Antimicrobial activity of esomeprazole versus omeprazole against Helicobacter pylori

OBJECTIVE: Esomeprazole is an enantiomorph of omeprazole, which inhibits gastric acid secretion more effectively than omeprazole. As proton pump inhibitors also exert an antibacterial activity, we aimed to compare esomeprazole and omeprazole for their antimicrobial activity against Helicobacter pylori in vitro. METHODS: We studied 52 H. pylori isolates obtained from gastric biopsies and inoculated onto agar plates containing the acid-converted drugs at different concentrations. The minimal concentrations that inhibited the growth of 50% and 90% of isolates were defined as MIC(50) and MIC(90). RESULTS: The MIC(50) and MIC(90) of esomeprazole were 16 and 32 mg/L; and those of omeprazole were 32 and 64 mg/L. Overall, 63.5% of isolates showed the same susceptibility to both drugs; 17 isolates were two- to 64-fold more susceptible to esomeprazole and two isolates were two-fold more susceptible to omeprazole. CONCLUSIONS: The increased antimicrobial activity in vitro of esomeprazole against H. pylori could contribute to improving the outcome of the eradication treatment of such an infection.     

Combining transductive and active learning to improve object-based classification of remote sensing images

In this letter, we propose a new active transductive learning (ATL) framework for object-based classification of satellite images. The framework couples graph-based label propagation with active learning (AL) to exploit positive aspects of the two learning settings. The transductive approach considers both labelled and unlabelled image objects to perform its classification as they are all available at training time while the AL strategy smartly guides the construction of the training set employed by the learner. The proposed framework was tested in the context of a land cover classification task using RapidEye optical imagery. A reference land cover map was elaborated over the whole study area in order to get reliable information about the performance of the ATL framework. The experimental evaluation underlines that, with a reasonable amount of training data, our framework outperforms state of the art classification methods usually employed in the field of remote sensing.     

Catechol‐O‐methyltransferase val158met and cognitive function in Parkinson's disease

Cognitive dysfunction is one of the most incapacitating non‐motor symptoms of Parkinson's disease (PD). Some cognitive deficits are thought to be related to abnormal dopamine homeostasis. The latter is influenced by catechol‐O‐methyltransferase (COMT), an enzyme that degrades dopamine. Previous research suggests a relationship between the COMT val158met functional polymorphism (SNP) and measures of executive function. We evaluated this hypothesis in a cohort of PD patients with an extensive neuropsychological test battery. Cognitive assessment and COMT genotyping were performed in 153 early PD patients from outpatient clinics general hospitals in the Netherlands. Our results do not support a direct effect of COMT val158met genotype on performance on neuropsychological measures of attention and executive function, but they suggest that genotype may interact with dopaminergic medication use to influence cognitive ability. © 2010 Movement Disorder Society     

Mycophenolate mofetil in children with steroid/cyclophosphamide-resistant nephrotic syndrome

The purpose of this study was to assess the results of therapy with mycophenolate mofetil (MMF) in children with idiopathic nephrotic syndrome (INS) who were both steroid- and cyclophosphamide-resistant. Treatment lasted a minimum of 6 months, and follow-up data were collected over a 2-year period. The children were divided into two groups: Group 1 (n?=?34) comprised patients who had received cyclosporine A (CsA) before the initiation of MMF therapy; Group 2 (n?=?18) comprised patients who received only MMF. Among the 34 patients of Group 1, complete and partial remission were achieved in seven (20.6%) and 13 patients (38.6%), respectively; there was no response in 14 patients (41.2%). Among the 18 patients in Group 2, complete and partial remission occurred in five (27.8%) and six (33.3%) patients, respectively; there was no response in seven patients (38.9%). Eight patients developed chronic kidney disease. The main side-effects were gastrointestinal complaints (n?=?11, 21%), recurring severe infections (n?=?1, 1.9%), and mild thrombocytopenia/leucopenia (n?=?1, 1.9%). MMF proved to be therapeutically effective in 59.5% of the cases. These beneficial effects need to be confirmed in studies with a long-term follow-up after discontinuation of the treatment. Our statistical analysis of the results of therapy with MMF did not reveal any significant difference between its use alone or following CsA administration.     

