Phenotyping chronic respiratory diseases with airways obstruction.

Given the high prevalence of asthma-chronic obstructive pulmonary disease overlap (ACO) in Vietnam, there is an urgent need to establish a simplified strategy for categorising patients as either having asthma or chronic obstructive pulmonary disease (COPD). This classification would streamline the application of treatment recommendations outlined by the Global Initiative for Asthma (GINA) and the Global Initiative for Chronic Obstructive Lung Disease (GOLD).Patients with obstructive lung function were classified as having COPD, asthma, or ACO based on GINA/GOLD guidelines. We hypothesised that ACO-like asthma (ACO-A) would present with positive skin prick tests (SPTs) or early onset of symptoms without a history of tuberculosis (TB), while those with ACO-like COPD (ACO-B) would exhibit negative SPTs and late onset of symptoms and/or a history of TB.Among 235 patients, the prevalence of asthma, ACO-A, ACO-B, and COPD was respectively 21%, 22%, 17%, and 40%. Allergic history, rhinitis, and childhood asthma were associated with ACO-A, while high cumulative smoking was correlated with ACO-B. Socio-economic and demographic parameters, medical history, clinical features, smoking habits, lung function, and para-clinical investigations significantly differed between "all asthma" (i.e., individuals with asthma combined with ACO-A) and "all COPD" (i.e., individuals with COPD combined with ACO-B).Based on SPTs, history of TB, and onset age, ACO patients may be defined as people with asthma or COPD..

Users of biologics in clinical practice: would they be eligible for phase III clinical studies? Cohort Study in the French Psoriasis Registry PSOBIOTEQ.

BACKGROUND: Numerous inclusion and exclusion criteria are involved in phase III moderate to severe psoriasis trials investigating the safety and efficacy of biologics. This questions the generalization of results. METHODS: In this cohort study, we applied inclusion/exclusion criteria for phase III trials from original protocols (adalimumab - REVEAL, ustekinumab - PHOENIX, brodalumab - AMAGINE, secukinumab FIXTURE) to all patients enrolled in the PsoBioTeq prospective registry who received a biological agent for the first time between July 2012 and November 2017. We then compared the efficacy, drug survival and occurrence of adverse events between patients who satisfied/did not satisfy the eligibility criteria for these phase III trials. RESULTS: A total of 1267 patients were enrolled, of whom 993 (78.4%) were not eligible for at least one RCT (randomized controlled trial) and 251 (19.1%) did not meet the PASI/PGA severity requirements. Apart from disease severity, the most frequent criteria resulting in exclusion were as follows: non-plaque psoriasis (12.6%), significant cardiac disease (8.4%), significant liver disease (7.3%), elevated liver enzymes (4.9-9.6%) and personal history of diabetes (9.2%). There was no difference in drug survival between the two groups. The incidence ratio of adverse events was significantly lower in eligible versus non-eligible patients [0.78 (95% CI 0.62-0.97) (P = 0.03)]. CONCLUSION: The majority of patients treated with biologics in the PsoBioTeq real-life registry would not have been eligible for phase III moderate to severe psoriasis trials. Patients not eligible for psoriasis phase III clinical trials have a higher incidence of adverse events.

Adherence to calcium channel blocker therapy in older adults: a comparison of amlodipine and felodipine.

The efficacy of dihydropyridine calcium channel blockers for treating hypertension appears to be similar, but a variety of factors, including patient characteristics, tolerability and pharmacokinetic properties, may influence treatment adherence and outcome. We aimed to evaluate treatment adherence in clinical practice among older hypertensive adults (50+ years) prescribed amlodipine or felodipine for the first time as part of the California Medicaid (Medi-Cal) program. We used a retrospective, matched, cohort-analysis design. Over 1 year, patients prescribed amlodipine were 21% less likely to discontinue study treatment than those prescribed felodipine. Discontinuation tended to occur early, with 20% and 30% of amlodipine and felodipine patients, respectively, discontinuing treatment after one prescription. A non-significant difference in favour of amlodipine was demonstrated for anti-anginal medication use among patients taking these drugs at baseline. This study suggests that use of amlodipine may be associated with improved adherence, compared with felodipine, among older out-patients in the Medi-Cal program.

