Oral p38 mitogen-activated protein kinase inhibition with BIRB 796 for active Crohn's disease: a randomized, double-blind, placebo-controlled trial.

BACKGROUND & AIMS: The p38 mitogen-activated protein kinase (MAPK) regulates the expression of proinflammatory cytokines, which play a critical role in the pathophysiology of Crohn's disease (CD). This study investigated the efficacy and safety of BIRB 796, a highly potent inhibitor of p38 MAPK, in chronic active CD. METHODS: In a multicenter, multinational trial, 284 patients with moderate to severe CD were randomized to receive placebo, or 10, 20, 30, or 60 mg of BIRB 796 twice daily for 8 weeks. Clinical endpoints were based on standard safety assessments, CD Activity Index, C-reactive protein levels, and quality of life (Inflammatory Bowel Disease Questionnaire). In a substudy, the Crohn's Disease Endoscopic Index of Severity and histologic results of biopsy specimens were assessed. RESULTS: No clinical efficacy (primary end point, clinical remission; secondary end point, clinical response; Inflammatory Bowel Disease Questionnaire; Crohn's Disease Endoscopic Index of Severity) was seen for BIRB 796 in comparison with placebo. A significant, dose-dependent decrease of C-reactive protein level was observed transiently after BIRB 796 after 1 week with a return to baseline level over time. The incidence of adverse events was comparable between all treatment groups, with the exception of a mild increase of transaminase levels that was seen more frequently in the BIRB 796 groups. Geographic center effects were observed with Russian centers producing distinctly higher remission and response rates and lower adverse event rates than in other countries in both placebo and active treatment groups. CONCLUSIONS: There was no evidence for clinical efficacy of BIRB 796 in CD. A remarkable difference in the course of CD exists between Russia and non-Russian centers.     

Nigrostriatal rAAV-mediated GDNF Overexpression Induces Robust Weight Loss in a Rat Model of Age-related Obesity

Intraventricular administration of glial cell line–derived neurotrophic factor (GDNF) in primate and humans to study Parkinson''s disease (PD) has revealed the potential for GDNF to induce weight loss. Our previous data indicate that bilateral continuous hypothalamic GDNF overexpression via recombinant adeno-associated virus (rAAV) results in significant failure to gain weight in young rats and weight loss in aged rats. Based on these previous results, we hypothesized that because the nigrostriatal tract passes through the lateral hypothalamus, motor hyperactivity mediated by nigrostriatal dopamine (DA) may have been responsible for the previously observed effect on body weight. In this study, we compared bilateral injections of rAAV2/5-GDNF in hypothalamus versus substantia nigra (SN) in aged Brown-Norway X Fisher 344 rats. Nigrostriatal GDNF overexpression resulted in significantly greater weight loss than rats treated in hypothalamus. The nigral or hypothalamic GDNF-induced weight loss was unrelated to motor activity levels of the rats, though some of the weight loss could be attributed to a transient reduction in food intake. Forebrain DA levels did not account for the observed effects on body weight, although GDNF-induced increases in nucleus accumbens DA may have partially contributed to this effect in the hypothalamic GDNF-treated group. However, only nigrostriatal GDNF overexpression induced activation of phosphorylated extracellular signal-regulated kinase (p-ERK) in a small population of corticotrophin-releasing factor [corticotrophin-releasing hormone (CRH)] neurons located specifically in the medial parvocellullar division (MPD) of the paraventricular nucleus of the hypothalamus. Activation of these hypothalamic CRH neurons likely accounted for the observed metabolic effects leading to weight loss in obese rats.     

The APC E1317Q and I1307K polymorphisms in non-colorectal cancers.

Mutation of the adenomatous polyposis coli (APC) gene is an important initiating factor in the early stages of the multi-step colorectal cancer (CRC) carcinogenesis. APC E1317Q and I1307K variants have been linked to CRC. The aim of this study was to examine the association of these variants with non-colorectal cancers. Mutation screening was performed using real-time PCR. The APC E1317Q variant was detected in 1.25% individuals undergoing testing. Among 2076 patients that were analyzed for this mutation, 404 had cancer outside of the colon. None of the non-colorectal cancer patients was a carrier of the E1317Q polymorphism. The I1307K variant was found in 32 subjects with non-CRC (7.9%). We conclude herein that the E1317Q gene variant in the APC gene is not found in cancers outside of the colon. The prevalence of the more common I1307K variant is similar to that of CRC.     