Modulation of Fronto-Cortical Activity by Modafinil: A Functional Imaging and Fos Study in the Rat

Modafinil (MOD) is a wake-promoting drug with pro-cognitive properties. Despite its increasing use, the neuronal substrates of MOD action remain elusive. In particular, animal studies have highlighted a putative role of diencephalic areas as primary neuronal substrate of MOD action, with inconsistent evidence of recruitment of fronto-cortical areas despite the established pro-cognitive effects of the drug. Moreover, most animal studies have employed doses of MOD of limited clinical relevance. We used pharmacological magnetic resonance imaging (phMRI) in the anesthetized rat to map the circuitry activated by a MOD dose producing clinically relevant plasma exposure, as here ascertained by pharmacokinetic measurements. We observed prominent and sustained activation of the prefrontal and cingulate cortex, together with weaker but significant activation of the somatosensory cortex, medial thalamic domains, hippocampus, ventral striatum and dorsal raphe. Correlation analysis of phMRI data highlighted enhanced connectivity within a neural network including dopamine projections from the ventral tegmental area to the nucleus accumbens. The pro-arousing effect of MOD was assessed using electroencephalographic recording under anesthetic conditions comparable to those used for phMRI, together with the corresponding Fos immunoreactivity distribution. MOD produced electroencephalogram desynchronization, resulting in reduced delta and increased theta frequency bands, and a pattern of Fos induction largely consistent with the phMRI study. Altogether, these findings show that clinically relevant MOD doses can robustly activate fronto-cortical areas involved in higher cognitive functions and a network of pro-arousing areas, which provide a plausible substrate for the wake-promoting and pro-cognitive effects of the drug.     

Platelet Cyclic Guanosine Monophosphate as a Biomarker of Phosphodiesterase Type 5 Inhibitor Efficacy in the Treatment of Erectile Dysfunction: A Randomized Placebo-Controlled Study

Background

Phosphodiesterase 5 inhibitors (PDE5-Is) are a mainstay in the therapy of erectile dysfunction (ED). The primary end point of clinical efficacy, both in clinical studies and normal practice, is represented by the International Index of Erectile Function (IIEF).

Objective

To evaluate if platelet cyclic guanosine monophosphate (cGMP) could represent a valuable marker for PDE5-I activity in ED.

Design, setting, and participants

The study enrolled 46 patients with psychogenic, organic, and mixed ED (20–71 yr of age; IIEF score <26). Patients were randomized to 6 wk of vardenafil, 5 mg/d at bedtime, or placebo.

Intervention

All patients donated two blood samples, one before starting the protocol and the second after 6 wk of treatment.

Measurements

Platelet cGMP was measured in both placebo and vardenafil groups. All the patients completed the IIEF-Erectile Function (EF) domain and the sexual encounter profile (SEP) and underwent visual sexual stimulation (VSS) coupled with Rigiscan. All the measurements were performed prior to starting the protocol and after the 6 wk of treatment.

Results and limitations

Platelet cGMP production was significantly (p < 0.05) elevated in patients taking 5 mg vardenafil versus placebo. Vardenafil was not superior to placebo in improving IIEF-EF and SEP scores. Conversely, VSS-Rigiscan revealed a significant amelioration (p < 0.028) in the vardenafil group versus placebo. The changes in platelet cGMP level correlated well with VSS-Rigiscan (p = 0.0037) but not with IIEF-EF and SEP.

Conclusions

Platelet cGMP could represent a relatively simple, reliable, and objective biomarker of PDE5-I activity in ED clinical studies. Larger clinical studies are needed to further validate the use, utility, and limits of this assay.     

Hiatal Hernia, Lower Esophageal Sphincter Incompetence, and Effectiveness of Nissen Fundoplication in the Spectrum of Gastroesophageal Reflux Disease

