Christine Gericke

A pilot study to evaluate the clinical relevance of endometriosis-associated nerve fibers in peritoneal endometriotic lesions.

OBJECTIVE To investigate the clinical relevance of endometriosis-associated nerve fibers in the development of endometriosis-associated symptoms. DESIGN Prospective nonrandomized study. SETTING University hospital endometriosis center. PATIENT(S) Fifty-one premenopausal patients underwent surgical laparoscopy because of chronic pelvic pain, dysmenorrhea, or for ovarian cysts. Endometriosis was diagnosed in 44 patients. INTERVENTION(S) The preoperative and postoperative pain scores were determined using a standardized questionnaire with a visual analogue scale from 1-10. Patients with peritoneal endometriosis were divided into two groups depending on their preoperative pain score: group A with a pain score of at least 3 or more and group B with a pain score of 2 or less. Patients without peritoneal endometriosis were classified as group C and patients without endometriosis were classified as group D. Immunohistochemical analysis of neurofilament and protein gene product 9.5 were used for nerve fiber detection. Occurrence of endometriosis-associated nerve fibers was correlated with the severity of pelvic pain and/or dysmenorrhea. RESULT(S) Peritoneal endometriosis-associated nerve fibers were found significantly more frequently in group A than in group B (82.6% vs. 33.3%). CONCLUSION(S) The present study suggests that the presence of endometriosis-associated nerve fibers in the peritoneum is important for the development of endometriosis-associated pelvic pain and dysmenorrhea.

Functional neurological recovery after spinal cord injury is impaired in patients with infections

Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham, AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale-classified A and B patients recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials. Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects (non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale conversions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1 year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients with infections [ASIA impairment scale A: 8 (4-12) versus 10 (5-17), P = 0.01; ASIA impairment scale B: 19.5 (8-53.5) versus 42 (20.5-64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients, the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36-2.63, P < 0.0005) or lower gain in ASIA motor score (regression coefficient: -8.21, 95% confidence interval: -12.29 to -4.14, P < 0.0005). Infections associated with spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury.

Possible roles of oxytocin receptor and vasopressin-1α receptor in the pathomechanism of dysperistalsis and dysmenorrhea in patients with adenomyosis uteri

OBJECTIVE To investigate the expression of oxytocin (OTR) and/or vasopressin (VP1αR) receptor in patients with and without adenomyosis uteri. DESIGN Retrospective nonrandomized study. SETTING University hospital endometriosis research center. PATIENT(S) Forty patients with histologically proven adenomyosis and 40 patients without adenomyosis who had undergone hysterectomy for dysmenorrhea, bleeding disorders, and fibroids. INTERVENTION(S) Immunohistochemical examination of both OTR and VP1αR expression in endometrium, myometrium, and adenomyotic lesions, and identification of smooth muscle cells using antibodies against OTR, VP1αR, and smooth muscle actin (sm-actin). MAIN OUTCOME MEASURE(S) The immunoreactive score (IRS) was used for expression of OTR, VP1αR, and sm-actin. RESULT(S) Expression of OTR in epithelial cells of adenomyotic lesions and surrounding myometrial cells was detectable. VP1αR was expressed only in myometrial cells and blood vessels. Using a specific anti-sm-actin antibody, another spindle cell population was characterized to represent smooth muscle cells which are in direct contact with the adenomyotic stroma. Compared with the unaffected myometrium, the surrounding adenomyosis-associated myometrium overexpressed OTR and showed changes in morphology. In the uteri of patients with adenomyosis, the junctional zone was often seen to be quite fissured. CONCLUSION(S) In addition to the specific expression of VP1αR, OTR expression and morphologic changes in the myometrial architecture of uteri having adenomyosis support the hypothesis that dysperistalsis plays an essential role in the development of endometriosis and dysmenorrhea. In the near future, specific inhibition of this receptor might yield a promising treatment for therapy.

Measurement and Reversal of Prophylactic and Therapeutic Peak Levels of Rivaroxaban An In Vitro Study

Background: Rivaroxaban (Xarelto, Bayer HealthCare, Leverkusen, Germany) is a new oral anticoagulant drug. Anticoagulants may cause bleeding, thereby requiring reliable monitoring and efficient therapy. We investigated thromboelastometry versus routine coagulation tests to measure prophylactic and therapeutic concentrations of rivaroxaban and their reversal with prothrombin complex concentrate (PCC) and activated recombinant factor VII (rFVIIa) in vitro. Methods: Rivaroxaban was solubilized, and PCC and rFVIIa were added in 2 concentrations to the rivaroxaban-spiked blood samples, and thromboelastometry and measurements were performed. Results: Rivaroxaban increased tissue factor–activated clotting time (CTExTEM) dose dependently. Activated partial prothrombin time (aPTT), prothrombin time ratio (PTR), and prothrombin time (PT) were changed significantly in both concentrations. Reversal with PCC in both dosages caused no significant change in the measured parameters. For prophylactic rivaroxaban dosage, rFVIIa changed the PT significantly but not CTExTEM, aPTT, and PTR. For therapeutic rivaroxaban dosage, the CTExTEM was significantly reduced. The other parameters remained unaffected. Conclusions: Thromboelastometry can detect rivaroxaban effects. In vitro rFVIIa seems highly effective for reversal in contrast to PCC.

