Association between metabolic syndrome and pelvic organ prolapse severity.

INTRODUCTION AND HYPOTHESIS: As in the case of cardiovascular and metabolic diseases, the prevalence of pelvic organ prolapse (POP) has been rising with the increasing proportion of elderly women in the population. The purpose of the present cross-sectional study was to evaluate the components of metabolic syndrome (MS) in urogynecological patients with a variable POP severity. METHODS: The MS risk factors (elevated waist circumference, elevated triglycerides, decreased high-density lipoprotein cholesterol, elevated blood pressure, hyperglycemia) were assessed in 100 women who were referred to our urogynecological center with pelvic floor disorders (PFD). POP was evaluated with the Pelvic Organ Prolapse Quantification system (POP-Q). RESULTS: The χ (2) test revealed that the diagnosis of MS and the presence of elevated triglycerides increased with the overall POP-Q stage. The other MS risk factors were not significantly associated with the overall POP-Q stage. MS and elevated triglycerides were predictors of the POP-Q stage ≥III [odds ratio (OR) 3.5, 95 % confidence interval (CI) 1.5-8.2 for MS and OR 3.4, 95 % CI 1.4-8.2 for elevated triglycerides, p < 0.01]. CONCLUSIONS: The diagnosis of MS and the presence of elevated triglycerides may be associated with the severity of POP in urogynecological patients. Longitudinal studies are required to assess whether the MS risk factors might predict the progression of POP and whether elimination of the risk factors might improve the prognosis in POP patients.

Mesh retraction correlates with vaginal pain and overactive bladder symptoms after anterior vaginal mesh repair.

INTRODUCTION AND HYPOTHESIS: The aim of the present study was to determine possible correlations between mesh retraction after anterior vaginal mesh repair and de novo stress urinary incontinence (SUI), overactive bladder (OAB), and vaginal pain symptoms. METHODS: One hundred and three women with symptomatic prolapse of the anterior vaginal wall, stages 3 and 4 based on the Pelvic Organ Prolapse Quantification (POP-Q) system, underwent Prolift anterior™ implantation. At a 6-month follow-up, the patients were interviewed for de novo SUI, OAB, and vaginal pain, and underwent an introital/transvaginal ultrasound examination to measure the mesh length in the midsagittal plane. RESULTS: Mesh retraction was significantly larger in a subgroup of patients (n = 20; 19.4 %) presenting de novo OAB symptoms on the follow-up assessment compared with those without this complication (5.0 cm vs. 4.3 cm; p < 0.05). Mesh retraction was also significantly larger in a subgroup of patients (n = 23; 22.3 %) reporting postoperative vaginal pain compared with the women who did not report any postoperative vaginal pain (5.3 cm vs. 4.2 cm; p < 0.01). A significant correlation was found between mesh retraction and the severity of vaginal pain (R = 0.4, p < 0.01). Mesh retraction did not differ between patients with de novo SUI symptoms and those without this complication. CONCLUSIONS: Mesh retraction assessed on ultrasound examination after anterior vaginal mesh repair may correlate with de novo OAB symptoms and vaginal pain.

Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour recurrence.

BACKGROUND: We reported that Notch-1, a potent breast oncogene, is activated in response to trastuzumab and contributes to trastuzumab resistance in vitro. We sought to determine the preclinical benefit of combining a Notch inhibitor (γ-secretase inhibitor (GSI)) and trastuzumab in both trastuzumab-sensitive and trastuzumab-resistant, ErbB-2-positive, BT474 breast tumours in vivo. We also studied if the combination therapy of lapatinib plus GSI can induce tumour regression of ErbB-2-positive breast cancer. METHODS: We generated orthotopic breast tumour xenografts from trastuzumab- or lapatinib-sensitive and trastuzumab-resistant BT474 cells. We investigated the antitumour activities of two distinct GSIs, LY 411 575 and MRK-003, in vivo. RESULTS: Our findings showed that combining trastuzumab plus a GSI completely prevented (MRK-003 GSI) or significantly reduced (LY 411 575 GSI) breast tumour recurrence post-trastuzumab treatment in sensitive tumours. Moreover, combining lapatinib plus MRK-003 GSI showed significant reduction of tumour growth. Furthermore, a GSI partially reversed trastuzumab resistance in resistant tumours. CONCLUSION: Our data suggest that a combined inhibition of Notch and ErbB-2 signalling pathways could decrease recurrence rates for ErbB-2-positive breast tumours and may be beneficial in the treatment of recurrent trastuzumab-resistant disease.

Taste responses in patients with Parkinson's disease.