Effects of stimulus-driven synchronization on sensory perception

A central issue in speech recognition is which basic units of speech are extracted by the auditory system and used for lexical access. One suggestion is that complex acoustic-phonetic information is mapped onto abstract phonological representations of speech and that a finite set of phonological features is used to guide speech perception. Previous studies analyzing the N1m component of the auditory evoked field have shown that this holds for the acoustically simple feature place of articulation. Brain magnetic correlates indexing the extraction of acoustically more complex features, such as lip rounding (ROUND) in vowels, have not been unraveled yet. The present study uses magnetoencephalography (MEG) to describe the spatial-temporal neural dynamics underlying the extraction of phonological features. We examined the induced electromagnetic brain response to German vowels and found the event-related desynchronization in the upper beta-band to be prolonged for those vowels that exhibit the lip rounding feature (ROUND). It was the presence of that feature rather than circumscribed single acoustic parameters, such as their formant frequencies, which explained the differences between the experimental conditions. We conclude that the prolonged event-related desynchronization in the upper beta-band correlates with the computational effort for the extraction of acoustically complex phonological features from the speech signal. The results provide an additional biomagnetic parameter to study mechanisms of speech perception.     

ORIGINAL RESEARCH—ED PHARMACOTHERAPY: Sildenafil Citrate 100 mg Starting Dose in Men with Erectile Dysfunction in an International,Double-Blind,Placebo-Controlled Study: Effect on the Sexual Experience and Reducing Feelings of Anxiety About the Next Intercourse Attempt

IntroductionSildenafil citrate 50 mg is the recommended starting dose for men with erectile dysfunction (ED); however, most men are later titrated to sildenafil 100 mg for improved efficacy.AimAssess the tolerability and efficacy of sildenafil initiated at the 100-mg dose in men with ED.MethodsMen with ED (score ≤25 on the Erectile Function domain of the International Index of Erectile Function) who had received ≤6 total doses of a phosphodiesterase type 5 inhibitor and none within 4 weeks were randomized to 8 weeks of double-blind, placebo-controlled (DBPC), fixed-dose treatment (50 or 100 mg sildenafil or placebo) followed by 4 weeks of open-label flexible-dose sildenafil (50 or 100 mg).Main Outcome MeasuresEfficacy, tolerability, treatment satisfaction, and other end points were measured at baseline and/or the end of the double-blind and open-label phases and compared between placebo and sildenafil initiated at doses of 50 and 100 mg.ResultsImprovements in DBPC patient-reported outcomes from baseline were statistically significant for both sildenafil 50 and 100 mg compared with placebo. At the end of DBPC treatment, 56% of men on the 100-mg dose felt no anxiety about the next intercourse attempt compared with 39% in the 50-mg group (odds ratio 2.03; P = 0.0197). Changes in functional scores from baseline were not statistically significant with the 100-mg dose compared with the 50-mg dose in the DBPC. Measures of treatment satisfaction and sexual experience significantly favored the 100-mg dose compared with the 50-mg dose in the DBPC. There was no increase in adverse events with the higher dose.ConclusionsSildenafil at 50 mg or 100 mg significantly improved erection quality, treatment satisfaction, anxiety levels, and the sexual experience compared with placebo during DBPC. Sildenafil 100 mg improved the sexual experience and treatment satisfaction, and reduced feelings of anxiety compared with the 50-mg dose. Loran OB, Ströberg P, Lee SW, Park NC, Kim SW, Tseng LJ, Collins S, and Stecher VJ. Sildenafil citrate 100 mg starting dose in men with erectile dysfunction in an international, double-blind, placebo-controlled study: Effect on the sexual experience and reducing feelings of anxiety about the next intercourse attempt. J Sex Med 2009;6:2826–2835.     