Sex differences in effects on sexual development in rat offspring after pre- and postnatal exposure to triphenyltin chloride.

Consumers are exposed to organotin compounds (OTCs) via contaminated fish and seafood due to the accumulation of these compounds in marine organisms. Certain OTCs are immunotoxic and may also have endocrine disrupting properties resulting in adverse effects on the reproductive tract in mollusks and mammals. Since effects of in utero exposure to endocrine disrupting chemicals on the reproductive system are dependent on the critical window of exposure during its development, we conducted a comprehensive study with the aim to identify the most sensitive window of exposure to TPTCl and to investigate the effects of pre- and postnatal treatment on sexual development in rats. Male and female offspring rats were exposed to 2 or 6 mg TPTCl/kg b.w. and day either in utero and during lactation (gestation day 6 until weaning on PND 21) or from gestation day 6 until termination. As previously reported, offspring in the 6 mg TPTCl dose group exhibited high perinatal mortality and therefore no further evaluation was carried out at this dose level (Grote, K., Hobler, C, Andrade, A.J.M., Wichert Grande, S., Gericke, C., Talsness, C.E., Appel, K.E., Chahoud, I., 2007. Effects of in utero and lactational exposure to triphenyltin chloride on pregnancy outcome and postnatal development in rat offspring. Toxicology 238, 177-185). In the present paper, results on postnatal development obtained from surviving offspring of dams exposed to 2mg TPTCl/kg b.w. are reported. Male offspring were sacrificed on PND 64 or 65 and female offspring at first estrus after PND 58. A clear sex difference in response to treatment was observed. Male postnatal development was severely affected with decreases in body weight gain, reproductive organ weights and testosterone concentration as well as a significant delay in the age at preputial separation. In contrast, females exhibited a precocious completion of vaginal opening while all other endpoints were unaffected. Most of these effects were already present in animals that were only exposed until weaning indicating that these effects may be irreversible and continued treatment until termination had contributed less than expected to the severity of the observed effects. The results of the present study suggest that the sensitive window for the evaluated endpoints seems to be the period of prenatal development and that male offspring rats were more susceptible to treatment.

Lack of effects of tomato products on endothelial function in human subjects: results of a randomised, placebo-controlled cross-over study.

Epidemiological studies suggest that consumption of tomato products reduces the risk of CVD via antioxidant, hypocholesterolaemic and anti-inflammatory mechanisms. Although experimental data also describe beneficial effects on endothelial function, clinical data in human subjects are lacking. To test the hypothesis that tomato ingestion ameliorates endothelial function, we randomised healthy non-smoking postmenopausal women to consume a buttered roll with and without tomato purée (70 g) in a cross-over design. Endothelial-dependent flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation of the brachial artery were assessed with high-resolution ultrasound (13 MHz linear array transducer). Acute (24 h) and long-term (7 d) effects were examined after daily consumption of the described meal. Nineteen volunteers completed the protocol and provided technically suitable ultrasound measurement data. Plasma lycopene levels increased from 0·30 (sem 0·04) (baseline) to 0·42 (sem 0·04) and to 0·74 (sem 0·06) μm after 24 h and 7 d, respectively, with tomato purée consumption. These data indicated an effective absorption of the tomato product. However, both acute and long-term tomato purée consumption had no effects on endothelium-dependent or -independent dilation of the brachial artery. In addition, we found no correlation between lycopene plasma levels and FMD. In conclusion, consumption of tomato products associated with a significant increase in plasma lycopene levels had no effects on endothelial function in healthy postmenopausal women.

Smoking decreases the level of circulating CD34+ progenitor cells in young healthy women - a pilot study

BackgroundDecreased levels of circulating bone marrow-derived progenitor cells have been associated with risk factors and cardiovascular diseases. Smoking is the most important modifiable risk factor for atherosclerosis in young women. The aim of this pilot study was to assess in healthy premenopausal women without other risk factors for cardiovascular disease the influence of nicotine abuse on the number of circulating progenitor cells in relation to endothelial function.MethodsThe number of endothelial progenitor cells, measured as colony-forming units in a cell-culture assay (EPC-CFU) and the number of circulating CD34 + and CD34 + /CD133 + cells, measured by flow cytometry, was estimated in 32 women at the menstrual phase of the menstrual cycle. In addition, flow-mediated dilation (FMD) was assessed as a marker for vascular function. In a subgroup of these women (n = 20), progenitor cells were also investigated at the mid-follicular and luteal phases of the menstrual cycle.ResultsCompared to non-smokers, the abundance of circulating CD34 + cells was significantly lower in smoking women in the menstrual, mid-luteal, and mid-follicular phases of the menstrual cycle. The number of CD34 + progenitor cells was revealed to have significant positive correlation with FMD in young healthy women, whereas CD34 + /CD133 + progenitor cells and EPC-CFU showed no significant correlation.ConclusionThe number of CD34 + progenitor cells positively correlates with FMD in young healthy women and is decreased by smoking.

