Effects of Chronic Pelvic Pain on Heart Rate Variability in Women.

PURPOSE: Interstitial cystitis/bladder pain syndrome and myofascial pelvic pain are frequently comorbid chronic pelvic pain disorders. Differences in bladder function between interstitial cystitis/bladder pain syndrome and myofascial pelvic pain suggest that efferent autonomic function may differentiate these syndromes. Heart rate variability, defined as the difference in duration of successive heartbeats, serves as an index of autonomic function by measuring its ability to modify heart rate in response to neurophysiological changes. High frequency heart rate variability was used as a reflection of more rapid vagally mediated (parasympathetic) changes. Low frequency heart rate variability signified slower fluctuations related to the baroreflex and sympathetic outflow. MATERIALS AND METHODS: Heart rate variability was derived by autoregressive frequency analysis of the continuous electrocardiogram recording of heart rate with the subject supine for 10 minutes, tilted 70 degrees with the head up for 30 minutes and supine again for 10 minutes. This institutional review board approved study included 105 female subjects, including 32 who were healthy, and 26 with interstitial cystitis/bladder pain syndrome, 12 with myofascial pelvic pain and 35 with interstitial cystitis/bladder pain syndrome plus myofascial pelvic pain. RESULTS: In all positions healthy controls had higher high frequency heart rate variability than women with interstitial cystitis/bladder pain syndrome and interstitial cystitis/bladder pain syndrome plus myofascial pelvic pain. Subjects with myofascial pelvic pain were similar to controls with greater high frequency heart rate variability at baseline (supine 1) and in upright positions than subjects with interstitial cystitis/bladder pain syndrome. Differences in low frequency heart rate variability were less evident while low-to-high frequency ratio differences appeared to be driven by the high frequency heart rate variability component. CONCLUSIONS: Subjects with interstitial cystitis/bladder pain syndrome had diminished vagal activity and a shift toward sympathetic nervous system dominance. Overall these data support the hypothesis that changes in autonomic function occur in interstitial cystitis/bladder pain syndrome but not in myofascial pelvic pain. These changes may result from interstitial cystitis/bladder pain syndrome or contribute to its pathophysiology through abnormal self-regulatory function.

Autonomic testing of women with interstitial cystitis/bladder pain syndrome.

PURPOSE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is characterized by urinary urgency, frequency, nocturia, pain worse as the bladder fills and improved after emptying. These features might suggest abnormal autonomic bladder control mechanisms. We compared the structural integrity of the autonomic nervous system (ANS) in IC/BPS and control subjects. METHODS: IRB-approved study at University Hospitals Case Medical Center, Cleveland, OH to evaluate the structural integrity of the ANS in adult females. Testing included cardiovascular response to deep breathing, Valsalva maneuver, 30 min head up tilt, and sudomotor test. RESULTS: Differences in ANS integrity for IC/BPS subjects and controls were determined by modified Composite Autonomic Severity Score (CASS) that includes sudomotor, adrenergic and cardiovascular indices. Baseline heart rate (HR) and HRs from each of three 10 min upright segments of a tilt test were compared and trend analyses performed using t tests. Healthy and IC/BPS subjects were demographically similar. The two groups did not differ in modified-CASS scores but elevated average peak heart rate was evident during baseline (supine; p = 0.057) for IC/BPS subjects prior to a tilt test. Difference at baseline was maintained at each interval during the tilt, with nearly identical slopes across intervals. The preliminary nature of this report denotes a small sample size and important differences may not be detected. CONCLUSIONS: The findings show no structural ANS abnormalities in IC/BPS subjects. Higher baseline HR supports the concept of functional rather than structural change in the ANS, such as abnormality of sympathetic/parasympathetic balance that will require further evaluation.

Intraosseous injection of RM1 murine prostate cancer cells promotes rapid osteolysis and periosteal bone deposition.