OBJECTIVE: Preclinical studies indicate that dopaminergic transmission in the basal ganglia may be involved in processing of both pleasant and unpleasant stimuli. Given this, the aim of the present study was to assess taste responses to sweet, bitter, sour, and salty substances in patients with Parkinson's disease (PD). METHODS: Rated intensity and pleasantness of filter paper discs soaked in sucrose (10-60%), quinine (0.025-0.5%), citric acid (0.25-4.0%), or sodium chloride (1.25-20%) solutions was evaluated in 30 patients with PD and in 33 healthy controls. Paper discs soaked in deionised water served as control stimuli. In addition, reactivity to 100 ml samples of chocolate and vanilla milk was assessed in both groups. Taste detection thresholds were assessed by means of electrogustometry. Sociodemographic and neuropsychiatric data, including cigarette smoking, alcohol consumption, tea and coffee drinking, depressive symptoms, and cognitive functioning were collected. RESULTS: In general, perceived intensity, pleasantness, and identification of the sucrose, quinine, citric acid, or sodium chloride samples did not differ between the PD patients and controls. Intensity ratings of the filter papers soaked in 0.025% quinine were significantly higher in the PD patients compared with the control group. No inter-group differences were found in taste responses to chocolate and vanilla milk. Electrogustometric thresholds were significantly (p = 0.001) more sensitive in the PD patients. CONCLUSIONS: PD is not associated with any major alterations in responses to pleasant or unpleasant taste stimuli. Patients with PD may present enhanced taste acuity in terms of electrogustometric threshold.

Chronic hypertension induced by ouabain but not digoxin in the rat: antihypertensive effect of digoxin and digitoxin.

Elevated circulating levels of an endogenous ouabain (EO) have been associated with essential hypertension. To investigate structure-activity relationships relevant to blood pressure, we infused either ouabain, ouabagenin, digoxin or digitoxin at 30 microg/kg/day in normal Sprague Dawley rats. After five weeks, the ouabain and ouabagenin infused rats were hypertensive, whereas blood pressures declined below their vehicle controls in rats infused with digoxin or digitoxin. In a second study, mean blood pressures were 118.5+/-1.7 mmHg in rats infused with ouabain (15 microg/kg/day) on day 35 vs. 98.3+/-1.8 and 100.3+/-1.1 mmHg in the digoxin (30 microg/kg/day) and vehicle infused groups (both p<0.005 vs. ouabain), respectively. Plasma and kidney levels of ouabain immunoreactivity were increased 4-8 fold in ouabain infused rats while blood pressure and plasma levels of ouabain returned to normal one week following discontinuation of the steroid infusion. In rats with ouabain-dependent hypertension, secondary infusions of digoxin or digitoxin (30 microg/kg/day) normalized blood pressure even though circulating ouabain remained elevated. In digoxin infused rats, neither blood pressure nor kidney digoxin immunoreactivity was raised whereas plasma digoxin was increased. Collectively, the results show that the hemodynamic effects of these sodium pump inhibitors differ dramatically during prolonged administration and that tissue rather than circulating levels of these agents appear to better explain their effects on blood pressure. These studies suggest that sodium pump inhibition is not the exclusive mediator of the hemodynamic effects of these cardiac glycosides and demonstrate the presence of structure-specific mechanisms that regulate their tissue levels and effects on long-term blood pressure.

Ouabain-induced hypertension in the rat: relationships among plasma and tissue ouabain and blood pressure.

OBJECTIVES: To determine the steady-state dose-dependence of blood pressure, plasma and tissue ouabain during continuous infusion of ouabain in the rat, and to evaluate the adrenal dependence and effect of a high salt intake on this form of hypertension. DESIGN AND METHODS: Ouabain was administered, via subcutaneous osmotic pumps, to normal and adrenalectomized male Sprague-Dawley rats for 5 weeks. Blood pressure, plasma renin and aldosterone, and circulating and tissue levels of ouabain were determined. RESULTS: Following a latent period, blood pressures and circulating ouabain were significantly elevated dose-dependently in glycoside-infused rats at 5 weeks. Upon withdrawal of the ouabain infusion, blood pressure and plasma ouabain levels normalized within 1 week. In rats that received 30 micrograms ouabain/kg per day, the circulating, kidney, hypothalamic and anterior pituitary levels of ouabain were increased significantly (by 7-, 15-, 2.8- and 2.1-fold, respectively), whereas the content of other tissues tested was unchanged. Blood pressure and plasma levels of ouabain correlated with hypothalamic and kidney glycoside content in the infused rats. High-performance liquid chromatography of the adrenal, renal, hypothalamic and pituitary extracts showed one major peak of ouabain immunoreactivity, with a retention time equivalent to that of commercial ouabain. Plasma renin activity was normal, whereas aldosterone levels were increased significantly to 2.9- and sevenfold in rats that received 10 and 30 micrograms ouabain/kg per day, respectively. Dietary salt loading suppressed aldosterone and did not exacerbate hypertension. In bilaterally adrenalectomized rats the ambient circulating and kidney levels of ouabain were low and ouabain infusion raised glycoside levels and blood pressure significantly. CONCLUSIONS: Prolonged infusion of ouabain in the normal rat raises the circulating, kidney, hypothalamic and anterior pituitary levels and induces a reversible hypertension with normal plasma renin activity. Although characterized by raised aldosterone levels, the hypertension does not require the adrenal glands and is not salt-sensitive. This model may be useful for exploring novel mechanisms of long-term regulation of blood pressure.

