Relationship between the size of hiatal hernia and esophageal acid exposure time in erosive and non-erosive reflux disease

BACKGROUND: In the last few years studies have demonstrated that hiatal hernias have an important role in the pathogenesis of reflux disease, promoting reflux by many different mechanisms, emphasizing that the larger the hiatal hernia, the higher the reflux intensity and erosive esophagitis prevalence. AIM: To correlate the size of hiatal hernias (small or large) with reflux intensity (measured by pH monitoring parameters) in patients with non-erosive and erosive reflux disease. PATIENTS AND METHODS: We reviewed pH monitoring from patients with typical reflux symptoms (heartburn) previously submitted to upper endoscopy. Reflux intensity was measured by the % of total time of pH < 4 (%TT) and by % of time of pH < 4 in upright (%UT) and supine (%ST) positions. Patients were classified as non-erosive reflux disease if no erosive esophagitis was found in endoscopy and pH monitoring was abnormal and as erosive reflux disease if they had erosive esophagitis. Hiatal hernias were classified as small if their size ranged from 2 to 4 cm and large if > or = 5 cm. RESULTS: A total of 192 patients were included, being 115 in erosive reflux disease group and 77 in non-erosive reflux disease group. In erosive reflux disease patients, there were 94 (81%) with small hiatal hernias and 21 (19%) with large ones and in non-erosive reflux disease patients there were 66 (85%) with small and 11(15%) with large hiatal hernias. In erosive reflux disease group, the %TT, %UT and %ST were of 13.1 +/- 7.1; 13.4 +/- 7.4 and 12.3 +/- 11.5 in small hiatal hernias and 20.2 +/- 12.3; 17.8 +/- 14.1 and 20.7 +/- 14.1 in large hiatal hernias, respectively (P < 0.05 for %TT and %TS). In non-erosive reflux disease patients, %TT, %UT and %ST were 9.6 +/- 4.8; 10.8 +/- 6.8 and 8.6 +/- 7.3 in small hiatal hernias and of 14.6 +/- 13.3; 11.2 +/- 7.5 and 18.1 +/- 21.0 in large hiatal hernias respectively (P < 0.05 for %TT and %TS). CONCLUSION: Large hiatal hernias increase acid exposure time only in supine position in erosive esophagitis patients and in non-erosive patients.     

Treatment of esophageal varices: a randomized controlled trial comparing endoscopic sclerotherapy and EUS-guided sclerotherapy of esophageal collateral veins

BACKGROUND: Endoscopic sclerotherapy (ES) and band ligation are standard treatments for esophageal varices. Unfortunately, recurrence is common and seems to be related to esophageal collateral vessels, easily identified by EUS. Eradication of these vessels might lead to a more durable therapeutic effect. OBJECTIVE: To compare ES with EUS-guided sclerotherapy of collateral vessels (EUS-ES). DESIGN: Randomized controlled trial. SETTING: Endoscopy Unit, Division of Gastroenterology. Universidade Federal de S?o Paulo, S?o Paulo, Brazil. PATIENTS AND INTERVENTIONS: Fifty cirrhotic patients with esophageal varices were randomized into 2 groups: ES (n = 25) and EUS-ES (n = 25). EUS-ES was targeted at collateral veins. Patients were followed-up for at least 6 months after eradication. MAIN OUTCOME MEASUREMENTS: Efficacy in eradication, complications, and recurrence of varices. RESULTS: Varices were eradicated in 48 patients who adhered to the study protocol. The mean (SD) number of sessions until eradication was 4.3 (1.5) for the ES group and 4.1 (1.2) for the EUS-ES group. In ES group, 4 patients had mild bleeding. In EUS-ES group, 4 patients had pain. The mean (SD) length of the follow-up period was 22.6 (6.9) months for the ES group and 24.9 (8.1) months for the EUS-ES group. Recurrence was seen in 4 patients after ES and in 2 after EUS-ES (P = .32). The presence of collateral vessels was associated with recurrence (P = .003). CONCLUSION: EUS-ES is as safe and effective as ES in variceal eradication. Recurrence tends to be less frequent and occurs later. Persistence of esophageal collateral vessels after sclerotherapy is a risk factor for recurrence.     

Role of nitric oxide/cyclic GMP and cyclic AMP in beta3 adrenoceptor-chronotropic response