Alterations in caspase cleavage motifs of NP and M2 proteins attenuate virulence of a highly pathogenic avian influenza virus

The NP and M2 proteins of influenza A viruses are cleaved by caspases. M2 cleavage occurs with both human and avian viruses, whereas NP cleavage is specific for human strains. In the present study we have modified fowl plaque virus (A/FPV/Rostock/34 (H7 N1)) by introducing the NP cleavage site and removing the M2 cleavage site and have analyzed the effects of these modifications on virus growth and pathogenicity. The viruses generated by reversed genetics were: mutant NPgd which had the NP cleavage site METD↓G₁₇, recombinant wild type virus and mutant NPdel with the non-cleavable motifs METGG₁₇ and MET-G₁₇, respectively, and mutant M2nn in which the M2 cleavage site VDVD↓DG₈₉ of wild type virus was replaced by the non-cleavable sequence VNVNDG₈₉. Mutant NPgd replicated in cell cultures and in chicken embryos equally well as wild type virus and mutant NPdel. This observation was in contrast to previous results obtained with the human WSN strain that required caspase cleavage of NP for optimal virus growth. Thus, it appears that acquisition of the NP cleavage site is an adaptive mutation promoting interspecies transmission from an avian to a mammalian host. Like mutant NPgd, mutant M2nn virus did not show replication defects in cell culture and in chicken embryos. However, there was a reduction in pathogenicity for chickens, that was moderate with NPgd and dramatic with M2nn. Single injections with NPgd and M2nn at low doses induced high antibody titers and protected chickens from lethal FPV infection. These results show that a highly pathogenic avian influenza virus can be attenuated by modulating the caspase cleavage sites of NP and M2 and that these sites should be considered as novel targets for the design of live vaccines.     

Prospective study of the changes in left ventricular mass and geometry patterns in hypertensive patients During 5 years of follow-up.

BACKGROUND: Left ventricular hypertrophy (LVH), as well as the geometry pattern of the left ventricle, is believed to be an independent risk factor for hypertension. The present study investigated the changes in left ventricular mass, diastolic function and geometry in hypertensive patients in a prospective 5-year follow-up in conjunction with an evaluation of the regularity and effectiveness of treatment. METHODS AND RESULTS: One hundred hypertensive patients older than 18 years were examined according to the study protocol, which included registration of weight, height, vital signs, and echocardiography. After 5 years a repeat examination was performed. Patients were divided into 3 groups according to blood pressure (BP) control: group 1 (n=32), no regular medication; group 2 (n=44), regular treatment but no target BP levels; group 3 (n=14), regular effective treatment. In group 1 an increase in LVH and worsening of diastolic function were observed; in group 2 LVH and isovolumetric relaxation time remained unchanged, while the early peak velocity/atrial peak velocity ratio decreased; in group 3 there was a significant decrease in LVH. The geometry pattern only changed in 21 (23%) patients. CONCLUSIONS: LVH can be successfully reversed in only hypertensive with adequate BP control. The remodeling pattern appears to be a stable characteristic of the patient and transformation of one pattern into another is infrequent.     

A purinergic component of the excitatory postsynaptic current mediated by P2X receptors in the CA1 neurons of the rat hippocampus

The pyramidal neurons in the CA1 area of hippocampal slices from 17- to 19-day-old rats have been investigated by means of patch clamp. Excitatory postsynaptic currents (EPSCs) were elicited by stimulating the Schaffer collateral at a frequency below 0.2 Hz. It was found that inhibition of glutamatergic transmission by 20 μm 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 100 μm 2-amino-5-phosphonovaleric acid (D-APV) left a small component of the EPSC uninhibited. The amplitude of this residual EPSC (rEPSC) comprised 25 ± 11% of the total EPSC when measured at a holding potential of ?50 mV. The rEPSC was blocked by selective P2 blocker pyridoxal phosphate-6-azophenyl-2′-4′-disulphonic acid (PPADS) 10 μm and bath incubation with non-hydrolysable ATP analogues, ATP-γ-S and α,β-methylene-ATP at 50 and 20 μm , respectively. The rEPSC was dramatically potentiated by external Zn²⁺ (10 μm ). In another series of experiments exogenous ATP was applied to the CA1 neurons in situ. An inward current evoked by ATP was inhibited by PPADS to the same extent as the rEPSC. It is concluded that, depending on membrane voltage, about one-fifth to one-quarter of the EPSC generated by the excitatory synaptic input to the hippocampal CA1 neurons of rat is due to the activity of P2X receptors.