On the complex relationship between resilience and hair cortisol levels in adolescence despite parental physical abuse: a fourth wave of resilience research.

Introduction: To understand the family's role in adolescents' mental health development and the connection to neurodevelopmental disorders related to experienced parental physical abuse, we first explored resilience pathways longitudinally and secondly, connected the identified patterns to adolescents' hair cortisol levels that are rooted in the hypothalamic-pituitary-adrenal axis as the main stress response system and connected brain structure alterations. Methods: We analyzed longitudinal online questionnaire data for three consecutive high school years (from seventh to ninth grade) and four survey waves from a representative sample of n = 1609 high school students in Switzerland on violence-resilience pathways. Furthermore, we collected students' hair samples from a subsample of n = 229 at survey wave 4. About 30% of the participating adolescents had been physically abused by their parents. Out of the overall sample, we drew a subsample of adolescents with parental abuse experiences (survey wave 1 n = 509; survey wave 2 n = 506; survey wave 3 n = 561; survey wave 4 n = 560). Results: Despite the odds, about 20-30% of adolescents who have experienced parental physical abuse escaped the family violence cycle and can be called resilient. By applying a person-oriented analytical approach via latent class and transition analysis, we longitudinally identified and compared four distinct violence-resilience patterns. We identified violence resilience as a multidimensional latent construct, which includes hedonic and eudaimonic protective and risk indicators. Because resilience should not solely be operationalized based on the lack of psychopathology, our latent construct included both feeling good (hedonic indicators such as high levels of self-esteem and low levels of depression/anxiety and dissociation) and doing well (eudaimonic indicators such as high levels of self-determination and self-efficacy as well as low levels of aggression toward peers). Discussion: The present study confirmed that higher cortisol levels significantly relate to the comorbid pattern (internalizing and externalizing symptoms), and further confirmed the presence of lasting alterations in brain structures. In this way, we corroborated the insight that when studying the resilience pathways and trajectories of abused adolescents, biological markers such as hair cortisol significantly enhance and deepen the understanding of the longitudinal mechanisms of psychological markers (e.g., self-determination, self-esteem, self-efficacy) that are commonly applied in questionnaires.

Integrating ayurvedic medicine into cancer research programs part 2: Ayurvedic herbs and research opportunities.

The aim of this two-part review in this issue is to provide some basic perspectives from Ayurveda, the traditional medicine of India, and to discuss how current research methodologies may be used to shed light on mechanisms of Ayurvedic treatments to support cancer care and prevention. It addresses some of the challenges for scientific validation of Ayurvedic herbal compounds, protocols, and modalities in four areas. Part 1 [1] has reviewed Ayurvedic theories and applications of body constitution (Prakriti), digestion (Agni and Ama) and mind-body-spirit health in relation to cancer. Here in Part 2, the focus is on preclinical and clinical research of Ayurvedic botanical herbs, with a review of pertinent literature on three selected herbs, Curcumin, Ashwagandha, and Triphala. A discussion of the challenges and possibilities of research in Ayurveda is offered to guide the development of translational research programs. Ayurvedic modalities are not intended as a substitute for allopathic treatments of cancer but as an integrative component for prevention and restoration of strength and immunity.

Integrating ayurvedic medicine into cancer research programs part 1: Ayurveda background and applications.

Integration of Ayurveda into our current health care research programs is critical to making progress in global wellness and in disease prevention and control, especially for cancer. Ayurveda promotes restoration of the innate healing mechanisms existing in the body for optimal immunity, resilience, and health. Ayurveda also has an abundant resource of botanical products containing diverse pharmaco-active ingredients and millennia of experience of clinical applications for health benefits. But there is a lack of evidence-based research to demonstrate its efficacy and potential. This 2-part review is written from the perspective of a western-trained biomedical scientist and student of Ayurveda. It aims to educate research scientist peers about the opportunities and challenges for scientific validation of Ayurvedic herbal compounds, protocols, and modalities and inspire more research in this area. Part 1 will review several aspects of Ayurveda including principles of body constitution (Prakriti), digestion (Agni and Ama) and mind-body health, in relation to cancer. Part 2 [1] will focus on Ayurvedic botanical resources used for cancer and research studies will be discussed on selected herbal compounds. Research gaps and opportunities will be identified to guide development of research programs to validate safety and efficacy of these therapies. Importantly, the use of Ayurvedic modalities is not intended to substitute for allopathic treatments for cancer but as an integrative component for prevention and restoration of strength and immunity post treatment.