In this study we determine different signaling pathways involved in beta(3) adrenoceptor (beta(3)-AR) dependent frequency stimulation in isolated rodent atria. Promiscuous coupling between different G-proteins and beta(3)-AR could explain the multiple functional effects of beta(3)-AR stimulation. We examine the mechanisms and functional consequences of dual adenylate cyclase and guanylate cyclase pathways coupling to beta(3)-AR in isolated rodent atria. The beta(3)-AR selective agonists ZD 7114 and ICI 215001 stimulated in a dose-dependent manner the contraction frequency that significantly correlated with cyclic AMP (cAMP) accumulation. Inhibition of adenylate cyclase shifted the chronotropic effect to the right. On the other hand, the ZD 7114 activity on frequency was enhanced by the inhibition of nitric oxide synthase (NOS) and soluble guanylate cyclase. This countervailing negative chronotropic nitric oxide-cyclic GMP (NO-cGMP) significantly correlated with the increase on NOS activity and cGMP accumulation. Current analysis showed a negative cross talk between cAMP chronotropic and NO-cGMP effects by inhibition of phospholipase C (PLC), calcium/calmodulin (CaM), protein kinase C (PKC), NOS isoforms and Gi-protein on the effects of beta(3)-AR stimulation. RT-PCR detected both eNOS and nNOS in isolated rat atria. NOS isoforms performed independently. Only nNOS participated in limiting the effect of beta(3)-AR stimulation. In eNOS-KO (eNOS-/-) mice the chronotropic effect of beta(3)-AR agonists did not differ from wild type (WT) mice atria, but it was increased by the inhibition of nNOS activity. Our results suggest that the increase in frequency by beta(3)-AR activation on isolated rodent atria is associated to a parallel increases in cAMP. The nNOS-cGMP pathway negatively modulates beta(3)-AR activation. Multiple signal transduction pathways between G-protein and beta(3)-AR may protect myocardium from catecholamine-induced cardiotoxic effects.     

Control of cardiac myofilament activation and PKC-betaII signaling through the actin capping protein, CapZ

Actin capping protein (CapZ) anchors the barbed ends of sarcomeric actin to the Z-disc. Myofilaments from transgenic mice (TG-CapZ) expressing a reduced amount of CapZ demonstrate altered function and protein kinase C (PKC) signaling [Pyle WG, Hart MC, Cooper JA, Sumandea MP, de Tombe PP, and Solaro RJ., Circ. Res. 90 (2002) 1299-306]. The aims of the current study were to determine the direct effects of CapZ on myofilament function and on PKC signaling to the myofilaments. Our studies compared mechanical properties of single myocytes from TG-CapZ mouse hearts to wild-type myocytes from which CapZ was extracted using PIP(2). We found that myofilaments from CapZ-deficient transgenic myocardium exhibited increased Ca(2+) sensitivity and maximum isometric tension. The extraction of CapZ from wild-type myofilaments replicated the increase in maximum isometric tension, but had no effect on myofilament Ca(2+) sensitivity. Immunoblot analysis revealed that the extraction of CapZ was associated with a reduction in myofilament-associated PKC-beta(II) and that CapZ-deficient transgenic myofilaments also lacked PKC-beta(II). Treatment of wild-type myofilaments with recombinant PKC-beta(II) reduced myofilament Ca(2+) sensitivity, whereas this effect was attenuated in myofilaments from TG-CapZ mice. Our results indicate that cardiac CapZ directly controls maximum isometric tension generation, and establish CapZ as an important component in anchoring PKC-beta(II) at the myofilaments, and for mediating the effects of PKC-beta(II) on myofilament function.     

Increased expression of hepatic pyruvate dehydrogenase kinases 2 and 4 in young and middle-aged Otsuka Long-Evans Tokushima Fatty rats: induction by elevated levels of free fatty acids

The activity of the pyruvate dehydrogenase complex (PDC) is regulated by covalent modification of its E1 component, which is catalyzed by specific pyruvate dehydrogenase kinases (PDKs) and phosphatases. In the liver, PDK2 and PDK4 are the most abundant PDK isoforms, which are responsible for inactivation of PDC when glucose availability is scarce in the body. In the present study, regulatory mechanisms of hepatic PDC were examined before and after the onset of type 2 diabetes mellitus in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, using Long-Evans Tokushima Otsuka (LETO) rats as controls. Plasma glucose and insulin concentrations were at normal levels in rats aged 8 weeks, but were significantly higher in OLETF than in LETO rats aged 25 weeks, indicating insulin resistance in OLETF rats. Plasma free fatty acids (FFAs) were 1.6-fold concentrated, and the liver PDC activity was significantly lower in OLETF than in LETO rats at both ages, suggesting suppression of pyruvate oxidative decarboxylation in OLETF rats before and after the onset of diabetes. Pyruvate dehydrogenase kinase activity and abundance of PDK2 and PDK4 proteins, as well as mRNAs, were greater in OLETF rats at both ages. These results suggest that persistently elevated levels of circulating free fatty acid in normal and diabetic OLETF rats play an important role in stimulating PDK2 and PDK4 expression in liver.     

