Administration of leuprolide acetate, a GnRH agonist, improves urodynamic parameters in ovariectomized rats.

AIM: To evaluate the effects of a treatment with leuprolide acetate (LA) on bladder overactivity as well as the expression of gonadotropin releasing hormone receptor (GnRH-R), and neurofilaments NF68 and NF200 in female rats with overactive bladder induced by castration. METHODS: Changes in the urodynamic parameters were determined in SHAM, ovariectomized (OVX) and ovariectomized rats treated with LA (OVX-LA). A semi-quantitative analysis for the expression pattern of GnRH-R and neurofilaments NF68 and NF200 were determined. RESULTS: Forty-three days after ovariectomy, rats from the OVX group have significant lower values for intercontractile interval (ICI) and compliance (C); as well as higher values for basal bladder pressure (BP) and frequency of non-voiding contractions (NVC). The systemic application of LA increased voiding volume (Vv) and pressure threshold (ThP) in the OVX-LA animals. The application of LA reduced the high frequency of NVC in the OVX rats. No significant differences were found for Vv and NVCs between the OVX-LA vs SHAM groups. At the mid part of the bladder, the presence of GnRH-R was evidenced in the urothelium of the SHAM group. The OVX animals showed different pattern of immunolabeling for GnRH-R as well as for neurofilaments NF200 and NF68, whereas in the OVX-LA group the immunofluorescence pattern was similar to the one seen in SHAM bladders (P < 0.05 for OVX vs OVX + LA). CONCLUSIONS: the results suggest that systemic application of LA can improve bladder dysfunction in castrated rats, and perhaps considered as a treatment for overactive bladder conditions secondary to menopause.

The effect of mirtazapine on gastric accommodation, gastric sensitivity to distention, and nutrient tolerance in healthy subjects.

BACKGROUND: Disturbances of gastric motor function of functional dyspepsia (FD) have been implicated in the pathogenesis of the symptoms, and hence, motility modifying agents are considered for its treatment. Mirtazapine was recently shown to improve symptoms and increase nutrient tolerance in FD patients with weight loss. We aim to evaluate the effect of mirtazapine on gastric sensorimotor function in healthy volunteers (HV). METHODS: Thirty-one HV underwent an intragastric pressure (IGP) and barostat measurements on separate days before and after 3 weeks of placebo or mirtazapine (15 mg). Gastric compliance, sensitivity and accommodation (GA) measured by the barostat. GA was quantitated as the difference (delta) in intra-balloon volume before and after ingestion of 200 mL of a nutrient drink (ND). GA measured by IGP was quantitated as the drop of IGP from baseline during the intragastric infusion of ND until maximal satiation. KEY RESULTS: Mirtazapine significantly increased the bodyweight of subjects (67.8±3.7 to 69.1±3.7 kg; P=.01). Barostat results showed no effect on gastric compliance, sensitivity, and GA. Nutrient tolerance was not affected after treatment (1170±129.4 vs 1104±133.6 kcal; P=.4), and mirtazapine was associated with lower symptom ratings. The IGP drop during meal ingestion was significantly suppressed (area under the curve: -43.3±4.5 mm Hg vs -28.9±3.1 mm Hg; P=.005). CONCLUSIONS & INFERENCES: In HVs, the occurrence of weight gain and decreased meal-induced symptoms in spite of a suppressed meal-induced IGP drop, point towards a central mode of action. Mirtazapine does not display changes in gastric sensorimotor function that could explain its beneficial effects on symptoms and nutrient tolerance in FD.

Norepinephrine reduces arterial compliance less than phenylephrine when treating general anesthesia-induced arterial hypotension.