Elevated concentrations of endogenous ouabain in patients with congestive heart failure.

BACKGROUND: An endogenous digitalis-like compound in mammals has long been postulated, but only recently has a substance indistinguishable from ouabain been identified in human plasma. Because of the potential significance of such a substance in patients with congestive heart failure, we sought to evaluate the pathophysiology of endogenous ouabain in these individuals. METHODS AND RESULTS: Using an immunoassay, we determined plasma ouabain concentrations in 51 patients with heart failure and in 19 control subjects. Plasma ouabain concentrations in control subjects ranged from 0.16 to 0.77 nM (mean, 0.44 +/- 0.20 nM). In 19 matched heart failure patients receiving digoxin, the mean ouabain was significantly elevated at 1.59 +/- 2.2 nM (range, 0.17-8.76 nM, p less than 0.05 versus control subjects). The ouabain concentration correlated inversely with both cardiac index (r = -0.62, p less than 0.005) and mean arterial pressure (r = -0.51, p less than 0.05). However, there was no correlation between ouabain and left ventricular filling (r = 0.19, NS) or right atrial pressures (r = 0.20, NS). In 16 heart failure patients not receiving digoxin, the mean ouabain was 1.52 +/- 2.58 nM. No relation between renal function and ouabain was detected. CONCLUSIONS: The unanticipated lack of correlation of ouabain with atrial pressures indicates that volume is not the chief determinant of ouabain concentration in patients with congestive heart failure. However, the significant relations of plasma ouabain concentration with cardiac index and mean arterial pressure imply that endogenous ouabain may be an important homeostatic factor in humans.

Isolation and characterization of a sodium pump inhibitor from human plasma.

An endogenous sodium pump inhibitor has been purified from human plasma. The purification scheme involved large scale dialysis, extraction of lyophilized dialysate by methanol followed by preparative and semipreparative scale reverse-phase high-performance chromatography. A single peak of biologically active material was obtained enriched by a factor of greater than 10 billion. This material showed high chromatographic polarity, was inactivated by charring, strong acid, or alkali, and was resistant to short-term boiling. The purified material had a molecular weight between 300 and 900 g/mol and was insensitive to type I esterase and a variety of proteolytic enzymes. The purified factor inhibited the ouabain-sensitive uptake of 86Rb by human erythrocytes, binding of [3H]ouabain, and activity of dog kidney Na,K-adenosine triphosphatase (ATPase) with high affinity (less than 0.3 nM) in a time- and dose-dependent manner. Maximally effective concentrations of the digitalislike factor showed no effect on either human red blood cell Mg- or Ca-ATPase, rabbit muscle sarcoplasmic reticulum Ca-ATPase, or guinea pig stomach H,K-ATPase. The purified material is a highly potent selective inhibitor of the ion transport, receptor, and hydrolytic functions of the sodium pump. The characteristic properties of this substance suggest it may be a mammalian endogenous digitalis and may be similar to the sodium transport inhibitor detected in the plasma of volume-sensitive forms of experimental and human hypertension.

Evaluation of potential topsoil productivity.

A biomass productivity model based on soil properties and climate is developed from literature and used to evaluate and compare potential effects of mining and reclamation on several soils in the continental United States. Soil productivity is assumed to vary as a product of root distribution function modified by five soil properties: available water, aeration porosity, bulk density, electrical conductivity, and pH. Yield limiting property levels are derived from literature and input soil data are obtained from available USDA Soil Conservation Service information on typical profiles. Modelled values of potential productivity after mining, indicate problems and limitations to be expected. The proposed model can be used as a guide to reclamation strategy, to restore the land to premining conditions, or at times to enhance productivity of a reclaimed area.