XRCC4 suppresses medulloblastomas with recurrent translocations in p53-deficient mice

Inactivation of the XRCC4 nonhomologous end-joining factor in the mouse germ line leads to embryonic lethality, in association with apoptosis of newly generated, postmitotic neurons. We now show that conditional inactivation of the XRCC4 in nestin-expressing neuronal progenitor cells, although leading to no obvious phenotype in a WT background, leads to early onset of neuronally differentiated medulloblastomas (MBs) in a p53-deficient background. A substantial proportion of the XRCC4/p53-deficient MBs have high-level N-myc gene amplification, often intrachromosomally in the context of complex translocations or other alterations of chromosome 12, on which N-myc resides, or extrachromosomally within double minutes. In addition, most XRCC4/p53-deficient MBs harbor clonal translocations of chromosome 13, which frequently involve chromosome 6 as a partner. One copy of the patched gene (Ptc), which lies on chromosome 13, was deleted in all tested XRCC4/p53-deficient MBs in the context of translocations or interstitial deletions. In addition, Cyclin D2, a chromosome 6 gene, was amplified in a subset of tumors. Notably, amplification of Myc-family or Cyclin D2 genes and deletion of Ptc also have been observed in human MBs. We therefore conclude that, in neuronal cells of mice, the nonhomologous end-joining pathway plays a critical role in suppressing genomic instability that, in a p53-deficient background, routinely contributes to genesis of MBs with recurrent chromosomal alterations.     

Cortisol levels in patients with severe community-acquired pneumonia

Objectives To evaluate cortisol levels and prevalence of adrenal insufficiency in patients with severe community-acquired pneumonia (CAP). Design and setting Retrospective cohort study in a 24-bed medical-surgical intensive care unit (ICU). Patients Forty patients with severe CAP admitted to the ICU from March 2003 and May 2005. Measurements and results Random cortisol levels were measured up to 72 h after ICU admission. A threshold of 20 μg/dl was considered for the diagnosis of adrenal insufficiency. Median cortisol levels were 15.5 μg/dl (IQR 10.8–25.1), and 26 patients (65%) met the criteria for adrenal insufficiency. Other cutoff levels of cortisol were evaluated, and 30 patients (75%) had cortisol levels below 25 μg/dl and 19 (47.5%) had cortisol levels below 15 μg/dl. When only patients with septic shock (n = 19) were evaluated, 12 (63%) had adrenal insufficiency. Conclusions Relative adrenal insufficiency occurs in a high proportion of patients with severe CAP. This finding highlights the importance of measuring cortisol levels and may help explain the potential benefits of hydrocortisone infusion in these patients.     

Influence of nitric oxide-donating nonsteroidal anti-inflammatory drugs on the evolution of acute pancreatitis

Microcirculatory disturbances and leukocyte activation are main events in the pathogenesis of acute pancreatitis (AP) that is characterized by inflammatory up-regulation. Nitric oxide-donating nonsteroidal anti-inflammatory drugs (NO-NSAIDs) regulate vascular function and mitigate inflammation. To investigate the influence of NO-NSAIDs on AP. AP was induced by the biliopancreatic duct outlet exclusion-closed duodenal loops model. Treatment with NO-flurbiprofen, NO-ibuprofen, NO-aspirin, or their parental drugs was done (i) 1 h before, (ii) 1 h after, (iii) 1 h before and 4 h after, or (iv) 4 h after surgery. The degree of severity was evaluated using biochemical and histopathological analyses. NO-NSAIDs given before and during the first hour of the noxia decreased blood levels of amylase, lipase, C-reactive protein, IL-6, IL-10, heat shock protein 72, prostaglandin E2 inactive metabolite, and 8-isoprostane, as well as pancreatic and lung myeloperoxidase and cyclooxygenase. Acinar and fat necrosis, hemorrhage, and leukocyte infiltrate were also reduced. The best protection was achieved when treatment was performed 1 h before and 4 h after triggering AP. NO-flurbiprofen was the most effective drug. AP severity was significantly ameliorated by NO-NSAIDs being the administration time essential to achieve optimal pancreatic protection that may result to be useful in the prevention of postendoscopic severe AP.     

The Na,K-ATPase alpha4 isoform from humans has distinct enzymatic properties and is important for sperm motility

In the rat, the Na,K-ATPase alpha4 isoform exhibits unique enzymatic characteristics and is important for sperm motility. In this work, we studied expression, localization and function of alpha4 in human spermatozoa. We show two catalytically active Na,K-ATPase alpha polypeptides with different ouabain affinity and identified expression of alpha1, alpha4, beta1 and beta3 isoforms in the gametes. In addition, human sperm presented two Na,K-ATPases composed of alpha4, alpha4beta1 and alpha4beta3. Kinetic analysis of these isozymes produced in insect cells showed that, compared with human alpha1beta1, alpha4beta1 and alpha4beta3 exhibit higher Na(+) and lower K(+) affinity and higher sensitivity to ouabain. These particular enzymatic properties suggested a role for alpha4 in sperm function. Using computer-assisted sperm analysis (CASA), we found that ouabain inhibition of alpha4 significantly decreased percentage sperm motility. In contrast, ouabain did not affect linearity of forward progression, amplitude of lateral head displacement, beat cross frequency and sperm straight-line, curvilinear or average path velocities. This suggests a primary role of alpha4 in flagellar motility. Accordingly, we found alpha4 in the sperm tail, predominating in the mid-piece of the flagellum. Therefore, similar to the rat ortholog, human Na,K-ATPase alpha4 isoform has a distinct activity that is essential for sperm function.