Focal Segmental Glomerulosclerosis Complicating Therapy With Inotersen, an Antisense Oligonucleotide Inhibitor: A Case Report.

Inotersen is an antisense oligonucleotide inhibitor licensed for the treatment of polyneuropathy complicating hereditary transthyretin amyloidosis (ATTRv). Nephrotoxicity has been reported with inotersen, including progression to kidney failure. We describe what is to our knowledge the first reported case of inotersen-associated nephrotic syndrome secondary to focal segmental glomerulosclerosis (FSGS) and review the literature concerning inotersen-induced nephrotoxicity. We report a woman in her early 30s with ATTRv associated with the V50M transthyretin (TTR) variant, who presented with nephrotic syndrome 7 months after commencement of inotersen. Renal histology demonstrated FSGS and scanty glomerular amyloid deposition. Discontinuation of inotersen alone resulted in complete clinical and biochemical resolution of nephrotic syndrome. Inotersen is associated with significant nephrotoxicity. In the phase 3 NEURO-TTR clinical trial, 3% of patients in the treatment arm developed a crescentic glomerulonephritis. All affected patients carried the V50M TTR variant, which is known to be associated with renal amyloid deposition. This case adds to the spectrum of kidney disease associated with inotersen and indicates that discontinuation of the drug alone may result in resolution of renal complications without additional immunosuppression. Monitoring of kidney function is essential in patients with ATTRv receiving inotersen, particularly if there is evidence of existing renal amyloid.

Motor, sensitive, and vegetative recovery in rats with compressive spinal-cord injury after combined treatment with erythropoietin and whole-body vibration.

BACKGROUND: Physical therapy with whole body vibration (WBV) following compressive spinal cord injury (SCI) in rats restores density of perisomatic synapses, improves body weight support and leads to a better bladder function. The purpose of the study was to determine whether the combined treatment with WBV plus erythropoietin (EPO) would further improve motor, sensory and vegetative functions after SCI in rats. METHODS: Severe compressive SCI at low thoracic level was followed by a single i.p. injection of 2,5µg (250 IU) human recombinant EPO. Physical therapy with WBV started on 14th day after injury and continued over a 12-week post injury period. Locomotor recovery, sensitivity tests and urinary bladder scores were analysed at 1, 3, 6, 9, and 12 weeks after SCI. The closing morphological measurements included lesion volume and numbers of axons in the preserved perilesional neural tissue bridges (PNTB). RESULTS: Assessment of motor performance sensitivity and bladder function revealed no significant effects of EPO when compared to the control treatments. EPO treatment neither reduced the lesion volume, nor increased the number of axons in PNTB. CONCLUSIONS: The combination of WBV + EPO exerts no positive effects on hind limbs motor performance and bladder function after compressive SCI in rats.

The effect of admission and pre-admission serum creatinine as baseline to assess incidence and outcomes of acute kidney injury in acute medical admissions.

BACKGROUND: Acute kidney injury (AKI) in hospital-admitted patients is a common complication associated with increased mortality. The diagnosis of AKI relies on the ascertainment of peak increase in serum creatinine (SCr). This study evaluated the incidence of AKI using the increase from mean 7-365 days pre-admission (AKIpre) and admission (AKIadm) SCr levels, and examined the associations of AKI and changes in SCr levels with all-cause mortality. METHODS: A total of 2436 patients admitted to a tertiary hospital were recruited and followed-up for a median of 47.70 (interquartile range 18.20) months. AKI incidence and severity were defined according to the Kidney Disease: Improving Global Outcomes-AKI Guidelines. Follow-up data were collected from the Hospital Episode Statistics and Office of National Statistics. Mortality was evaluated during a short- (30 days), mid- (1 year) and long-term (4 years) period. RESULTS: No difference in the AKI rates using AKIpre and AKIadm (12.5% versus 12.2%; P = 0.695) or in the AKI severity (P = 0.261) was evident. Agreement between the two definitions was modest (Kappa-statistic = 0.596, P < 0.001). Patients with AKIpre or AKIadm had increased all-cause mortality compared with those without AKI during all follow-up periods. In fully adjusted regression analysis, AKIpre [hazard ratio (HR) = 2.226, 95% confidence interval (CI) 1.140-4.347; P = 0.027] and AKIadm (HR = 2.105, 95% CI 1.090-4.064; P = 0.027) remained associated with 30-day mortality. Results for the 1- and 4-year periods were similar. Increases of >4.00 µmol/L and >6.06% from pre-admission or >6.00 µmol/L and >17.24% from admission SCr levels presented increased mortality risk during follow-up. CONCLUSIONS: Use of admission or pre-admission SCr provides similar incidence rates, but they diagnose different sets of patients. Even minor increases in SCr, below those required for the classification of AKI, were associated with increased mortality. These findings can help the clinicians to identify patients at higher risk for adverse outcomes.

Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis.

BACKGROUND: The survival rate is poor in breast cancer patients with brain metastases. Thus, new concepts for therapeutic approaches are required. During metastasis, the cytoskeleton of cancer cells is highly dynamic and therefore cytoskeleton-associated proteins are interesting targets for tumour therapy. METHODS: Screening for genes showing a significant correlation with brain metastasis formation was performed based on microarray data from breast cancer patients with long-term follow up information. Validation of the most interesting target was performed by MTT-, Scratch- and Transwell-assay. In addition, intracellular trafficking was analyzed by live-cell imaging for secretory vesicles, early endosomes and multiple vesicular bodies (MVB) generating extracellular vesicles (EVs). EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), Western blotting, mass spectrometry, and ingenuity pathway analysis (IPA). Effect of EVs on the blood-brain-barrier (BBB) was examined by incubating endothelial cells of the BBB (hCMEC/D3) with EVs, and permeability as well as adhesion of breast cancer cells were analyzed. Clinical data of a breast cancer cohort was evaluated by χ2-tests, Kaplan-Meier-Analysis, and log-rank tests while for experimental data Student's T-test was performed. RESULTS: Among those genes exhibiting a significant association with cerebral metastasis development, the only gene coding for a cytoskeleton-associated protein was Tubulin Tyrosine Ligase Like 4 (TTLL4). Overexpression of TTLL4 (TTLL4plus) in MDA-MB231 and MDA-MB468 breast cancer cells (TTLL4plus cells) significantly increased polyglutamylation of ß-tubulin. Moreover, trafficking of secretory vesicles and MVBs was increased in TTLL4plus cells. EVs derived from TTLL4plus cells promote adhesion of MDA-MB231 and MDA-MB468 cells to hCMEC/D3 cells and increase permeability of hCMEC/D3 cell layer. CONCLUSIONS: These data suggest that TTLL4-mediated microtubule polyglutamylation alters exosome homeostasis by regulating trafficking of MVBs. The TTLL4plus-derived EVs may provide a pre-metastatic niche for breast cancer cells by manipulating endothelial cells of the BBB.

Acute kidney injury calculated using admission serum creatinine underestimates 30-day and 1-year mortality after acute stroke.

BACKGROUND: Acute kidney injury (AKI) diagnosis requires ascertainment of change from a known baseline. Although pre-admission serum creatinine (SCr) is recommended, to date, all studies of AKI in acute stroke have used the first SCr on admission. METHODS: All patients admitted with an acute stroke to an emergency hospital were recruited. We compared use of pre-admission SCr with admission SCr to diagnose AKI. Regression analyses were used to identify risk factors for 30-day and 1-year mortality, respectively. RESULTS: A total of 1354 patients were recruited from December 2012 to September 2015. Incidence of AKI was 18.7 and 19.9% using pre-admission SCr and admission SCr, respectively. Diagnosis of AKI was associated with significantly increased 30-day and 1-year mortality. Diagnosis of AKI using pre-admission SCr had a stronger relationship with both 30-day and 1-year mortality. In 443 patients with a pre-admission SCr and at least two SCr during admission, AKI diagnosed using pre-admission SCr had a stronger relationship than AKI diagnosed using admission SCr with 30-day mortality [odds ratio (OR) = 2.64; 95% confidence interval (CI) 1.36-5.12; P = 0.004 versus OR = 2.10; 95% CI 1.09-4.03; P = 0.026] and 1-year mortality [hazard ratio (HR) = 1.90, 95% CI 1.32-2.76; P = 0.001 versus HR = 1.47; 95% CI 1.01-2.15; P = 0.046] in fully adjusted models. CONCLUSIONS: AKI after stroke is common and is associated with increased 30-day and 1-year mortality. Using first SCr on admission gives a comparable AKI incidence to pre-admission SCr, but underestimates 30-day and 1-year mortality risk.