Tyrosine nitration of a synaptic protein synaptophysin contributes to amyloid beta-peptide-induced cholinergic dysfunction.

Amyloid beta (Abeta) is a critical factor involved in the pathogenesis of Alzheimer's disease (AD). We have previously demonstrated that continuous intracerebroventricular infusion of Abeta1-40 induced a time-dependent expression of the inducible nitric oxide (NO) synthase (iNOS) and an overproduction of NO in the rat hippocampus. The pathophysiological significance of the overproduction of NO on brain function was manifested by an impairment of nicotine-evoked acetylcholine(ACh) release and memory deficits.(4) Molecular mechanisms by which NO participates in the Abeta-induced brain dysfunction, however, remain to be determined. Here we show that chronic Abeta1-40 infusion caused a robust peroxynitrite formation and subsequent tyrosine nitration of proteins in the hippocampus. Immunoprecipitation and Western blot analyses further revealed that synaptophysin, a synaptic protein, was a main target of tyrosine nitration. Chronic infusion of Abeta1-40 resulted in an impairment of nicotine-evoked ACh release as analyzed by microdialysis. Daily treatment with the iNOS inhibitor aminoguanidine (AG) or the peroxynitrite scavenger uric acid (UA) prevented the tyrosine nitration of synaptophysin as well as the impairment of nicotine-evoked ACh release induced by Abeta. Our findings suggest that the tyrosine nitration of synaptophysin is related to Abeta-induced impairment of ACh release.

Immunocytochemical evidence that amyloid beta (1-42) impairs endogenous antioxidant systems in vivo.

Amyloid beta, the major constituent of the senile plaques in the brains of patients with Alzheimer's disease, is cytotoxic to neurons and has a central role in the pathogenesis of the disease. We have previously demonstrated that potent antioxidants idebenone and alpha-tocopherol prevent learning and memory impairment in rats which received a continuous intracerebroventricular infusion of amyloid beta, suggesting a role for oxidative stress in amyloid beta-induced learning and memory impairment. To test the hypothesis, in the present study, we investigated alterations in the immunoreactivity of endogenous antioxidant systems such as mitochondrial Mn-superoxide dismutase, glutathione, glutathione peroxidase and glutathione-S-transferase following the continuous intracerebroventricular infusion of amyloid beta for 2 weeks. The infusion of amyloid beta (1-42) resulted in a significant reduction of the immunoreactivity of these antioxidant substances in such brain areas as the hippocampus, parietal cortex, piriform cortex, substantia nigra and thalamus although the same treatment with amyloid beta (40-1) had little effect. The alterations induced by amyloid beta (1-42) were not uniform, but rather specific for each immunoreactive substance in a brain region-dependent manner. These results demonstrate a cytological effect of oxidative stress induced by amyloid beta (1-42) infusion. Furthermore, our findings may indicate a heterogeneous susceptibility to the oxidative stress produced by amyloid beta.

Phosphatidylinositol 3-kinase: a molecule mediating BDNF-dependent spatial memory formation.

Brain-derived neurotrophic factor (BDNF) plays a critical role in synaptic plasticity such as long-term potentiation (LTP), a form of synaptic correlate of learning and memory. BDNF is also implicated in learning and memory. We have demonstrated that radial arm maze training in rats for spatial learning and memory results in a significant increase in the BDNF mRNA expression in the hippocampus. Moreover, antisense BDNF oligonucleotide treatment impaired not only acquisition, but also maintenance and/or recall of spatial memory in the maze. Although these results suggest a role of BDNF for spatial memory processes, the signal transduction mechanisms that mediate the actions of BDNF remain unknown. Here we show that phosphorylation of BDNF receptor tyrosine kinase B (TrkB), phosphatidylinositol 3-kinase (PI3-K) and Akt, a target of PI3-K, in the hippocampus increased in parallel with spatial memory formation. Moreover, an activation of translational processes was suggested in the hippocampus after the maze training. When spatial learning was inhibited by antisense BDNF oligodeoxynucleotide, the activation was diminished. Chronic treatment with PI3-K inhibitor wortmannin impaired spatial learning. Our findings suggested that activation of TrkB/PI3-K and protein synthesis signaling pathway by BDNF in the hippocampus is important for spatial memory.