Background and Aims  Gastroesophageal reflux disease (GERD) is a spectrum of disease that includes nonerosive reflux disease (NERD), erosive reflux disease (ERD), and Barrett’s esophagus (BE). Treatment outcomes for patients with different stages have differed in many studies. In particular, acid suppressant medication therapy is reported to be less effective for treating patients with NERD and Barrett’s esophagus. The aims of this study were to investigate (1) the role of mechanical factors including hiatal hernia and lower esophageal sphincter (LES) competence in the spectrum of GERD and (2) outcomes of Nissen fundoplication. Methods  From the records of patients who had undergone laparoscopic Nissen fundoplication after an abnormal pH study, we identified 50 symptomatic consecutive patients with each of the GERD stages: (1) NERD, (2) mild ERD, defined as esophagitis that was healed with acid suppression therapy, (3) severe ERD, defined as esophagitis that persisted despite medical therapy, and (4) BE. Exclusion criteria were normal distal esophageal acid exposure, esophageal pH monitoring performed elsewhere, antireflux surgery less than 1 year previously or previous fundoplication, and a named esophageal motility disorder or distal esophageal low amplitude hypomotility. Patients who could not be contacted for the study were also excluded. All patients completed a detailed preoperative questionnaire; underwent preoperative upper gastrointestinal endoscopy, stationary manometry, and distal esophageal pH monitoring; and were interviewed at least 1 year after operation. Results  One hundred sixty patients meeting the entry criteria were studied. The mean follow-up period was 36.7 months. The only significant preoperative symptom difference was that patients with BE had more moderately severe or severe dysphagia compared to patients with NERD. Patients with severe ERD or BE had a significantly higher prevalence of hiatal hernia, lower LES pressures, and more esophageal acid exposure. Hiatal hernia and hypotensive LES were present in most patients with severe ERD or BE but in only a minority of patients with NERD or mild ERD. Surgical therapy resulted in similarly excellent symptom outcomes for patients in all GERD categories. Conclusions  Compared to mild ERD and NERD, severe ERD and BE are associated with significantly greater loss of the mechanical antireflux barrier as reflected in the presence of hiatal hernia and LES measurements. Restoration of the antireflux barrier and hernia reduction by laparoscopic Nissen fundoplication provides similarly excellent symptom control in all patients.     

Pkd1 Haploinsufficiency Increases Renal Damage and Induces Microcyst Formation following Ischemia/Reperfusion