The Role of Lineage Plasticity in Prostate Cancer Therapy Resistance.

Lineage plasticity has emerged as an important mechanism of treatment resistance in prostate cancer. Treatment-refractory prostate cancers are increasingly associated with loss of luminal prostate markers, and in many cases induction of developmental programs, stem cell-like phenotypes, and neuroendocrine/neuronal features. Clinically, lineage plasticity may manifest as low PSA progression, resistance to androgen receptor (AR) pathway inhibitors, and sometimes small cell/neuroendocrine pathologic features observed on metastatic biopsy. This mechanism is not restricted to prostate cancer as other malignancies also demonstrate lineage plasticity during resistance to targeted therapies. At present, there is no established therapeutic approach for patients with advanced prostate cancer developing lineage plasticity or small cell neuroendocrine prostate cancer (NEPC) due to knowledge gaps in the underlying biology. Few clinical trials address questions in this space, and the outlook for patients remains poor. To move forward, urgently needed are: (i) a fundamental understanding of how lineage plasticity occurs and how it can best be defined; (ii) the temporal contribution and cooperation of emerging drivers; (iii) preclinical models that recapitulate biology of the disease and the recognized phenotypes; (iv) identification of therapeutic targets; and (v) novel trial designs dedicated to the entity as it is defined. This Perspective represents a consensus arising from the NCI Workshop on Lineage Plasticity and Androgen Receptor-Independent Prostate Cancer. We focus on the critical questions underlying lineage plasticity and AR-independent prostate cancer, outline knowledge and resource gaps, and identify strategies to facilitate future collaborative clinical translational and basic studies in this space.

Incidence and impact on outcomes of acute kidney injury after a stroke: a systematic review and meta-analysis.

BACKGROUND: Patients with chronic kidney disease have worse outcomes after stroke. However, the burden of acute kidney injury after stroke has not been extensively investigated. METHODS: We used MEDLINE and Embase to conduct a systematic review and meta-analysis of published studies that provided data on the risk of AKI and outcomes in adults after ischemic and hemorrhagic stroke. Pooled incidence was examined using the Stuart-Ord method in a DerSimonian-Laird model. Pooled Odds Ratios and 95% confidence intervals were calculated for outcomes using a random effects model. This review was registered with PROSPERO (CRD42017064588). RESULTS: Eight studies were included, five from the United States, representing 99.9% of included patients. Three studies used established acute kidney injury criteria based on creatinine values to define acute kidney injury and five used International Classification of Diseases coding definitions. Overall pooled incidence was 9.61% (95% confidence interval 8.33-10.98). Incidence for studies using creatinine definitions was 19.51% (95% confidence interval 12.75-27.32%) and for studies using coding definitions 4.63% (95% confidence interval 3.65-5.72%). Heterogeneity was high throughout. Mortality in stroke patients who sustained acute kidney injury was increased (Odds Ratio 2.45; 95% confidence interval 1.47-4.10). Three studies reported risk factors for acute kidney injury. There was sparse information on other outcomes. CONCLUSIONS: Mortality in stroke patients who develop acute kidney injury is significantly increased. However the reported incidence of AKI after stroke varies widely and is underestimated using coding definitions. Larger international studies are required to identify potentially preventable factors to reduce acute kidney injury after stroke and improve outcomes.

Fractures in Kidney Transplant Recipients: A Comparative Study Between England and New York State.

OBJECTIVES: Fractures are associated with high morbidity and are a major concern for kidney transplant recipients. No comparative analysis has yet been conducted between countries in the contemporary era to inform future international prevention trials. MATERIALS AND METHODS: Data were obtained from the Hospital Episode Statistics and the Statewide Planning and Research Cooperative databases on all adult kidney transplants performed in England and New York State from 2003 to 2013, respectively, and on posttransplant fracture-related hospitalization from 2003 to 2014. RESULTS: Our analysis included 18 493 English and 11 602 New York State kidney transplant recipients. Overall, 637 English recipients (3.4%) and 398 New York State recipients (3.4%) sustained a fracture, giving an unadjusted event rate of 7.0 and 5.9 per 1000 years, respectively (P = .948). Of these, 147 English (0.8%) and 101 New York State recipients (0.9%) sustained a hip fracture, giving an unadjusted event rate of 1.6 and 1.5 per 1000 years, respectively (P = .480). There were no differences in the cumulative incidence of all fractures or hip fractures. One-year mortality rates after any fracture (9% and 11%) or after a hip fracture (15% and 17%) were not different between cohorts. CONCLUSIONS: Contemporaneous English and New York State kidney transplant recipients have similar fracture rates and mortality rates postfracture.

