzed. Changes in microvascular density in the posterior part of the mucosa were investigated in sections from ten patients and ten controls by a computer‐assisted image‐processing program. Induced vasoconstriction of terminal arterioles in the same posterior area was also studied. RESULTS Significant increases in perfusion values were registered in the posterior parts of the vestibular mucosa in patients compared with controls. The highest blood flow was registered in the posterior fourchette. The most pronounced erythema was also located in the posterior vestibule in the patients. However, there was no significant correlation between perfusion values and degree of erythema in the same individual. The microvascular density or the ability of vestibular arterioles to constrict did not differ between patients and controls. CONCLUSION Women with vestibulitis have an increased superficial blood flow and erythema in the posterior parts of the vestibular mucosa. The increased perfusion, most probably caused by a neurogenic vasodilatation contributes to, but does not fully explain the erythema. Atrophic changes of the surface epithelium should also be considered in the evaluation of an erythema.

Clinical and histological safety assessment of rectocele repair using collagen mesh

Aim.  To clinically and histologically evaluate inflammatory response following rectocele repair using porcine collagen mesh.

Steroid receptor expression and morphology in provoked vestibulodynia.

OBJECTIVE This study was undertaken to survey the steroid receptor expression and morphology in the vulvar vestibular mucosa in women with provoked vestibulodynia. STUDY DESIGN Fourteen patients and 25 controls without oral contraceptives were included. Vestibular biopsy specimens were obtained and analyzed by using immunohistochemistry, followed by computerized image analysis of estrogen receptors alpha and beta, progesterone receptors A and B, glucocorticoid receptor, androgen receptor, and the proliferation marker Ki67. The morphology was estimated by measuring 4 parameters in the epithelium. RESULTS There was a significantly higher expression of estrogen receptor alpha in both the epithelium (P = .04) and the stroma (P = .02) in the patient specimens compared with the controls. There were no significant differences in the other analyses performed. CONCLUSION There is an increased expression of estrogen receptor alpha in the vestibular mucosa but the epithelial morphology seems unaffected in women with provoked vestibulodynia. Further studies regarding plausible associations to neurogenic inflammation are needed.

The vulval vestibular mucosa—morphological effects of oral contraceptives and menstrual cycle

Background  An erythematous and hypersensitive vestibular mucosa has been observed during the use of combined oral contraceptives (COC). Hormonal effects on the vestibular morphology have not been studied.

Delivering Horseradish Peroxidase as a Respirable Powder to the Isolated, Perfused, and Ventilated Lung of the Rat: The Pulmonary Disposition of an Inhaled Model Biopharmaceutical

BACKGROUND Our aim was to investigate the potential of the DustGun aerosol technology integrated with the isolated, perfused, and ventilated lung of the rat (IPL) to study the pulmonary disposition of an inhaled model biopharmaceutical, the 40-kDa protein horseradish peroxidase (HRP). METHOD The DustGun aerosol technology was used to deliver respirable powder aerosols of HRP (the mass median aerodynamic diameter: 1.7 μm) as an 80-sec bolus to the IPL perfused in a single-pass mode. Lung perfusate was repeatedly sampled for 125 min after the HRP exposure. The amount of active HRP clearing with the perfusate or being retained in the lung was measured enzymatically. RESULTS AND CONCLUSIONS The total amount of HRP deposited in the lungs was 335 ± 100 μg and 568 ± 47 μg for a low- and high-dose exposure, respectively. After inhalation, the initial appearance of HRP in the perfusate was rapid. However, the total amount of HRP that cleared with the perfusate remained below 0.5% of the deposited dose. The effect of opening the tight junctions between the alveolar epithelial cells on HRP absorption was studied by exposing the IPL to nebulized aerosols of either 0.02, 0.2, or 2% poly-L-Arginine (PLA) (MW 42.5 kDa) in phosphate-buffered saline (PBS) for 5 min, at 40 min after the HRP exposure. Subsequent exposure to 0.02% PLA did not affect HRP absorption. However, exposure to 0.2% PLA increased the absorption rate ninefold, and the total amount of HRP clearing with the perfusate increased to approximately 4% of the deposited dose. No further increase was obtained with 2% PLA, indicating a steep dose-response for the enhancer. It was concluded that the pulmonary absorption of HRP is quite slow, and absorption enhancers affecting tight junctions have a distinctive, yet limited efficiency. The presented inhalation technology can be very useful in studying the pulmonary absorption of biopharmaceuticals.

