Effects of acute magnesium loading on pulmonary function of stable COPD patients

Background: Magnesium (Mg) use has the potential to promote bronchodilatation and to improve lung function in obstructive diseases. IV administration of Mg during exacerbations of chronic obstructive pulmonary disease (COPD) has led to improved peak flow. This study aimed to investigate the effects of acute IV Mg loading on respiratory parameters of stable COPD patients. Material/Methods: This was a randomized, double-blind, placebo-controlled crossover study. Twenty-two male COPD patients (64 +/- 6 years old, FEV1: 49 +/- 20%) received an IV infusion of 2 g of magnesium sulfate or placebo on two distinct occasions. Spirometry and mouth maximal respiratory pressures were obtained before and 45 minutes after the infusions. Results: Mg use led to significant changes in functional respiratory capacity (-0.48 1,95% CI: -0.96, -0.01), inspiratory capacity (0.21 1,95% CI: 0.04, 0.37). The treatment was also associated with a marginally significant decrease in residual volume (-0.47 1,95% CI: -0.96, 0.02, p=0.06). Conclusions: Acute IV Mg loading in stable COPD patients was associated with a reduction in lung hyperinflation and improvement of respiratory muscle strength. The clinical potential for chronic magnesium supplementation in COPD deserves further investigation.

Constitutional Telomerase Mutations Are Genetic Risk Factors for Cirrhosis

Some patients with liver disease progress to cirrhosis, but the risk factors for cirrhosis development are unknown. Dyskeratosis congenita, an inherited bone marrow failure syndrome associated with mucocutaneous anomalies, pulmonary fibrosis, and cirrhosis, is caused by germline mutations of genes in the telomerase complex. We examined whether telomerase mutations also occurred in sporadic cirrhosis. In all, 134 patients with cirrhosis of common etiologies treated at the Liver Research Institute, University of Arizona, between May 2008 and July 2009, and 528 healthy subjects were screened for variation in the TERT and TERC genes by direct sequencing; an additional 1,472 controls were examined for the most common genetic variation observed in patients. Telomere length of leukocytes was measured by quantitative polymerase chain reaction. Functional effects of genetic changes were assessed by transfection of mutation-containing vectors into telomerase-deficient cell lines, and telomerase activity was measured in cell lysates. Nine of the 134 patients with cirrhosis (7%) carried a missense variant in TERT, resulting in a cumulative carrier frequency significantly higher than in controls (P = 0.0009). One patient was homozygous and eight were heterozygous. The allele frequency for the most common missense TERT variant was significantly higher in patients with cirrhosis (2.6%) than in 2,000 controls (0.7%; P = 0.0011). One additional patient carried a TERC mutation. The mean telomere length of leukocytes in patients with cirrhosis, including six mutant cases, was shorter than in age-matched controls (P = 0.0004). Conclusion: Most TERT gene variants reduced telomerase enzymatic activity in vitro. Loss-of-function telomerase gene variants associated with short telomeres are risk factors for sporadic cirrhosis. (HEPATOLOGY 2011;53:1600-1607)

Postprandial gastric antral contractions in patients with gastro-oesophageal reflux disease: a scintigraphic study

Disturbed gastric contractility has been found in manometric studies in patients with gastro-oesophageal reflux disease (GORD), but the pathophysiological role of this abnormality is unclear. We aimed at assessing postprandial gastric antral contractions and its relationships with gastric emptying and gastro-oesophageal reflux in GORD patients. Fasted GORD patients (n = 13) and healthy volunteers (n = 13) ingested a liquid meal labelled with 72 MBq of (99m)Technetium-phytate. Gastric images were acquired every 10 min for 2 h, for measuring gastric emptying half time. Dynamic antral scintigraphy (one frame per second), performed for 4 min at 30-min intervals, allowed estimation of both mean dominant frequency and amplitude of antral contractions. In GORD patients (n = 10), acidic reflux episodes occurring 2 h after the ingestion of the same test meal were determined by ambulatory 24-h oesophageal pH monitoring. Gastric emptying was similar in GORD patients and controls (median; range: 82 min; 58-126 vs 80 min; 44-122 min; P = 0.38). Frequency of antral contractions was also similar in both groups (3.1 cpm; 2.8-3.6 vs 3.2 cpm; 2.4-3.8 cpm; P = 0.15). In GORD patients, amplitude of antral contractions was significantly higher than in controls (32.7%; 17-44%vs 23.3%; 16-43%; P = 0.01), and correlated positively with gastric emptying time (R-s = 0.58; P = 0.03) and inversely with the number of reflux episodes (R-s = -0.68; P = 0.02). Increased amplitude of postprandial gastric antral contractions in GORD may comprise a compensatory mechanism against delayed gastric emptying and a defensive factor against acidic gastro-oesophageal reflux.