Modulation of stroke risk in chronic kidney disease.

Stroke is the second most common cause of death and the leading cause of neurological disability worldwide, with huge economic costs and tragic human consequences. Both chronic kidney disease (CKD) and end-stage kidney disease are associated with a significantly increased risk of stroke. However, to date this has generated far less interest compared with the better-recognized links between cardiac and renal disease. Common risk factors for stroke, such as hypertension, hypercholesterolaemia, smoking and atrial fibrillation, are shared with the general population but are more prevalent in renal patients. In addition, factors unique to these patients, such as disorders of mineral and bone metabolism, anaemia and its treatments as well as the process of dialysis itself, are all also postulated to further increase the risk of stroke. In the general population, advances in medical therapies mean that effective primary and secondary prevention therapies are available for many patients. The development of specialist stroke clinics and acute stroke units has also improved outcomes after a stroke. Emerging therapies such as thrombolysis and thrombectomy are showing increasingly beneficial results. However, patients with CKD and on dialysis have different risk profiles that must be taken into account when considering the potential benefits and risks of these treatments. Unfortunately, these patients are either not recruited or formally excluded from major clinical trials. There is still much work to be done to harness effective stroke treatments with an acceptable safety profile for patients with CKD and those on dialysis.

Fracture risk and mortality post-kidney transplantation.

BACKGROUND: Fractures are associated with high morbidity and economic costs. There is a paucity of information on fractures after kidney transplantation outside the United States. METHODS: Data were obtained from the Hospital Episode Statistics database on kidney transplants performed in England between 2001 and 2013 and post-transplant fracture-related hospitalization. Mortality data were obtained from the Office for National Statistics. RESULTS: In total, 21 769 first kidney transplant procedures were analyzed with 112 512 patient-years follow-up. Overall, 836 (3.8%) kidney allograft recipients developed a fracture requiring hospitalization. Event rate was 9.99 for any fracture and 1.54 for a hip fracture per 1000 patient-years. Accounting for the competing risk of mortality, increasing age, female gender, white ethnicity, and a history of pre-transplant diabetes mellitus or previous fracture were associated with increased fracture risk post-kidney transplantation. Death occurred in 2407 (11.1%) kidney allograft recipients, with 173 deaths occurring post-fracture. In an extended Cox model, hip fracture as a time-varying factor was independently associated with an increased risk of death (hazard ratio, 3.288; 95% confidence intervals, 2.513-4.301; p < 0.001). CONCLUSIONS: Fracture rates in English kidney transplant recipients are lower than previously reported in US cohorts. Sustaining a hip fracture is associated with an increased mortality risk. Our results can be used to power future fracture prevention trials.

Acute Care QUAliTy in chronic Kidney disease (ACQUATIK): a prospective cohort study exploring outcomes of patients with chronic kidney disease.

INTRODUCTION: Chronic kidney disease (CKD) is common and carries a high risk of morbidity, including hospital admissions and readmissions and mortality. This is largely attributed to an increased risk of cardiovascular disease. Patients with CKD are less likely to receive evidence-based treatments for cardiovascular disease. However, these treatments are based on trials which generally exclude patients with CKD. It is therefore unclear whether this patient group derives the same benefits without an increased risk of adverse effects. METHODS AND ANALYSIS: The Acute Care QUAliTy in chronic Kidney disease (ACQUATIK) study is a prospective, observational, multicentre cohort study. Over 4000 patients will be recruited with an enrolment period of 2 years and a follow-up period of 2-4 years. Patients under follow-up by a renal team will be excluded. Data will be obtained from patient and hospital records during the index admission. Preadmission data will be extracted from general practice records based on the Quality and Outcomes Framework. Diagnosis, comorbidities and procedure data pertaining to the index and subsequent admissions will be extracted from the Hospital Episode Statistics database and long-term mortality data will be tracked using the Office of National Statistics. This information will allow us to examine a complete patient journey through primary and secondary care, providing unequalled levels of information on treatment and outcomes of patients with CKD. The combined data set will be used to compare outcomes and treatments among patients with CKD versus patients without CKD. The primary end point is hospital readmission rates. The relationship between age, sex, ethnicity, socioeconomic status and concurrent comorbidities will be analysed to determine their influence on outcomes and treatments. ETHICS AND DISSEMINATION: The ACQUATIK study has been approved by the NRES Committee West Midlands-South Birmingham-Reference 13/WM/0317. The results from ACQUATIK will be submitted for publication in peer-reviewed journals and presented at primary and secondary care conferences. TRIAL REGISTRATION NUMBER: ISRCTN37237454.