INTRODUCTION: During general anesthesia, arterial hypotension is frequent and may be an important contributor to perioperative morbidity. We assessed the effect of a 5 µg bolus of Norepinephrine (NA) when compared with 50 µg bolus of Phenylephrine (PE) administered to treat hypotension during maintenance anesthesia, on MAP, derived cardiac output and arterial stiffness parameters. METHODS: Patients scheduled for a neurosurgical procedure under general anesthesia were prospectively included. Monitoring included invasive blood pressure, esophageal Doppler, and arterial tonometer used to estimate central aortic pressure with arterial stiffness parameters, such as augmentation index (Aix). After initial resuscitation, hypotensive episodes were corrected by a bolus administration of NA or PE in a peripheral venous line. RESULTS: There were 269 bolus administrations of vasopressors (149 NA, 120 PE) in 47 patients with no adverse effects detected. A decrease in stroke volume (SV) was observed with PE compared with NA (-18 ± 9% vs. -14 ± 7%, P < 0.001). This decrease was associated with an increase in Aix, which was greater for PE than for NA (+10 ± 8% vs. +6 ± 6%, P < 0.0001), and a decrease in total arterial compliance greater for PE compared to NA (Ctot = SV/Central Pulse Pressure) (-35 ± 9% vs. -29 ± 10%, P < 0.001). DISCUSSION: This study suggests that 5 µg of NA administered as a bolus in a peripheral venous line could treat general anesthesia-induced arterial hypotension with a smaller decrease in SV and arterial compliance when compared to PE.

Prophylactic and therapeutic treatment with the flavonone sakuranetin ameliorates LPS-induced acute lung injury.

Sakuranetin is the main isolate flavonoid from Baccharis retusa (Asteraceae) leaves and exhibits anti-inflammatory and antioxidative activities. Acute respiratory distress syndrome is an acute failure of the respiratory system for which effective treatment is urgently necessary. This study investigated the preventive and therapeutic effects of sakuranetin on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. Animals were treated with intranasal sakuranetin 30 min before or 6 h after instillation of LPS. Twenty-four hours after ALI was induced, lung function, inflammation, macrophages population markers, collagen fiber deposition, the extent of oxidative stress, and the expression of matrix metalloprotease-9 (MMP-9), tissue inhibitor of MMP-9 (TIMP-1) and NF-κB were evaluated. The animals began to show lung alterations 6 h after LPS instillation, and these changes persisted until 24 h after LPS administration. Preventive and therapeutic treatment with sakuranetin reduced the neutrophils in the peripheral blood and in the bronchial alveolar lavage. Sakuranetin treatment also reduced macrophage populations, particularly that of M1-like macrophages. In addition, sakurnaetin treatment reduced keratinocyte-derived chemokines (IL-8 homolog) and NF-κB levels, collagen fiber formation, MMM-9 and TIMP-1-positive cells, and oxidative stress in lung tissues compared with LPS animals treated with vehicle. Finally, sakuranetin treatment also reduced total protein, and the levels of TNF-α and IL-1ß in the lung. This study shows that sakuranetin prevented and reduced pulmonary inflammation induced by LPS. Because sakuranetin modulates oxidative stress, the NF-κB pathway, and lung function, it may constitute a novel therapeutic candidate to prevent and treat ALI.

Does serelaxin treatment alter passive mechanical wall properties in small resistance arteries?

The peptide hormone relaxin is recognized for its connective tissue remodeling actions in the reproductive tract during pregnancy and parturition, but it also has vascular remodeling actions independent of pregnancy. Recombinant human relaxin (serelaxin) treatment in male and non-pregnant female rodents enhances passive arterial compliance in the renal vasculature. This review focuses on serelaxin's actions on passive mechanical wall properties in small arteries and highlights the diversity of responses to serelaxin treatment in rodents. Different experimental approaches (duration of serelaxin treatment, rat strain, age) and animal models of disease (obesity, hypertension) will be considered. Most studies in young rodents demonstrate that serelaxin treatment fails to alter passive compliance in resistance-size arteries (mesenteric and femoral arteries and cerebral parenchymal arterioles), suggesting that serelaxin's beneficial effects are minimal in healthy animals. Short-term serelaxin treatment (5d) in aged, obese, and spontaneously hypertensive rats (SHRs) is largely without effect on passive mechanical wall properties. However, a longer duration of serelaxin treatment in SHRs (14d) enhances passive compliance in large muscular arteries as well as resistance-size arteries. In conclusion, serelaxin is capable of vascular remodeling. Its actions are vascular bed-dependent, more prominent in disease, and likely requires a longer duration of treatment to be effective.