Epoxiconazole causes changes in testicular histology and sperm production in the Japanese quail (Coturnix coturnix japonica)

The fungicide epoxiconazole (Epox), a triazole, belongs to the group of azole compounds that are extensively used as fungicides in various fruit crops. The frequent use of agricultural lands for wintering by migrating birds can be the source of their increased dietary intake of agricultural pesticides. We investigated whether exposure to Epox causes effects on avian fertility and reproduction, using the Japanese quail (Coturnix coturnix japonica) as a model species for the assessment of reproductive effects of pesticides in wild birds. Epox was administered to adult Japanese quail for three weeks at dietary levels of 10, 50, and 500 ppm, and possible effects on reproduction were investigated. Epox administration resulted in a significantly decreased number of spermatids in the 50- and 500-ppm dose groups. Histopathology showed a reduced number of testicular canaliculi with visible germ cells and a reduction in spermatid number. However, testis weight was not affected up to the highest dose level. No impact was observed on hormone levels, fertility, and reproductive outcome, as laying rate and percentage of fertile eggs were not altered. Likewise, treatment had no influence on the egg or chick parameters evaluated. A time- and dose-related transfer of Epox into the eggs was determined in all treatment groups. We conclude that dietary treatment of Japanese quail with 50 and 500 ppm of the triazole fungicide Epox resulted in a clear impact on the testis. The evaluation of the additional endpoints spermatid count and testicular histology have proven useful and are recommended for future studies on avian reproduction.

Sex-dependent aromatase activity in rat offspring after pre- and postnatal exposure to triphenyltin chloride

Triphenyltin (TPT) is an organotin compound (OTC) previously widely used as an antifouling agent in paints applied in the marine environment, a fungicide, and as an agricultural pesticide. In female aquatic invertebrates, certain OTCs induce the so-called imposex, an abnormal induction of male sex characteristics. OTC-induced environmental endocrine disruption also occurs in fish and mammals and a number of in vivo and in vitro studies have argued that OTCs may act through inhibition of the aromatase enzyme. In vivo studies supporting the aromatase inhibition hypothesis in mammals are lacking. Recently, the causal relationship between inhibition of aromatase and imposex was questioned, suggesting aromatase independent mechanisms of action for this phenomenon. We conducted a comprehensive investigation to identify the most sensitive window of exposure to TPTCl and to examine the effects of pre- and postnatal exposure on postnatal development in rats. The results on brain and gonadal aromatase activity obtained from offspring of dams exposed to 2 mg TPTCl/kg bw are reported here. Female and male offspring rats were exposed to 2 mg TPTCl/kg bw/d in utero from gestation day 6 through lactation until weaning on PND 21, or from gestation day 6 until termination at adulthood. Male offspring were sacrificed from PND 58 and female offspring at first estrus after PND 58. Pre- and postnatal TPT exposure clearly affected brain and gonadal aromatase activity in a sex-dependent fashion. While brain aromatase activity was significantly increased on PND 21 and at adulthood in female offspring, male offspring exhibited a significant decrease in brain aromatase activity only at adulthood. Ovarian aromatase activity was unaffected at both time points investigated. In contrast, testicular aromatase activity was significantly increased in males on PND 21 and significantly decreased at adulthood independent from the duration of treatment. The results of the present study confirm our previously reported observations regarding sex-dependent differences in sexual development after TPT exposure with the male rat being more susceptible to disturbances through this endocrine active compound than the female. We conclude that TPT administered during the particularly vulnerable period of development can affect aromatase activity in rats.

Examination of Japanese quail chicks in one-generation feeding studies for effects of the agrochemicals dimethoate, fentin hydroxide, and vinclozolin on skeletal development

An established method for evaluation of skeletal anomalies was successfully adapted to Japanese quail (Coturnix coturnix japonica) and performed on 793 untreated 1-day old chicks to develop an historical control database. Incomplete ossification of the pelvic bones and irregular position of the toes were rather frequently observed. Subsequently, 702 chicks from the treatment groups in three one-generation reproduction studies with the pesticides dimethoate, triphenyltin (fentin) hydroxide, and vinclozolin were compared to their respective controls and the whole historical database. Presumed treatment-related effects were confined to a higher number of chicks with incomplete ossification of vertebrae and pelvis when the hens had been administered fentin hydroxide at a dietary level of 30 ppm for up to 6 weeks, corresponding to a mean daily substance intake of 3.1-3.9 mg kg−1 body weight (bw). Thus, inclusion of teratological findings as a further endpoint confirmed the previously established NOAEL of 3 ppm (equal to 0.28-0.35 mg kg−1 bw/day) based on reproductive effects in this study. No effects on skeletal development were seen with dimethoate and vinclozolin up to the highest dietary concentrations of 70 and 500 ppm, corresponding to estimated mean daily intakes of about 8 or 56 mg kg−1 bw. The suitability of the method for reliable detection of skeletal anomalies was proven. The established method can be considered useful in providing additional information for ecotoxicological risk assessment.