Cardiovascular actions of mineralocorticoid receptor antagonists in patients with chronic kidney disease: A systematic review and meta-analysis of randomized trials.

INTRODUCTION: The safety and actions of mineralocorticoid receptor antagonists on surrogate markers of cardiovascular disease as well as major patient level cardiovascular end-points in patients with chronic kidney disease are unclear. METHODS: MEDLINE, EMBASE, Trip Database, Cochrane Central Register of Controlled Trials, Cochrane Renal Group specialized register, Current Controlled Trials and clinicaltrials.gov were searched for relevant trials. RESULTS: Twenty-nine trials (1581 patients) were included. Overall, mineralocorticoid receptor antagonists lowered both systolic and diastolic blood pressure (-5.24, 95% confidence interval (CI) -8.65, -1.82 mmHg; p=0.003 and -1.96, 95% CI -3.22, -0.69 mmHg; p=0.002 respectively). There were insufficient data to perform a meta-analysis of other cardiovascular effects. However, a systematic review of the studies included suggested a consistent improvement in surrogate markers of cardiovascular disease. Overall, the use of mineralocorticoid receptor antagonists was associated with an increased serum potassium (0.23, 95% CI 0.13, 0.33 mmol/l; p<0.0001) and higher risk ratio (1.76, 95% CI 1.20, 2.57; p=0.001) of hyperkalemia. Data on long-term cardiovascular outcomes and mortality were not available in any of the trials. CONCLUSIONS: The long-term effects of mineralocorticoid receptor antagonists on cardiovascular events, mortality and safety need to be established.

TGFß1 alters androgenic metabolites and hydroxysteroid dehydrogenase enzyme expression in human prostate reactive stromal primary cells: Is steroid metabolism altered by prostate reactive stromal microenvironment?

The inflammatory tissue microenvironment can be an active promoter in preneoplastic cancer lesions. Altered steroid hormone metabolism as induced by the inflammatory microenvironment may contribute to epithelial cancer progression. Dehydroepiandrosterone sulfate (DHEAS) is the most abundant endogenous steroid hormone present in human serum and can be metabolized to DHEA, androgens and/or estrogens in peripheral tissues. We have previously reported that TGFß1-induced reactive prostate stromal cells increase DHEA metabolism to active androgens and alter prostate cancer cell gene expression. While much of the focus on mechanisms of prostate cancer and steroid metabolism is in the epithelial cancer cells, this study focuses on TGFß1-induced effects on DHEA metabolic pathways and enzymes in human prostate stromal cells. In DHEA-treated primary prostate stromal cells, TGFß1 produced time- and dose-dependent increases in metabolism of DHEA to androstenedione and testosterone. Also TGFß1-treated prostate stromal cells exhibited changes in the gene expression of enzymes involved in steroid metabolism including up-regulation of 3ß hydroxysteroid dehydrogenase (HSD), and down-regulation of 17ßHSD5, and 17ßHSD2. These studies suggest that reactive prostate stroma and the inflammatory microenvironment may contribute to altered steroid metabolism and increased intratumoral androgens.

Remodeling of estrogen-dependent sympathetic nerve fibers seems to be disturbed in adenomyosis.