Short-Term Effects of Relamorelin on Descending Colon Motility in Chronic Constipation: A Randomized, Controlled Trial.

BACKGROUND: The pentapeptide ghrelin agonist, relamorelin, accelerates colonic transit in patients with chronic constipation (CC). In a murine model, relamorelin decreased excitability of colonic circular smooth muscle cells and colonic intraluminal pressure. AIM: To determine short-term effects of relamorelin on colonic motility measured by barostat and multilumen manometry in CC. METHODS: In a placebo-controlled, single-dose, double-blind, randomized study in patients with CC, we investigated the motor effects of relamorelin, 100 µg, SQ (12 patients) compared to placebo SQ (six patients). A motility-barostat balloon assembly was used to measure colonic compliance; tone and phasic pressure activity were measured before and after a 1000-kcal milkshake meal (administered ~60 min post-medication). Overall "background" phasic pressure activity was assessed by: average amplitude and motility index (MI = ln[sum amplitudes × #contractions + 1]) over defined periods. High-amplitude propagating contractions (HAPCs) were characterized by amplitude >75 mmHg and propagating contractions >50 mmHg; both were propagated over at least 10 cm. Postprandial HAPCs were the primary end point. The study sample had 80% power to detect an increase of 3.3 HAPCs in the hour post-meal. RESULTS: Relamorelin, 100 µg, significantly induced more pre-meal propagated contractions [PCs of either >50 or >75 mmHg] compared to placebo (p < 0.05). Relamorelin also induced more post-meal PCs >50 or >75 mmHg than placebo. Relamorelin did not significantly alter colonic compliance, fasting or postprandial phasic pressure activity (20 min pre-meal fasting MI) or tone, and 60 min postprandial phasic pressure amplitude or MI, or tone. CONCLUSIONS: Relamorelin stimulates propagated colonic contractions without alteration of background irregular contractions in CC. ClinicalTrial.Gov registration number: NCT 01781104.

Video-urodynamic effects of mirabegron, a ß3 -adrenoceptor agonist, in patients with low-compliance bladder.

OBJECTIVES: To investigate video-urodynamic effects of mirabegron, a ß3 -adrenoceptor agonist, on low-compliance bladder. METHODS: We retrospectively reviewed nine patients (three men, six women, age 17-68 years) who had been diagnosed with lower urinary tract dysfunction with low-compliance bladder, and who underwent video-urodynamic study before and during administration of mirabegron 50 mg once daily. Urodynamic parameters were compared before and after treatment. RESULTS: Mirabegron treatment significantly increased first desire to void and cystometric capacity with an average increment of 80 mL (P = 0.027) and 123 mL (P = 0.005), respectively. Bladder compliance also significantly increased (mean value 8.1 mL/cmH2 O before, 18.2 mL/cmH2 O after, P = 0.024). In the six patients who had been taking anticholinergic agents at baseline video-urodynamic study and then switched to mirabegron, mean cystometric capacity and bladder compliance were also increased significantly from 208.3 to 346.8 mL (P = 0.015) and from 7.2 to 17.5 mL/cmH2 O (P = 0.047), respectively. Vesicoureteral reflux grade was improved in three of the four patients who had shown vesicoureteral reflux on cystography before treatment. CONCLUSIONS: Mirabegron improves cystometric capacity and bladder compliance, and it lowers vesicoureteral reflux grade in patients with low-compliance bladder. Thus, mirabegron might represent a good alternative drug for low-compliance bladder refractory to anticholinergic treatment.

Opposing effects of oxytocin on overt compliance and lasting changes to memory.