Liver mitochondrial function in familial amyloidotic polyneuropathy

The objective of the present study was to analyze hepatic mitochondrial function in patients with familial amyloidotic polyneuropathy (FAP) undergoing cadaveric donor orthotopic liver transplantation. From February `2005 to May 2007, eight patients with FAP, ranging in age from 34 to 41 years and with Model for End-Stage Liver Disease scores ranging from 24 to 29. Underwent orthotopic transplantation using a liver from a deceased donor by the piggyback method. Immediately before beginning the recipient hepatectomy in a patient with FAP, a biopsy was obtained for analysis of mitochondrial function (FAP group). The control group consisted of 15 patients undergoing hepatic surgery to treat small tumors of the liver. Mitochondrial respiration was determined on the basis of oxygen consumption by energized mitochondria using a polarographic method. The membrane potential of the mitochondria was determined spectrofluorometrically. Data were analyzed statistically by the Mann-Whitney test, with the level of significance set at 5%. State 3 and 4 values, respiratory control ratio, and membrane potential were 47 +/- 8 versus 28 +/- 10 natoms O/min/mg protein (P <.05); 14 +/- 3 vs 17 +/- 7 nat.O/min/ mg.prot.mit. (P >.05); 3.6+/- .5 vs 1.7 +/- 0.7 (P <.05); and 135 +/- 5.2 vs 135 +/- 6 mV (P >.05) for control versus FAP patients, respectively, demonstrating a decreased energy status of the liver in FAP.

Poly(ethylene glycol) decorated poly(methylmethacrylate) nanoparticles for protein adsorption

Poly(ethylene glycol) decorated poly( methyl methacrylate) particles were synthesized by means of emulsion polymerization using poly(ethylene glycol) sorbitan monolaurate (Tween-20) as surfactant. PMMA/PEG particles presented mean diameter (195 +/- 15) nm, indicating narrow size distribution. The adsorption behavior of bovine serum albumin (BSA) and concanavalin A (ConA) onto PMMA/PEG particles was investigated by means of spectrophotometry. Adsorption isotherms obtained for BSA onto PMMA/PEG particles fitted well sigmoidal function, which is typical for multilayer adsorption. Con A adsorbed irreversibly onto PMMA/PEG particles. The efficiency of ConA covered particles to induce dengue virus quick agglutination was evaluated. (C) 2010 Elsevier B.V. All rights reserved.

Sustained Ventricular Tachycardia Is Associated with Regional Myocardial Sympathetic Denervation Assessed with (123)I-Metaiodobenzylguanidine in Chronic Chagas Cardiomyopathy

Cardiac sympathetic denervation and ventricular arrhythmia are frequently observed in chronic Chagas cardiomyopathy (CCC). This study quantitatively evaluated the association between cardiac sympathetic denervation and sustained ventricular tachycardia (SVT) in patients with CCC. Methods: We prospectively investigated patients with CCC and left ventricular ejection fraction (LVEF) greater than 35% with SVT (SVT group: n = 5 15; mean age +/- SD, 61 +/- 8 y; LVEF, 51% +/- 8%) and patients without SVT (non-SVT group: n = 11; mean age +/- SD, 55 +/- 10 y; LVEF, 57% +/- 10%). Patients underwent myocardial scintigraphy with (123)I-metaiodobenzylguanidine ((123)I-MIBG) for the evaluation of sympathetic innervation and resting perfusion with (99m)Tc-methoxyisobutylisonitrile ((99m)Tc-MIBI) for the evaluation of myocardial viability. A visual semiquantitative score was attributed for regional uptake of each radiotracer using a 17-segment left ventricular segmentation model (0, normal; 4, absence of uptake). A mismatch defect was defined as occurring in segments with a 99mTc-MIBI uptake score of 0 or 1 and a (123)I-MIBG score of 2 or more. Results: Compared with the non-SVT group, the SVT group had a similar (99m)Tc-MIBI summed score (6.9 +/- 7.5 vs. 4.4 +/- 5.2, respectively, P = 0.69) but a higher (123)I-MIBG summed score (10.9 +/- 7.8 vs. 22.4 +/- 9.5, respectively, P = 0.007) and a higher number of mismatch defects per patient (2.0 +/- 2.2 vs. 7.1 +/- 2.0, respectively, P < 0.0001). The presence of more than 3 mismatch defects was strongly associated with the presence of SVT (93% sensitivity, 82% specificity; P = 0.0002). Conclusion: In CCC, the amount of sympathetically denervated viable myocardium is associated with the occurrence of SVT. Myocardial sympathetic denervation may participate in triggering malignant ventricular arrhythmia in CCC patients with relatively well-preserved ventricular function.