Mutations in PKD1 cause the majority of cases of autosomal dominant polycystic kidney disease (ADPKD). Because polycystin 1 modulates cell proliferation, cell differentiation, and apoptosis, its lower biologic activity observed in ADPKD might influence the degree of injury after renal ischemia/reperfusion. We induced renal ischemia/reperfusion in 10- to 12-wk-old male noncystic Pkd1^+/− and wild-type mice. Compared with wild-type mice, heterozygous mice had higher fractional excretions of sodium and potassium and higher serum creatinine after 48 h. In addition, in heterozygous mice, also cortical damage, rates of apoptosis, and inflammatory infiltration into the interstitium at time points out to 14 d after injury all increased, as well as cell proliferation at 48 h and 7 d. The mRNA and protein expression of p21 was lower in heterozygous mice than wild-type mice at 48 h. After 6 wk, we observed dilated tubules, microcysts, and increased renal fibrosis in heterozygotes. The early mortality of heterozygotes was significantly higher than that of wild-type mice when we extended the duration of ischemia from 32 to 35 min. In conclusion, ischemia/reperfusion induces a more severe injury in kidneys of Pkd1-haploinsufficient mice, a process that apparently depends on a relative deficiency of p21 activity, tubular dilation, and microcyst formation. These data suggest the possibility that humans with ADPKD from PKD1 mutations may be at greater risk for damage from renal ischemia/reperfusion injury.Autosomal dominant polycystic kidney disease (ADPKD) is the most common monogenic renal disease, with a prevalence of 1:400 to 1:1000. Mutations of the PKD1 gene are responsible for approximately 85% of the disease cases, whereas approximately 15% are caused by mutations in PKD2.¹ Only half of patients reach the age of 58 yr without ESRD.² ADPKD is a systemic disorder, however, including extrarenal manifestations typically represented by liver cysts, intracranial aneurysms, and heart valve alterations.The PKD1 gene encodes polycystin 1, a large glycoprotein with an approximately 3000–amino acid extracellular portion that comprises domains that seem to be involved in protein–protein and protein–carbohydrate interactions. A number of studies support the involvement of the primary apical cilium in the pathogenesis of PKD by modulating signal transduction via intracellular Ca²⁺ transients.³ Polycystins 1 and 2 (PC1 and PC2) are thought to participate actively in this process.^3–6 Ciliary mechanosensation has also been associated with STAT6-dependent changes in gene expression.⁷ In addition, the cellular effects of polycystins seem to rely on interaction with the cytoskeleton and mediation of cell–cell adhesion.^8,9PC1 and PC2 activate a number of other pathways. PC1 may function as a G protein–coupled receptor.¹⁰ Its activation, following a process dependent on PC2, may also activate JAK2, leading to phosphorylation and activation of STAT1 and generation of STAT1 homodimers.¹¹ These dimers bind to the p21 promoter in the nucleus, promoting its upregulation, reduction of Cdk2 activity, and cell arrest in G0/G1. It has also been shown that PC1 induces phosphatidylinositol 3 kinase–dependent Akt activation,¹² whereas its C-terminus may interact with tuberin, regulating mammalian target of rapamycin activity.¹³ Moreover, PC1 is subjected to an autoproteolytic process in the G protein-coupled receptor proteolytic site domain, generating an extracellular N-terminal fragment,¹⁴ whereas its C-terminus seems to be cleaved, to be translocated to the nucleus, and to activate AP-1.¹⁵Ischemia/reperfusion (IR) injury is a common cause of acute kidney injury (AKI), including patients with ADPKD. The cellular damage is secondary to a chain of biochemical and biologic abnormalities.^16,17 An abnormal proliferative response of ADPKD cells to cAMP has been reported, apparently associated with defective intracellular Ca²⁺ homeostasis,¹⁸ and animal models of PKD have been associated with dysregulated cell-cycle activity.¹⁹ Piontek et al.,²⁰ however, have shown that the effects of Pkd1 inactivation in mice are determined by a developmental switch on postnatal day 13. Interestingly, in this model, cellular proliferation was not significantly increased.In this scenario, we hypothesized that a lower PC1 biologic activity might amplify the IR injury degree. Although the focal cyst formation in ADPKD is likely dependent on a two-hit mechanism,²¹ the functional effects of PC1 seem to rely on activity thresholds.²² PKD1-haploinsufficient kidney cells, therefore, might be unable to achieve the required PC1 activity level when exposed to IR. Although studies on the ischemia/PC2 relation have brought some potential contributions to this question,^23,24 the relationship between PC1 and IR is basically unknown. By coordinating cell planar polarity in renal tubules, PC1 might exert a protective effect after an ischemic insult. In this study, this potential mechanism was investigated in Pkd1^+/− mice obtained from an inbred mouse line with a Pkd1 null mutation. Our findings of a more severe renal lesion in Pkd1-null heterozygotes suggest an increased risk for renal IR injury in Pkd1-haploinsufficient mice. Development of tubular dilation (TD) and microcysts (MCs) and increased renal fibrosis, in turn, suggest that the IR aggression has a higher long-term negative impact on Pkd1^+/− kidneys.     

Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high on antiretroviral therapy

OBJECTIVE: To examine the relationships between blood CD4 natural regulatory T (Treg) cells, plasma HIV RNA level, CD4 T-cell count and immune activation in untreated HIV-infected patients and immunodeficient patients beginning antiretroviral therapy (ART), using a novel phenotype to define Treg cells (CD25CD127CD4). Data were compared with established Treg cell markers (FoxP3, CTLA-4 and GITR). METHODS: Twenty-nine untreated HIV-infected patients with CD4 T-cell counts of < 300 or > 400/microl were compared in a cross-sectional study and 12 patients beginning combination ART with < 100 CD4 T cells/mul were followed for 1 year on therapy. Three- and four-colour flow cytometry was used to quantitate proportions of Treg cells. RESULTS: In control donors and patients with high CD4 T-cell counts, 28-89% (median 60%) of CD25CD127CD4 cells were FoxP3, but < 10% expressed GITR or CTLA-4. Immunodeficient patients also had CD4-negative lymphocytes with the phenotype FoxP3CD127. Proportions of CD25CD127 cells and activated (HLA-DR) cells in the CD4 T-cell population were increased in patients with low CD4 T cell counts. The proportion of CD25CD127CD4 T cells correlated positively with plasma HIV RNA level and CD4 T-cell activation, but inversely with CD4 T-cell count. Longitudinal studies of 12 patients receiving ART in two distinct cohorts (Western Australia and Malaysia) showed that the proportion of CD25CD127CD4 cells decreased slightly over time, but remained above levels seen in non-HIV controls. CONCLUSIONS: Proportions of circulating T cells with a regulatory cell phenotype increase with HIV-associated immune activation and remain high after 1 year on ART.