From infancy we learn to comply with societal norms. However, overt compliance is not necessarily accompanied by a change in internal beliefs. The neuromodulatory processes underlying these different phenomena are not yet understood. Here, we test the role of oxytocin in controlling overt compliance versus internalization of information delivered by a social source. After intranasal oxytocin administration, participants showed enhanced compliance to the erroneous opinion of others. However, this expression was coupled with a decrease in the influence of others on long-term memories. Our data suggest that this dissociation may result from reduced conflict in the face of social pressure, which increases immediate conforming behavior, but reduces processing required for deep encoding. These findings reveal a neurobiological control system that oppositely affects internalization and overt compliance.

Left ventricular diastolic dysfunction and myocardial stiffness in diabetic mice is attenuated by inhibition of dipeptidyl peptidase 4.

AIMS: Obesity and Type 2 diabetes mellitus (DM) induce left ventricular (LV) diastolic dysfunction, which contributes to an increasing prevalence of heart failure with a preserved LV ejection fraction. We investigated the effects of sitagliptin (SITA), an inhibitor of dipeptidylpeptidase-4 (DPP-4) and anti-diabetic drug, on LV structure and function of obese mice with Type 2 DM. METHODS AND RESULTS: Obese Type 2 diabetic mice (Lepr(db/db), BKS.Cg-Dock7(m)+/+ Lepr(db)/J), displaying increased cardiomyocyte and LV stiffness at the age of 16 weeks, were treated with SITA (300 mg/kg/day) or vehicle for 8 weeks. SITA severely impaired serum DPP-4 activity, but had no effect on glycaemia. Invasive haemodynamic recordings showed that SITA reduced LV passive stiffness and increased LV stroke volume; LV end-systolic elastance remained unchanged. In addition, SITA reduced resting tension of isolated single cardiomyocytes and intensified phosphorylation of the sarcomeric protein titin. SITA also increased LV concentrations of cGMP and increased activity of protein kinase G (PKG). In vitro activation of PKG decreased resting tension of cardiomyocytes from vehicle-treated mice, but had no effect on resting tension of cardiomyocytes from SITA-treated mice. CONCLUSIONS: In obese Type 2 diabetic mice, in the absence of hypoglycaemic effects, inhibition of DPP-4 decreases LV passive stiffness and improves global LV performance. These effects seem at least partially mediated by stimulatory effects on the myocardial cGMP-PKG pathway and, hence, on the phosphorylation status of titin and the hereto coupled cardiomyocyte stiffness modulus.

Lipoic acid, but not tempol, preserves vascular compliance and decreases medial calcification in a model of elastocalcinosis.

Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.

Endothelial function, arterial wall mechanics and intima media thickness in juvenile idiopathic arthritis.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory disease of children which might persist into adulthood. Systemic inflammation seen in adult RA patients has been shown to be associated with alteration in endothelial function, arterial wall mechanics and intima media thickness. Our study was planned to assess similar changes in JIA patients. METHODS: Thirty-one newly diagnosed JIA patients and a similar number of age- and sex-matched controls were enrolled in the study. Endothelial function was assessed by measuring flow mediated dilation and glyceryl trinitrate (GTN)-mediated dilation of the brachial artery. To assess arterial stiffness, various arterial wall mechanic parameters such as cross-sectional compliance, cross-sectional distensibility, shear stress and elastic modulus were derived. Intima media thickness of the common carotid artery was measured as a marker of subclinical atherosclerosis. RESULTS: The brachial artery diameter at rest was found to be slightly lower in the patients than controls (0.258 ± 0.042 vs. 0.264 ± 0.039; p=0.54). No significant difference was found in flow mediated dilation (17.71 ± 9.26 vs. 16.31 ± 8.23; p=0.53), GTN mediated dilation (25.25 ± 10.02 vs. 23.66 ± 9.79; p=0.53) or FMD: GTN mediated dilation ratio (0.730 ± 0.432 vs. 0.717 ± 0.280; p=0.89) between the cases and controls. There was also no significant difference in carotid artery intima media thickness (0.065 ± 0.0068 vs. 0.068 ± 0.007; p=0.084) between cases and controls. Cases in different subsets of JIA were also analysed separately with regards to FMD, GTN mediated dilation and cIMT but no difference was found between cases in each subset and their controls. Cross-sectional compliance was significantly lower in cases than controls (0.0016 ± 0.0005 vs. 0.002 ± 0.001; p=0.034). Cross-sectional distensibility (0.009 ± 0.003 vs. 0.011 ± 0.006; p=0.14) was also found to be lower whereas diastolic wall shear stress (299.9 ± 47.08 vs. 294.9 ± 59.5; p=0.72) and elastic modulus (1138.5 ± 1085.8 vs. 911 ± 453; p=0.19) were found to be higher in cases as compared to controls. But these differences were not statistically significant. When the subsets were analysed separately for vessel wall indices, cross-sectional compliance was found to be significantly lower in systemic arthritis patients as compared to controls. A high level of intra- and inter-observer agreement was found for all the ultrasonographically evaluated parameters. CONCLUSIONS: Arterial wall indices were found altered in JIA patients indicating increased arterial stiffness. Larger studies are required to assess endothelial dysfunction, intima media thickness and arterial stiffness in each subset of JIA patients.