The molecular mechanisms associated with prostate cancer (PCa) progression within bone remain a topic of intense investigation. With the availability of transgenic mouse strains, a model of PCa for use in immune competent/transgenic mice would be highly beneficial. This study was designed to explore the utility of RM1 mouse PCa cells in investigations of tumor:bone interactions. The efficacies of several implantation techniques were examined for reliably producing intra-bone RM1 tumor growth and bone lesion formation in immune competent mice. Longitudinal monitoring of bone remodeling and lesion phenotypes was conducted by microcomputed tomography (muCT) and histological analyses. Our results indicate that direct intrabone injections of RM1 cells are necessary for tumor growth within bone and direct implantation promotes the rapid development of osteolytic bone lesions with periosteal bone deposition post-cortical breach. In vitro, RM1 cells promote the proliferation of osteoblast (MC3T3-E1) and osteoclast (Raw264.7) progenitors in a dose dependent manner. Conditioned culture media from RM1 cells appears to promote earlier expression of genes/proteins associated with osteoblastic differentiation. While clearly stimulating osteoclast function in vivo, RM1 cells had little effect on differentiation and tartate resistant acid phosphatase (TRAP) expression by Raw264.7 cells. These data, coupled with in vivo muCT images, indicate the ability of RM1 cells to induce mixed, yet predominentally osteolytic, responses in bone and illustrate the potential of RM1 cells as a model of investigating prostate tumor:stroma interactions in immune competent/transgenic mice on a C57BL/6 background.

In vivo and in vitro effect of baicalein on human prostate cancer cells.

We investigated the in vitro effects of baicalein and baicalin on human umbilical vein endothelial cells (HUVECs) and on human prostate tumor cells (DU-145 and PC3) as well as the effect of orally administered baicalein on the growth of DU-145 cells after subcutaneous injection into SCID mice. In vitro effects of baicalein and baicalin treatment on human prostate cancer cell lines DU-145 and PC-3 were assessed by employing cell proliferation (MTS) assay, cytotoxicity (LIVE/DEAD) assay, and TUNEL assay. In vitro anti-proliferative and anti-angiogenic properties of baicalein and baicalin were studied on HUVECs by sprout assay. The effect of orally administered baicalein on tumor growth in SCID mice was studied in four groups (n=10) of animals injected subcutaneously with DU-145 cells and treated daily for 28 days. The control group received only vehicle (carboxymethylcellulose), whereas the other three groups received escalating doses of baicalein (10, 20, and 40 mg/kg per day). Baicalein and baicalin exhibit dose-dependent growth inhibitory effects on human prostate cancer cells and umbilical vein endothelial cells in vitro. Also, treatment by these two flavonoid compounds significantly decreased the average number and length of sprouts formed by the endothelial cell aggregates in a dose-dependent manner. In vivo, treatment of mice with baicalein demonstrated a statistically significant tumor volume reduction (p<0.01) when compared to the control. This is the first study demonstrating an in vivo growth inhibitory effect of orally administered baicalein on human prostate tumors in mice.

Structure of curcumin in complex with lipoxygenase and its significance in cancer.

Scientific research provides documented evidence that fatty acid metabolites have profound impact on carcinogenesis. Intervention into dioxygenase pathways might therefore effect development, metastasis and progression of many types of cancers. This work delivers the first 3D structural data and explains how curcumin interacts with the fatty acid metabolizing enzyme, soybean lipoxygenase. Curcumin binds to lipoxygenase in a non-competitive manner. Trapped in that complex, it undergoes photodegradation in the X-rays, but utilizes enzyme catalytic ability to form the peroxy complex Enz-Fe-O-O-R as 4-hydroperoxy-2-methoxy-phenol, that later transforms into 2-methoxycyclohexa-2,5-diene-1,4-dione. Our observations about this radiation and time-dependent inhibition add new information to the role that curcumin might play in cancer prevention and treatment.

Interstitial Cystitis - Elucidation of Psychophysiologic and Autonomic Characteristics (the ICEPAC Study): design and methods.

BACKGROUND AND PURPOSE: Interstitial cystitis/bladder pain syndrome (IC/BPS) is relatively common and associated with severe pain, yet effective treatment remains elusive. Research typically emphasized the bladder's role, but given the high presence of systemic comorbidities, the authors hypothesized a pathophysiologic nervous system role. This paper reports the methodology and approach to study the nervous system in women with IC/BPS. The study compares neurologic, urologic, gynecologic, autonomic, gastrointestinal, and psychological features of women with IC/BPS, their female relatives, women with myofascial pelvic pain (MPP), and healthy controls to elucidate the role of central and peripheral processing. METHODS AND RESULTS: In total, 228 women (76 IC/BPS, 76 MPP, 38 family members, and 38 healthy controls) will be recruited. Subjects undergo detailed screening, structured neurologic examination of limbs and pelvis, tender point examination, autonomic testing, electrogastrography, and assessment of comorbid functional dysautonomias. Interpreters are blinded to subject classification. Psychological and stress response characteristics are examined with assessments of stress, trauma history, general psychological function, and stress response quantification. As of December 2012, data collection is completed for 25 healthy controls, 33 IC/BPS ± MPP, eight MPP, and three family members. Recruitment rate is accelerating and strategies emphasize maintaining and encouraging investigator participation in study science, internet advertising, and presentations to pelvic pain support groups. CONCLUSION: The study represents a comprehensive, interdisciplinary approach to sampling autonomic and psychophysiologic characteristics of women with IC/BPS. Despite divergent opinions on study methodologies based on specialty experiences, the study has proven feasible to date and different perspectives have proved to be one of the greatest study strengths.