Stapled haemorrhoidopexy transiently decreases rectal compliance and sensitivity

Aim Stapled haemorrhoidopexy may damage the anorectal musculature and its sensorimotor function. Most studies have not used a barostat for the measurement of compliance. This study aimed to investigate the effect of stapled haemorrhoidopexy on rectal compliance and sensitivity. Method After Ethical Committee approval, we studied 10 male patients (mean age 33.8 years) with third- or fourth-degree haemorrhoids. Rectal compliance and sensitivity were measured with a 600-ml bag and an electronic barostat. Volunteers were submitted to two consecutive rectal distension protocols, including continuous distension at 2, 4 and 6 months after stapled haemorrhoidopexy. Intraluminal volume and pressure were recorded, including the first rectal sensation, desire to defecate and onset of rectal pain. Another group of 10 male control patients (mean age 24.9 years) with pilonidal sinus and no haemorrhoids was also included in the study. Results Two months after stapled haemorrhoidopexy, rectal compliance decreased (7.1 +/- 0.2 vs 5.3 +/- 0.1, 6.4 +/- 0.1 vs 5.1 +/- 0.1 and 5.6 +/- 0.2 vs 4.7 +/- 0.1 ml/mmHg for first rectal sensation, desire to defecate and rectal pain, respectively; P < 0.05). The sensitivity threshold volume did not change for the first sensation but decreased significantly for the desier to defecate and pain (p < 0.05) (116.8 +/- 13.8 vs 148.4 +/- 14.61, 251.1 +/- 8.9 vs 185.8 +/- 8.6 and 293.3 +/- 16.6 vs 221.2 +/- 6.0 ml for first rectal sensation, desire to defecate and rectal pain, respectively). Four and 6 months after surgery, rectal compliance and sensitivity returned to levels similar to those in the basal period. Muscle tissue was found in only three of the 10 resected doughnuts. Controls remained without any change in rectal compliance and sensitivity. Conclusion Stapled haemorrhoidopexy transiently decreases rectal compliance and sensitivity threshold in young male patients.

Improved Endothelial Function and Reversal of Myocardial Perfusion Defects after Aerobic Physical Training in a Patient with Microvascular Myocardial Ischemia

The objective of this report is to document the effects of an aerobic training program on myocardial perfusion, and endothelial function abnormalities, and on the relief of angina in a patient with microvascular myocardial ischemia. A 53-year-old female patient exhibited precordial pain on effort and angiographically normal coronaries. Her symptoms had been present for 4 yrs despite pharmacologic treatment for the control of risk factors, with myocardial perfusion scintigraphy revealing an extensive reversible perfusion defect. She was submitted to aerobic training for 4 mos, obtaining significant improvement of the anginal symptoms. Additionally, after the aerobic training program, scintigraphy revealed the disappearance of the myocardial perfusion defect, with a marked improvement of endothelium-dependent vasodilatory response and an improved quality-of-life score. These results suggest that aerobic training can improve endothelial function, leading to a reduction of ischemia and an improved quality-of-life in patients with microvascular myocardial ischemia.