OBJECTIVE: To investigate neuronal remodeling processes in the uterine innervation, particularly a remodeling of sympathetic nerve fibers, as well as the role of estrogen in this modulation in adenomyosis. DESIGN: Retrospective case-control study. SETTING: University hospital endometriosis center. PATIENT(S): Forty-two patients with histologically proven adenomyosis and 19 patients without adenomyosis. INTERVENTION(S): Endometrial and myometrial tissue were immunohistochemically analyzed to further characterize the uterine innervation. MAIN OUTCOME MEASURE(S): Immunohistochemical analysis was used to identify PGP 9.5-, substance P-, and tyrosine hydroxylase-positive nerve fibers. The expression of the aromatase cytochrome P450 was evaluated in uterine tissue, and the expression of the estrogen receptor (ER) -α and ERß in uterine nerve fibers was analyzed. RESULT(S): Adenomyotic lesions are not innervated. The density of sympathetic nerve fibers in the myometrium of women with adenomyosis is reduced when compared with the nonadenomyosis group. The aromatase expression in the myometrium of women with adenomyosis was increased when compared with the control group. The ERα/ERß ratio is in trend shifted to the ERα side in the myometrial tyrosine hydroxylase-positive nerve fibers in adenomyosis compared to the controls. CONCLUSION(S): The disruption of the modulation of the uterine sympathetic innervation seems to be an important aspect in the pathogenesis of adenomyosis. Estrogen and its receptors seem to play a crucial role in the depletion of myometrial sympathetic nerve fibers.

Evidence of neurotrophic events due to peritoneal endometriotic lesions.

To investigate the neurotrophic properties of endometriosis, as well as the involvement of neurotrophic factors in the development of chronic pelvic pain in patients with endometriosis, we performed a prospective clinical study. The presence of neurotrophins was investigated in the peritoneal fluid (PF) of patients with peritoneal endometriotic lesions or adenomyosis, as well as from women with non-endometriotic adhesions and from women without endometriosis/adenomyosis/adhesions. The PF from patients with peritoneal endometriotic lesions was divided in three groups: asymptomatic endometriosis, minimal pain and severe pain. PF from patients with adenomyosis or with non-endometriotic adhesions and the control group were divided in patients without pain and with pain. Neurotrophin expression in PF was analyzed using Elisa and the neuronal growth assay with cultured chicken sensory ganglia (dorsal-root-ganglia, DRG) and sympathetic ganglia. PF from women with peritoneal endometriotic lesions overexpress nerve growth factor (NGF) and neurotrophin-3 (NT-3), but not brain derived neurotrophic factor (BDNF), whereas the PF of women with adenomyosis or adhesions seems to express normal amounts of these factors. Neurotrophin expression did not differ among the pain groups. Furthermore, the PF from patients with peritoneal endometriotic lesions induced a strong sensory and a marginal sympathetic neurite outgrowth, while the PF from women with adenomyosis and non-endometriotic adhesions induced an outgrowth similar to the control group. The induced neurite outgrowth could only be inhibited in DRG incubated with peritoneal endometriotic lesions. Interestingly, the outgrowth of sympathetic ganglia was inhibited in all studied groups. The present study suggests that only peritoneal endometriotic lesions lead to an increased release of NGF and NT-3 into the PF and that NGF modulates the nerve fiber growth in endometriosis.

Neuroimmunomodulatory alterations in non-lesional peritoneum close to peritoneal endometriosis.

OBJECTIVES: An imbalance in the ratio of sensory to sympathetic nerve fibre (NF) density in peritoneal endometriotic lesions (pEL) has recently been demonstrated and leads to the assumption that this preponderance of the sensory pro-inflammatory milieu is a major cause of pain in endometriosis. Therefore, the density of sensory and sympathetic NFs was determined in distal unaffected peritoneum of endometriosis patients to be able to detect possible alterations in unaffected peritoneum. METHODS: In serial pEL sections (n = 40), lesional and matching unaffected peritoneum as well as healthy peritoneum (HP) from patients without endometriosis (n = 15) were immunohistochemically analysed to identify protein gene product 9.5-, substance P- and tyrosine hydroxylase-positive NFs (intact, sensory and sympathetic NFs, respectively). In addition, the amount of immune cell infiltrates and the expression of nerve growth factor (NGF) and interleukin (IL)-1ß in nerves of peritoneal endometriotic specimens were compared to those in the HP. RESULTS: The overall NF density in the non-lesional, unaffected peritoneum of endometriosis patients is significantly reduced in comparison to both HP and pEL, while sensory NFs remain the same; the sympathetic NF density is significantly decreased compared to HP, but is still higher than the density close to the pEL. Immune cell infiltrates as well as NGF and IL-1ß expression in nerves is significantly elevated in distal unaffected peritoneum in comparison to HP. CONCLUSION: The altered NF density in the non-lesional, unaffected peritoneum of endometriosis patients suggests new aspects in the understanding of the development of endometriosis and pain management in endometriosis.