Memory deficits and increased emotionality induced by beta-amyloid (25-35) are correlated with the reduced acetylcholine release and altered phorbol dibutyrate binding in the hippocampus.

In the present study we found that chronic infusion of beta-amyloid fragment (25-35) at nanomolar concentration into rat cerebral ventricle impairs learning and memory. At a concentration of 3 nmol/day but not 0.3 nmol/day, beta-amyloid significantly reduced the spontaneous alternation behavior and the memory performance in the water maze and multiple passive avoidance tests. A significant increase in anxiety was also found in the animals infused with 3 nmol/day beta-amyloid fragment. Memory deficits and the increased emotionality were correlated with a decreased nicotine-evoked acetylcholine release from the frontal cortex/hippocampus, as assessed by microdialysis, in freely moving rats. The amyloid fragment infused either at pico- or nanomolar concentrations reduced the affinity of [3H] phorbol dibutyrate binding, an index of activated protein kinase C (PKC), and increased the total number of binding sites in the hippocampal particulate fraction. Our results suggest that the amnesic and anxiogenic effects of chronic infusion of beta-amyloid (25-35) are related to the decreased acetylcholine release and reduced PKC activation.

Molecular mechanism of cholinergic dysfunction and cognitive deficits induced by amyloid beta-peptide.

Amyloid beta-peptide (A beta) plays a critical role in the development of Alzheimer's disease (AD). Much progress has been made in understanding this age-related neurodegenerative disorder; thus an insight into the cellular actions of A beta and resulting functional consequences may contribute to preventive and therapeutic approaches for AD. In this review, recent evidence of A beta-induced brain dysfunction, especially cholinergic impairment and memory deficits, is summarized. Moreover, proposed mechanisms for A beta-induced neurotoxicity such as oxidative stress, ion-channel formation, and A beta-receptor interaction are discussed.

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H1 and H2 histamine receptors.

To investigate whether H1 and H2 histamine receptors are implicated in the modulation of acetylcholine release by endogenous histamine, the ventral striatum of the conscious, freely moving rat was superfused by the push-pull superfusion technique with drugs and the release of acetylcholine was determined in the superfusate. Superfusion with the H1 receptor agonist 2-thiazolylethylamine (TEA, 50 micromol/l) enhanced the release of acetylcholine, while the H1 receptor antagonist triprolidine (50 micromol/l) reduced acetylcholine outflow and abolished the TEA-evoked release of the neurotransmitter. The inhibitory effect of triprolidine was not influenced either on simultaneous superfusion with 10 micromol/l (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-benzazepine (SKF-83566, D1 dopamine receptor antagonist) and 50 micromol/l quinpirole (D2/D3 dopamine receptor agonist) or on superfusion with the GABAA receptor antagonist bicuculline (50 micromol/l). The H2 receptor antagonists ranitidine or famotidine (50 micromol/l each) greatly enhanced acetylcholine release rate in the ventral striatum. Presuperfusion with alpha-fluoromethylhistidine (FMH, 1 mmol/l), which inhibits neuronal synthesis of histamine, abolished the famotidine-induced release of acetylcholine. The releasing effect of famotidine was also abolished on simultaneous superfusion with 10 micromol/l SKF-83566 and 50 micromol/l quinpirole. The release of acetylcholine elicited by famotidine was reversed to a decreased acetylcholine outflow when the striatum was superfused with the GABA(A) receptor antagonist bicuculline (50 micromol/l) prior to famotidine. Superfusion with the H2 receptor agonist impromidine (1 micromol/l) decreased acetylcholine outflow, while the H2 agonist dimaprit (50 micromol/l) exerted the opposite effect. The releasing effect of dimaprit was not influenced by FMH (1 mmol/l), but it was abolished in the presence of SKF-83566 (10 micromol/l) and quinpirole (50 micromol/l). In the presence of bicuculline the release of acetylcholine by dimaprit was enhanced and prolonged. It seems possible that dimaprit and impromidine stimulate different subtypes of H2 receptors. The findings suggest that the release of acetylcholine in the striatum is modulated by neighbouring histaminergic neurons in a complex way. Stimulation of H1 histamine receptors, probably located on cholinergic neurons, enhances acetylcholine release. Stimulation by histamine of H2 receptors located on cholinergic or GABAergic neurons enhances the release of acetylcholine, while stimulation of H2 receptors located on dopaminergic neurons exerts the opposite effect.