Lipoic acid, but not tempol, preserves vascular compliance and decreases medial calcification in a model of elastocalcinosis

Vascular calcification decreases compliance and increases morbidity. Mechanisms of this process are unclear. The role of oxidative stress and effects of antioxidants have been poorly explored. We investigated effects of the antioxidants lipoic acid (LA) and tempol in a model of atherosclerosis associated with elastocalcinosis. Male New Zealand white rabbits (2.5-3.0 kg) were fed regular chow (controls) or a 0.5% cholesterol (chol) diet+104 IU/day vitamin D2 (vitD) for 12 weeks, and assigned to treatment with water (vehicle, n=20), 0.12 mmol·kg-1·day-1 LA (n=11) or 0.1 mmol·kg-1·day-1 tempol (n=15). Chol+vitD-fed rabbits developed atherosclerotic plaques associated with expansive remodeling, elastic fiber disruption, medial calcification, and increased aortic stiffness. Histologically, LA prevented medial calcification by ∼60% and aortic stiffening by ∼60%. LA also preserved responsiveness to constrictor agents, while intima-media thickening was increased. In contrast to LA, tempol was associated with increased plaque collagen content, medial calcification and aortic stiffness, and produced differential changes in vasoactive responses in the chol+vitD group. Both LA and tempol prevented superoxide signals with chol+vitD. However, only LA prevented hydrogen peroxide-related signals with chol+vitD, while tempol enhanced them. These data suggest that LA, opposite to tempol, can minimize calcification and compliance loss in elastocalcionosis by inhibition of hydrogen peroxide generation.

Safety and efficacy of tolcapone in the long-term use in Parkinson disease: an observational study.

OBJECTIVES: The aim of this observational study was to investigate the safety and efficacy of tolcapone under practice conditions. METHODS: This 12-month non-interventional study was conducted from November 2005 to August 2009. Safety parameters were incidence of adverse drug reactions (ADRs), signs and symptoms of liver failure, and liver monitoring. Efficacy was evaluated on the basis of the assessment by physicians and patients by means of the clinical global impression scale. RESULTS: Data from 391 patients were available for evaluation. Fifty-six ADRs were documented in 45 patients: most frequently, increase in liver enzymes (5.6%), diarrhea (2.6%), and nausea (1.3%). No serious ADRs or fulminant hepatotoxicity occurred. Sixteen patients discontinued the treatment with tolcapone because of adverse events, thereof 7 because of increase in liver enzymes, as prespecified in the protocol. Sixty-two elevations of aspartate aminotransferase or alanine aminotransferase occurred in 34 patients (8.7%), most of them within the first 3 months after initiating tolcapone. Five patients (1.3%) experienced clinically relevant elevations (>2xULN). In most patients with minimally elevated transaminase levels, tolcapone was continued, leading to normalization of transaminase levels in 74% of these patients. Two patients died but without causal relationship to tolcapone. The physicians reported improvement of clinical global impression for 71.7% of the patients after 3 months and for 59.1% of the patients after 12 months. CONCLUSIONS: Under routine practice conditions, tolcapone was shown to be safe and effective in patients with Parkinson disease. Significant liver transaminase elevations were rare and generally returned to normal without intervention in most patients. This study confirms the low risk for hepatotoxicity associated with tolcapone.