Expression of angiopoietins 1, 2 and their common receptor tie-2 in relation to the size of endothelial lining gaps and expression of VEGF and VEGF receptors in idiopathic menorrhagia

OBJECTIVE To investigate whether idiopathic menorrhagia (IM) is associated with alterations of the vascular expression of angiopoietin-1, angiopoietin-2, and tie-2 receptor. DESIGN Prospective clinical study. SETTING University Hospital, Department of Gynecology. PATIENT(S) Twenty-four patients with IM and 18 women with eumenorrhea. INTERVENTION(S) Endometrial samples underwent immunohistochemical staining for CD34, angiopoetin-1, angiopoietin-2, tie-2, and smooth muscle actin-alpha. Previously published data on gap size and expression of vascular endothelial growth factor family members were used. MAIN OUTCOME MEASURE(S) Differences in immunostaining for these markers by computer-assisted stereological analysis. RESULT(S) There was significantly more angiopoetin-1 positive vessels in IM in the secretory phase, but not of angiopoetin-2 and tie-2, compared with controls. Densities of angiopoetin-1 positive vessels correlated significantly to those of angiopoetin-2 and vascular endothelial growth factor receptor 3. Smooth muscle actin-alpha positive pericytes covered the gaps. Double staining for CD34 and tie-2 receptor was partly identical, but gaps were covered by tie-2 stain. CONCLUSION(S) The discrete deregulation observed of the angiopoetin-1 expression before menstruation might affect vascular integrity, thereby contributing to the excessive blood loss in IM.

Tesaglitazar, a Dual PPAR-α/γ Agonist, Hamster Carcinogenicity, Investigative Animal and Clinical Studies

Tesaglitazar was developed as a dual peroxisome proliferator–activated receptor (PPARα/γ). To support the clinical program, a hamster carcinogenicity study was performed. The only neoplastic findings possibly related to treatment with tesaglitazar were low incidences of hemangioma and hemangiosarcoma in the liver of male animals. A high-power, two-year investigative study with interim necropsies was performed to further elucidate these findings. Treatment with tesaglitazar resulted in changes typical for exaggerated PPARα pharmacology in rodents, such as hepatocellular hypertrophy and hepatocellular carcinoma, but not an increased frequency of hemangiosarcomas. At the highest dose level, there was an increased incidence of sinusoidal dilatation and hemangiomas. No increased endothelial cell (EC) proliferation was detected in vivo, which was confirmed by in vitro administration to ECs. Immunohistochemistry and gene expression analyses indicated increased cellular stress and vascular endothelial growth factor (VEGF) expression in the liver, which may have contributed to the sinusoidal dilatation. A two-fold increase in the level of circulating VEGF was detected in the hamster at all dose levels, whereas no effect on VEGF was observed in patients treated with tesaglitazar. In conclusion, investigations have demonstrated that tesaglitazar does not produce hemangiosarcomas in hamster despite a slight effect on vascular morphology in the liver.

Proliferative and Molecular Effects of the Dual PPARα/γ Agonist Tesaglitazar in Rat Adipose Tissues: Relevance for Induction of Fibrosarcoma

The dual peroxisome-proliferator-activated receptor (PPAR) α/γ agonist tesaglitazar has been shown to produce fibrosarcomas in rats. Here, the authors studied morphology, proliferation, differentiation, and inflammation markers in adipose tissue from rats exposed to 1, 3, or 10 µmol/kg tesaglitazar for 2 or 12 weeks, including recovery groups (12 weeks treatment followed by 12 weeks recovery), and 3 or 10 µmol/kg tesaglitazar for 24 weeks. Subcutaneous white and brown fat revealed reversible dose-related histopathological alterations and after 12 and 24 weeks developed areas of thickened skin (fatty lumps). There was a dose-dependent increase in proliferation of interstitial cells in white and brown fat as shown by increased mitotic index in all dose groups after 2 weeks. This was limited to the high dose after 12 and 24 weeks in white fat. Gene expression analyses showed that while tesaglitazar induced differentiation of adipose tissue characterized with a switch in cyclin D1 and D3 mRNA by 12 weeks, longer exposure at high doses reversed this differentiation concurrent with a reappearance of early adipocyte and inflammatory markers. These data suggest that sustained increased turnover of mesenchymal cells in adipose tissues, concomitant with onset of inflammation and fibrosis, drives development of fibrosarcomas in rats treated with tesaglitazar.