Histaminergic neurons modulate acetylcholine release in the ventral striatum: role of H3 histamine receptors.

To investigate whether histaminergic neurons influence the activity of cholinergic neurons, the ventral striatum was superfused through a push-pull cannula and the release of endogenous acetylcholine was determined in the superfusate. Local inhibition of histamine synthesis by superfusion with alpha-fluoromethylhistidine (FMH) gradually decreased the release rate of acetylcholine. Superfusion with histamine increased the release of acetylcholine. The releasing effect of histamine was greatly inhibited when the striatum was simultaneously superfused with the D2/D3 agonist quinpirole and the D1 antagonist (+/-)-7-bromo-1-(fluoresceinylthioureido)phenyl-8-hydroxy-3-methyl -2,3,4,5-tetrahydro-1H-3-benzapine (SKF 83566). The effect of histamine on acetylcholine release was abolished by the GABA(A) receptor antagonist bicuculline. Superfusion with the H3 receptor agonists imetit or immepip increased acetylcholine release rate in the striatum. The releasing effects of the two H3 agonists were FMH resistant, while superfusion with quinpirole and SKF 83566 abolished the H3 receptor agonist-induced acetylcholine release. Superfusion with the H3 receptor antagonist thioperamide enhanced acetylcholine release rate. The releasing effect of thioperamide was abolished after inhibition of histamine synthesis by FMH. The release of acetylcholine by thioperamide was also abolished on simultaneous superfusion with quinpirole and SKF 83566. The findings show that, in the striatum, the activity of cholinergic neurons is permanently modulated by neighbouring histaminergic nerve terminals and axons. The release of acetylcholine is also permanently inhibited by neighbouring GABAergic neurons. The enhanced release of acetylcholine by the H3 receptor agonists imetit and immepip is due to stimulation of H3 heteroreceptors, while the increase of acetylcholine release by the H3 receptor antagonist thioperamide is elicited via blockade of H3 autoreceptors. Histamine released from histaminergic nerve terminals increases the release of acetylcholine in part by inhibition of dopamine release which, in turn, decreases GABAergic transmission. A dopamine-independent way seems also to be involved in the histamine-evoked acetylcholine release.

Neonatal Borna disease virus infection in the rat causes a loss of Purkinje cells in the cerebellum.

Viral insults that occur during early postnatal periods, can affect neuronal systems which exhibit significant postnatal development, such as the cerebral cortex and cerebellum. Borna disease virus (BDV) is a single-strand RNA virus which replicates in the nervous system of many species after experimental inoculation and causes acute neurological disease. Neonatal rats infected with BDV do not mount an aggressive response to the virus like their adult counterparts, but instead develop a persistent BDV infection with less overt clinical sequelae. Recently, the cerebellum, a neural structure associated with regulation of motor behavior, and perhaps with higher cognitive functions, has been demonstrated to be a target of neonatal BDV infections in rats (Bautista et al, 1995). In the present study neonatal rats were infected with BDV and their cerebella were analyzed histologically and immunohistochemically at 7 months of age. The cerebella of infected animals were reduced in size but normal foliation and laminar organization was present. However, as visualized with immunohistochemistry for the Purkinje cell-specific antigen calbindin, there were numerous gaps within the Purkinje cell layer and in the molecular layer which contains the Purkinje cell dendritic trees. We estimated the number of Purkinje cells and found there was an approximately 75% loss of PC in adult rats neonatally infected with BDV. These results suggest that neonatal BDV infection may either (1) target the PC and cause the death of these cells directly or (2) acts indirectly by triggering an immune response which is then responsible for the loss of these cells.

CT-appearance of intraluminal duodenal diverticulum. The "halo" sign.