Biocompatible tissue scaffold compliance promotes salivary gland morphogenesis and differentiation.

Substrate compliance is reported to alter cell phenotype, but little is known about the effects of compliance on cell development within the context of a complex tissue. In this study, we used 0.48 and 19.66 kPa polyacrylamide gels to test the effects of the substrate modulus on submandibular salivary gland development in culture and found a significant decrease in branching morphogenesis in explants grown on the stiff 19.66 kPa gels relative to those grown on the more physiologically compliant 0.48 kPa gels. While proliferation and apoptosis were not affected by the substrate modulus, tissue architecture and epithelial acinar cell differentiation were profoundly perturbed by aberrant, high stiffness. The glands cultured on 0.48 kPa gels were similar to developing glands in morphology and expression of the differentiation markers smooth muscle alpha-actin (SM α-actin) in developing myoepithelial cells and aquaporin 5 (AQP5) in proacinar cells. At 19.66 kPa, however, tissue morphology and the expression and distribution of SM α-actin and AQP5 were disrupted. Significantly, aberrant gland development at 19.66 kPa could be rescued by both mechanical and chemical stimuli. Transfer of glands from 19.66 to 0.48 kPa gels resulted in substantial recovery of acinar structure and differentiation, and addition of exogenous transforming growth factor beta 1 at 19.66 kPa resulted in a partial rescue of morphology and differentiation within the proacinar buds. These results indicate that environmental compliance is critical for organogenesis, and suggest that both mechanical and chemical stimuli can be exploited to promote organ development in the contexts of tissue engineering and organ regeneration.

Effects of mosapride on esophageal motor activity and esophagogastric junction compliance in healthy volunteers.

BACKGROUND: The effects of the prokinetic drug mosapride on esophageal motor activity vary at standard doses. In addition to esophageal motor activities, compliance of the esophagogastric junction (EGJ) is important for prevention of gastroesophageal reflux. However, the effects of mosapride on EGJ compliance have not been reported. Here, we investigated the effects of high-dose mosapride on esophageal motor activities and EGJ compliance. METHODS: Nine healthy volunteers were enrolled in the study. Peristaltic esophageal contraction and lower esophageal sphincter pressures before and after administration of 40 mg mosapride were examined by high resolution esophageal manometry. Esophageal compliance was also investigated by intra-esophageal impedance planimetry (EndoFLIP(®)). RESULTS: High-dose mosapride augmented peristaltic contractions, especially in the distal esophageal segments (P < 0.05). The mean resting lower esophageal sphincter pressure was elevated from 25.0 mmHg before administration to 28.9 mmHg after (P < 0.05). In addition, mosapride significantly reduced EGJ compliance (P < 0.05). CONCLUSIONS: Mosapride at 40 mg augmented esophageal motor activities and reduced EGJ compliance in healthy volunteers.

Oxidative stress contributes to large elastic arterial stiffening across the stages of the menopausal transition.