Perception of dysphagia: lack of correlation with objective measurements of esophageal function

Background The mechanism underlying increased perception of food bolus passage in the absence of esophageal mechanical obstruction has not been completely elucidated. A correlation between the intensity of the symptom and the severity of esophageal dysfunction, either motility (manometry) or bolus transit (impedance) has not been clearly demonstrated. The aim of this study was to analyze the correlation between objective esophageal function assessment (with manometry and impedance) and perception of bolus passage in healthy volunteers (HV) with normal and pharmacologically-induced esophageal hypocontractility, and in patients with gastro-esophageal reflux disease (GERD) with and without ineffective esophageal motility (IEM). Methods Combined manometry-impedance was performed in 10 HV, 19 GERD patients without IEM and nine patients with IEM. Additionally, nine HV were studied after 50 mg sildenafil, which induced esophageal peristaltic failure. Perception of each 5 mL viscous swallow was evaluated using a 5-point scale. Manometry identified hypocontractility (contractions lower than 30 mmHg) and impedance identified incomplete bolus clearance. Key Results In HV and in GERD patients with and without IEM, there was no association between either manometry or impedance and perception on per swallow analysis (OR: 0.842 and OR: 2.017, respectively), as well as on per subject analysis (P = 0.44 and P = 0.16, respectively). Lack of correlation was also found in HV with esophageal hypocontractility induced by sildenafil. Conclusions & Inferences There is no agreement between objective measurements of esophageal function and subjective perception of bolus passage. These results suggest that increased bolus passage perception in patients without mechanical obstruction might be due to esophageal hypersensitivity.

Effects of Inspiratory Muscle Training on Muscular and Pulmonary Function After Bariatric Surgery in Obese Patients

This study seeks to assess the effect of inspiratory muscle training (IMT) on pulmonary function, respiratory muscle strength, and endurance in morbidly obese patients submitted to bariatric surgery. Thirty patients were randomly assigned to sham muscular training, or to IMT with a threshold device (40% of maximum inspiratory pressure, MIP), for 30 min/day, from the 2nd until 30th postoperative (PO) day. All of them were submitted to a standard respiratory kinesiotherapy and early deambulation protocol. Data on spirometry, maximum static respiratory pressures, and respiratory muscle endurance were collected on the PO days 2, 7, 14, and 30 in a blinded matter. IMT enabled increases in PO MIP and endurance, and an earlier recovery of the spirometry parameters FEV(1), PEF, and FEF(25-75%). Comparing to preoperative values, MIP was increased by 13% at the 30th PO day in the trained group, whereas control group had a reduction of 8%, with higher values for the IMT group (30th PO, IMT-130.6 +/- 22.9 cmH(2)O; controls-112.9 +/- 25.1 cmH(2)O; p < 0.05). Muscular endurance at the 30th PO day was increased in the trained group comparing to preoperative value (61.5 +/- 39.6 s vs 114.9 +/- 55.2 s; p < 0.05), a finding not observed in the control group (81.7 +/- 44.3 vs 95.2 +/- 42.0 s). IMT improves inspiratory muscle strength and endurance and accounts for an earlier recovery of pulmonary airflows in morbidly obese patients submitted to bariatric surgery.

Regulation of type 17 helper T-cell function by nitric oxide during inflammation

Type 17 helper T (Th17) cells are implicated in the pathogenesis many of human autoimmune diseases. Development of Th17 can be enhanced by the activation of aryl hydrocarbon receptor (AHR) whose ligands include the environmental pollutant dioxin, potentially linking environmental factors to the increased prevalence of autoimmune disease. We report here that nitric oxide (NO) can suppress the proliferation and function of polarized murine and human Th17 cells. NO also inhibits AHR expression in Th17 cells and the downstream events of AHR activation, including IL-22, IL-23 receptor, and Cyp1a1. Conversely, NO did not affect the polarization of Th17 cells from mice deficient in AHR. Furthermore, mice lacking inducible nitric oxide synthase (Nos2(-/-)) developed more severe experimental autoimmune encephalomyelitis than WT mice, with elevated AHR expression, increased IL-17A, and IL-22 synthesis. NO may therefore represent an important endogenous regulator to prevent overexpansion of Th17 cells and control of autoimmune diseases caused by environmental pollutants.