Augmented osteolysis in SPARC-deficient mice with bone-residing prostate cancer.

Prostate cancer preferentially metastasizes to bone, which is rich in structural and matricellular proteins capable of altering prostate cancer progression. This study explores the role of the bone stromal matricellular protein SPARC (osteonectin/BM-40) in the progression of bone metastatic prostate cancer. Quantification of bone destruction analyzed by micro-computed tomography showed augmented osteoclastic resorption, characterized by decreases in several morphometric bone parameters in SPARC knock out (KO) tibiae harboring RM1 murine prostate cancer cells compared with wild type (WT) animals. Tumor progression stimulated osteoclast formation, which was augmented in SPARC KO mice. In vitro differentiation of SPARC KO osteoclasts indicated accelerated progenitor expansion and formation of tartrate-resistant acid phosphatase-positive osteoclast-like cells with increased resorptive capacity, a mechanism resulting in enhanced tumor-induced bone loss in vivo. Whereas altered bone structure due to SPARC KO played a role in increased osteolysis, the enhanced osteolysis was primarily the result of increased resorption by SPARC KO osteoclasts. Our findings indicate that bone stromal SPARC suppresses tumor-induced bone lesion expansion by limiting osteoclast maturation and function.

The angiogenic response is dictated by beta3 integrin on bone marrow-derived cells.

Angiogenesis is dependent on the coordinated action of numerous cell types. A key adhesion molecule expressed by these cells is the alpha(v)beta(3) integrin. Here, we show that although this receptor is present on most vascular and blood cells, the key regulatory function in tumor and wound angiogenesis is performed by beta(3) integrin on bone marrow-derived cells (BMDCs) recruited to sites of neovascularization. Using knockin mice expressing functionally stunted beta(3) integrin, we show that bone marrow transplantation rescues impaired angiogenesis in these mice by normalizing BMDC recruitment. We demonstrate that alpha(v)beta(3) integrin enhances BMDC recruitment and retention at angiogenic sites by mediating cellular adhesion and transmigration of BMDCs through the endothelial monolayer but not their release from the bone niche. Thus, beta(3) integrin has the potential to control processes such as tumor growth and wound healing by regulating BMDC recruitment to sites undergoing pathological and adaptive angiogenesis.

Vascular endothelial growth factor production in human prostate cancer cells is stimulated by overexpression of platelet 12-lipoxygenase.

BACKGROUND: Elevated platelet 12-Lipoxygenase (P12-LOX) expression is associated with advanced stage and grade prostate cancer and overexpression in PC-3 cells promotes tumor growth and angiogenesis. The mechanisms underlying the role of P12-LOX in angiogenesis remain unclear. METHODS: Enzyme linked immunosorbent assays were used to measure 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE) and vascular endothelial growth factor (VEGF) in conditioned media of PC-3 cells stably overexpressing human P12-LOX. Immunoblotting was used to observe stimulation of signal transduction in prostate cancer cell lines following exposure to 12(S)-HETE. RESULTS: P12-LOX overexpression promotes increased accumulation of 12(S)-HETE and VEGF in culture media leading to constitutive ERK1/2 phosphorylation. 12(S)-HETE stimulates ERK1/2 phosphorylation via a pertussis toxin sensitive G-protein coupled receptor (GPCR) and MEK; the inhibition of which reduces VEGF accumulation by 36% and 70%, respectively. CONCLUSIONS: Our data provide insight into a possible mechanism by which prostate cancer cells with elevated expression of P12-LOX stimulate VEGF production, thus increasing their angiogenic potential.