The barium appearance of intraluminal duodenal diverticulum has been classically described as a "windsock" appearance. However, the CT-scan appearance of this abnormality has not been well documented. A case report of a patient with intraluminal duodenal diverticulum is presented. The authors believe the CT-scan findings in the patient are virtually pathognomonic for this lesion and propose the term "halo" sign be applied to this previously undescribed finding.

Nitric oxide-induced release of acetylcholine in the nucleus accumbens: role of cyclic GMP, glutamate, and GABA.

We have previously shown that the basal acetylcholine release in the ventral striatum is under the enhancing influence of endogenous nitric oxide (NO) and that NO donors cause pronounced increases in the acetylcholine release rate. To investigate the role of cyclic GMP, glutamate, and GABA in the NO-induced acetylcholine release, we superfused the nucleus accumbens, (Nac) of the anesthetized rat with various compounds through a push-pull cannula and determined the neurotransmitter released in the perfusate. Superfusion of the Nac with the NO donors diethylamine/NO (DEANO; 100 micromol/L), S-nitroso-N-acetylpenicillamine (SNAP; 200 micromol/L), or 3-morpholinosydnonimine (SIN-1; 200 micromol/L) enhanced the acetylcholine release rate. The guanylyl cyclase inhibitor 1H-(1,2,4)-oxodiazolo(4,3-a)quinoxalin-1-one (ODQ; 10 micromol/L) abolished the effects of DEANO and SIN-1. 6-(Phenylamino)-5,8-quinolinedione (LY-83583; 100 micromol/L), which also inhibits cyclic GMP synthesis, inhibited the releasing effects of DEANO and of SNAP, whereas the effect of SIN-1 on acetylcholine release was not influenced. The DEANO-induced release of acetylcholine was also abolished in the presence of 20 micromol/L 6,6-dinitroquinoxaline-2,3-dione (DNQX) and 10 micromol/L (+/-)-2-amino-5-phosphonopentanoic acid (AP-5). Simultaneous superfusion with 50 micromol/L quinpirole and 10 micromol/L 7-bromo-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine (SKF 83566) was ineffective. Superfusion with 500 micromol/L DEANO decreased the release of acetylcholine. The inhibitory effect of 500 micromol/L DEANO was reversed to an enhanced release on superfusion with 20 micromol/L bicuculline. Bicuculline also enhanced the basal release rate. These findings indicate that cyclic GMP mediates the NO-induced release of acetylcholine by enhancing the outflow of glutamate. Dopamine is not involved in this process. Only high concentrations of NO increase the output of GABA, which in turn decreases acetylcholine release. Our results suggest that cells that are able to release glutamate, such as glutamatergic neurons, are the main target of NO in the Nac.

Glial cells participate in histamine inactivation in vivo.

The ability of glial cells to take up histamine in vitro suggests that these cells may be involved in histamine inactivation. This prompted us to study the possible interactions between neuronal and glial processes which determine the histamine concentration in the synaptic cleft. In vitro experiments showed that the glial metabolic toxin, fluoroacetate (20 and 40 mmol/l) depressed histamine uptake into cultured astroglial cells and dissociated hypothalamic cells of rats. For in vivo experiments, the push-pull superfusion technique was used. In anaesthetized rat, the anterior hypothalamic area was superfused through the push-pull cannula with artificial cerebrospinal fluid (aCSF) or with aCSF which contained fluoroacetate and the release of endogenous histamine was determined in the superfusate. Hypothalamic superfusion with fluoroacetate (20 mmol/l) led to a pronounced increase in extracellular histamine. The effect of fluoroacetate was inhibited by 5 micromol/l tetrodotoxin. Superfusion with Ca++-free, Mg++-rich (12 mmol/l) aCSF inhibited the basal release rate of histamine. Under these conditions, 20 mmol/l fluoroacetate did not modify the level of the amine in the superfusate. These data demonstrate that depression of glial function enhances the concentration of histamine in the extracellular space by slowing down the uptake of the amine into the glial cells. Thus, under in vivo conditions, glial cells are directly involved in the continuous removal of neuronal histamine from the synaptic cleft.