Activation of the ET-1/ETA Pathway Contributes to Erectile Dysfunction Associated with Mineralocorticoid Hypertension

The cavernosal tissue is highly responsive to endothelin-1 (ET-1), and penile smooth muscle cells not only respond to but also synthesize ET-1. Considering that ET-1 is directly involved in end-organ damage in salt-sensitive forms of hypertension, we hypothesized that activation of the ET-1/ET(A) receptor pathway contributes to erectile dysfunction (ED) associated with mineralocorticoid hypertension. Wistar rats were uninephrectomized and submitted to deoxycorticosterone acetate (DOCA)-salt treatment for 5 weeks. Control (Uni [uninephrectomized control]) animals were uninephrectomized and given tap water. Uni and DOCA-salt rats were simultaneously treated with vehicle or atrasentan (ET(A) receptor antagonist, 5 mg/Kg/day). Cavernosal reactivity to ET-1, phenylephrine (PE), ET(B) receptor agonist (IRL-1620) and electric field stimulation (EFS) were evaluated in vitro. Expression of ROCK alpha, ROCK beta, myosin phosphatase target subunit 1 (MYPT-1), and extracellular signal-regulated kinase 1/2 (ERK 1/2) were evaluated by western blot analysis. ET-1 and ET(A) receptor mRNA expression was evaluated by real-time reverse-transcriptase polymerase chain reaction. Voltage-dependent increase in intracavernosal pressure/mean arterial pressure (ICP/MAP) was used to evaluate erectile function in vivo. ET(A) receptor blockade prevents DOCA-salt-associated ED. Cavernosal strips from DOCA-salt rats displayed augmented preproET-1 expression, increased contractile responses to ET-1 and decreased relaxation to IRL-1620. Contractile responses induced by EFS and PE were enhanced in cavernosal tissues from DOCA-salt hypertensive rats. These functional changes were associated with increased activation of the RhoA/Rho-kinase and ERK 1/2 pathways. Treatment of rats with atrasentan completely prevented changes in cavernosal reactivity in DOCA-salt rats and restored the decreased ICP/MAP, completely preventing ED in DOCA-salt rats. Activation of the ET-1/ET(A) pathway contributes to mineralocorticoid hypertension-associated ED. ET(A) receptor blockade may represent an alternative therapeutic approach for ED associated with salt-sensitive hypertension and in pathological conditions where increased levels of ET-1 are present. Carneiro FS, Nunes KP, Giachini FRC, Lima VV, Carneiro ZN, Nogueira EF, Leite R, Ergul A, Rainey WE, Webb RC, and Tostes RC. Activation of the ET-1/ETA pathway contributes to erectile dysfunction associated with mineralocorticoid hypertension. J Sex Med **;**:**-**.

Nitric oxide inhibition in paraventricular nucleus on cardiovascular and autonomic modulation after exercise training in unanesthetized rats

It is well known that regular physical exercise alter cardiac function and autonomic modulation of heart rate variability (HRV). The paraventricular nucleus of hypothalamus (PVN) is an important site of integration for autonomic and cardiovascular responses, where nitric oxide (NO) plays an important role. The aim of our study was to evaluate the cardiovascular parameters and autonomic modulation by means of spectral analysis after nitric oxide synthase (NOS) inhibition in the PVN in conscious sedentary (S) or swimming trained (ST) rats. After swimming training protocol, adult male Wistar rats, instrumented with guide cannulas to PVN and femoral artery and vein catheters were submitted to mean arterial pressure (MAP) and heart rate (HR) recording. At baseline, the physical training induced a resting bradycardia (S: 374 +/- 5, ST: 346 +/- 1 bpm) and promoted adaptations in HRV characterized by an increase in high-frequency oscillations (HF; 26.43 +/- 6.91 to 88.96 +/- 244) and a decrease in low-frequency oscillations (LF; 73.57 +/- 6.91 to 11.04 +/- 2.44) in normalized units. The microinjection of N(omega)-nitro-L-arginine methyl ester (L-NAME) in the PVN of sedentary and trained rats promoted increase in MAP and HR. L-NAME in the PVN did not significantly alter the spectral parameters of HRV of sedentary animals, however in the trained rats increased LF oscillations (11.04 +/- 2.44 to 27.62 +/- 6.97) and decreased HF oscillations (88.96 +/- 2.44 to 72.38 +/- 6.97) in normalized units compared with baseline. Our results suggest that NO in the PVN may collaborate to cardiac autonomic modulation after exercise training. (c) 2010 Elsevier B.V. All rights reserved.