OBJECTIVE: It is unclear how changes in ovarian hormones during the menopausal transition contribute to age-associated arterial stiffening. We sought to evaluate differences in arterial stiffness and the role of oxidative stress across the stages of the menopausal transition in healthy women. METHODS: Arterial stiffness (carotid artery compliance and ultrasound) was measured during immediate infusions of saline (control) and ascorbic acid (experimental model to immediately decrease oxidative stress) in 97 healthy women (22-70 y) classified as premenopausal (n = 24; mean [SD] age, 33 [7] y), early perimenopausal (n = 21; 49 [3] y) or late perimenopausal (n = 21; 50 [4] y), or postmenopausal (n = 31; 57 [5] y). RESULTS: Basal carotid artery compliance was different among the groups (P < 0.001). Mean [SD] compliance was highest in premenopausal women (1.31 [0.25] mm/mm Hg × 10), with progressive decrements in perimenopausal (early perimenopausal, 0.98 [0.31] mm/mm Hg × 10; late perimenopausal, 0.90 [0.25] mm/mm Hg × 10) and postmenopausal (0.75 [0.24] mm/mm Hg × 10) women. Ascorbic acid infusion improved compliance in late perimenopausal (15% [18%] increase, P = 0.001) and postmenopausal (17% [26%] increase, P = 0.002) women but not in early perimenopausal or premenopausal women. CONCLUSIONS: Arterial stiffening worsens across the stages of the menopausal transition in healthy women. This seems to be mediated, in part, by oxidative stress, particularly during the late perimenopausal and postmenopausal periods. It remains uncertain whether this is specifically caused by loss of ovarian function or aging.

Enhancing medical compliance of patients with convulsive epilepsy in rural community: a randomized intervention trial.

PURPOSE: This randomized intervention trial was to determine whether the implementation of a practical intervention was effective in enhancing medical compliance and improving seizure control among patients with convulsive epilepsy in rural communities in western China. METHODS: Two of four areas were randomly selected for this study and assigned to be the intervention group (IG) and the control group (CG), respectively. An intervention package with four components (intensive education, consultation services, maintenance of an epilepsy tracking card, and repeated reminders) was formulated. Medical compliance included antiepileptic drug (AED) adherence and lifestyle; each was graded on a 6-point scale with possible scores. Medical compliance and seizure control were measured and compared between the groups before and after the intervention. In addition, correlation of both changes in medical compliance and seizure frequency were investigated. KEY FINDINGS: After 1-year follow-up, 183 patients in the IG (105 male) and 177 in the CG (99 male) remained for the analysis. At the end of the study, the average number of seizures in the IG declined 18.3% compared to that prior to the intervention (after 6-month phenobarbital monotherapy), nearly twice as much as in CG (9.1%) with statistical difference (p = 0.023). The proportion of patients with a reduction in seizures >50% (including those who were seizure-free) rose to 79.8% in the IG compared to 61.0% in the CG (p < 0.05). With regard to medical compliance, the majority of the IG members were rated as excellent or very good, but medical compliance remained nearly unchanged for the CG. A moderate correlation was found between the changes in AED adherence and seizure control (r = 0.4, p < 0.05), and a weaker correlation was found between lifestyle and seizure control (r = 0.328, p < 0.05). SIGNIFICANCE: This intervention package proved to be efficient in enhancing medical compliance and improving seizure control in rural communities of resource-poor areas.

Effects of isoflurane anesthesia on aortic compliance and systemic hemodynamics in compliant and noncompliant aortas.

OBJECTIVES: To investigate the effect of general anesthesia on aortic compliance and other cardiovascular hemodynamics in chronically instrumented pigs with compliant and noncompliant (stiff) aortas. DESIGN: Experimental study. SETTING: University animal laboratory. PARTICIPANTS: Twelve adult Yucatan miniature pigs. INTERVENTIONS: Chronic instrumentation of a compliant (control; n = 7) and noncompliant (n = 5) group to measure pressure and flow in the ascending aorta. A Teflon prosthesis was wrapped around the aorta (noncompliant group) to limit wall compliance. MEASUREMENTS AND MAIN RESULTS: Hemodynamic parameters were recorded on the 15th postoperative day, both awake and after general anesthesia. Banding the aorta caused a significant decrease in arterial compliance (-49%, p<0.001) and increases in systolic blood pressure (SBP: +38%, p = 0.001) and pulse pressure (+107%, p< 0.01). Induction of anesthesia in the control group produced a 15% increase in arterial compliance (p<0.05), resulting in a subtle decrease in SBP (-12%), diastolic blood pressure (DBP; -13%) and mean blood pressure (MBP; -12%). Induction of anesthesia in the noncompliant group also caused a significant increase in arterial compliance (17%, p<0.001), but caused significant decreases in SBP (21%, p<0.01), DBP (23%, p<0.01) and MBP (22%, p<0.01) as compared with controls. CONCLUSIONS: Induction of general anesthesia caused a similar increase in total arterial compliance and was associated with a decrease in SBP that was more pronounced in animals with noncompliant aortas. These results indicated that anesthesia caused a greater hemodynamic effect on noncompliant (stiff) aortas and may explain the extensive hemodynamic fluctuation and instability often observed in atherosclerotic, elderly patients with stiff aortas.

Mechanical compliance and immunological compatibility of fixative-free decellularized/cryopreserved human pericardium.

BACKGROUND: The pericardial tissue is commonly used to produce bio-prosthetic cardiac valves and patches in cardiac surgery. The procedures adopted to prepare this tissue consist in treatment with aldehydes, which do not prevent post-graft tissue calcification due to incomplete xeno-antigens removal. The adoption of fixative-free decellularization protocols has been therefore suggested to overcome this limitation. Although promising, the decellularized pericardium has not yet used in clinics, due to the absence of proofs indicating that the decellularization and cryopreservation procedures can effectively preserve the mechanical properties and the immunologic compatibility of the tissue. PRINCIPAL FINDINGS: The aim of the present work was to validate a procedure to prepare decellularized/cryopreserved human pericardium which may be implemented into cardiovascular homograft tissue Banks. The method employed to decellularize the tissue completely removed the cells without affecting ECM structure; furthermore, uniaxial tensile loading tests revealed an equivalent resistance of the decellularized tissue to strain, before and after the cryopreservation, in comparison with the fresh tissue. Finally, immunological compatibility, showed a minimized host immune cells invasion and low levels of systemic inflammation, as assessed by tissue transplantation into immune-competent mice. CONCLUSIONS: Our results indicate, for the first time, that fixative-free decellularized pericardium from cadaveric tissue donors can be banked according to Tissue Repository-approved procedures without compromising its mechanical properties and immunological tolerance. This tissue can be therefore treated as a safe homograft for cardiac surgery.

Effects of solifenacin in patients with neurogenic detrusor overactivity as a result of spinal cord lesion.

STUDY DESIGN: Retrospective analysis. OBJECTIVES: To investigate the urodynamic effects of solifenacin treatment for neurogenic detrusor overactivity (NDO) in patients with spinal cord injury (SCI). SETTING: Paraplegic center in Switzerland. METHODS: Retrospective analysis of case histories and urodynamic data of 35 SCI patients receiving solifenacin for treatment of NDO between 2008 and 2012. Patients were categorized as being at risk of renal damage when maximum detrusor pressure was >40 cm H2O or detrusor compliance was <20 ml cm(-1) H2O. RESULTS: Solifenacin treatment was initiated 7.3 years after SCI. Most patients (63%) had already been taking other antimuscarinic drugs. After 13.1 months (median, interquartile range 6.1-19.5 months), solifenacin treatment had resulted in significant (P<0.03) improvements in bladder capacity (median +30.0 ml), maximum detrusor pressure (median -7.0 cm H2O), reflex volume (median +62.5 ml) and detrusor compliance (median +25.0 ml cm(-1) H2O). Furthermore, fewer patients presented with a risk of renal damage. However, this difference was not significant (P>0.1). The number of patients suffering from incontinence had not changed significantly. Eight and two patients discontinued solifenacin treatment as a result of insufficient efficacy and intolerable adverse events, respectively. One patient had discontinued solifenacin treatment without further explanation. CONCLUSION: Solifenacin treatment significantly improved bladder capacity, detrusor compliance, reflex volume and maximum detrusor pressure. Solifenacin treatment seems to be an effective oral treatment of NDO after SCI.