Interleukin (IL) 4 and IL-13 act on human lung fibroblasts. Implication in asthma.

Airway hyperresponsiveness leading to subepithelial fibrosis is mediated by inflammatory cells activated by T helper (Th) 2-derived cytokines such as IL-4 and IL-5. By analyzing the phenotype and response of human lung fibroblasts derived from either fetal (ICIG7) or adult (CCL202) tissue as well as from a Th2-type stromal reaction (FPA) to IL-4 and IL-13, we provide evidence that human lung fibroblasts may behave as inflammatory cells upon activation by IL-4 and IL-13. We show that the three types of fibroblasts constitute different populations that display a distinct pattern in cell surface molecule expression and proinflammatory cytokine and chemokine release. All fibroblasts express functional but different IL-4/IL-13 receptors. Thus, while IL-4 receptor (R) alpha and IL-13Ralpha1 chains are present in all the cells, CCL202 and FPA fibroblasts coexpress the IL-13Ralpha2 and the IL-2Rgamma chain, respectively, suggesting the existence of a heterotrimeric receptor (IL-4Ralpha/IL-13Ralpha/IL-2Rgamma) able to bind IL-4 and IL-13. Stimulation with IL-4 or IL-13 triggers in the fibroblasts a differential signal transduction and upregulation in the expression of beta1 integrin and vascular cell adhesion molecule 1 and in the production of IL-6 and monocyte chemoattractant protein 1, two inflammatory cytokines important in the pathogenesis of allergic inflammation. Our results suggest that when activated by IL-4 and IL-13, different subsets of lung fibroblasts may act as effector cells not only in the pathogenesis of asthma but also in lung remodeling processes. They may also differentially contribute to trigger and maintain the recruitment, homing, and activation of inflammatory cells.     

Prognostic value of blood and bone marrow T-colony-forming cells (T-CFC) in patients with lymphadenopathy syndrome (LAS)

The in vitro proliferation capacity of peripheral blood committed T-cell precursors (T-CFC) from LAS patients was studied in order to define whether this parameter could be associated with transition to AIDS. In all patients a significantly (P less than 0.0001) decreased plating efficiency was detected. However, the lowest T-cell colony growth (less than 50 colonies/5 x 10(4) cells) was observed in the 23 patients who subsequently developed the full-blown disease within 150-570 days. Conversely, only one patient (n = 107) whose T-CFC generated greater than 50 colonies/5 x 10(4) cells developed AIDS after a mean follow-up of 867 days (range 120-1260 days). T-CFC from these patients displayed an impaired in vitro differentiation and self-renewal capacity which was independent of the clinical evolution of the disease. In 5 out of 12 AIDS patients, adherent cell-depletion of peripheral blood mononuclear cells (PBMC) enhanced the plating efficiency. Moreover, patients' but not normal adherent cells could inhibit normal T-cell colony growth in a dose-dependent manner. Media conditioned by patients' unstimulated adherent cells (LCM-A+p) also inhibited normal T-cell colony formation. In addition, LCM-A+p were capable of inhibiting interleukin 2-receptor (IL 2-R) expression and interleukin 2 (IL 2) production by normal mitogen-stimulated T-cells. These findings suggest that adherent cell-derived inhibitory activity(ies) could be responsible for the low T-cell colony formation observed in some AIDS patients.     

Driving After Left Ventricular Assist Device Implantation

Literature on driving capacities of ventricular assist device patients is rare and driving restrictions differ from center to center. Currently, no guidelines exist on whether and when left ventricular assist device (LVAD) patients are allowed to begin driving cars after device implantation. In this study, we assess the driving abilities of patients after LVAD implantation. Three hundred and ninety LVAD patients have been surveyed in a worldwide, multicenter study. The single survey followed a multi‐method design, including online, phone, and face‐to‐face interviews. Out of 390 patients, 72% are still driving and 28% did not continue driving after LVAD implantation. Reasons for discontinuation were capability (24%), insecurity (17%), and disapproval by family members (9%) or doctors (5%). Ninety percent of the patients describe their ability to drive as perfect or adequate. Sixty‐nine percent state that they are not restricted in their general driving capacity. Forty‐nine percent report not to be restricted in agility to drive by the device equipment. The majority of patients have not been involved in car accidents or major complications (94%). Eight accidents were reported (3%). Out of those, all were minor collisions. No patient reported the occurrence of a fatal accident or casualties. LVAD alarms did occur in six incidents (2%) with the majority being low battery alarms. The results of this study suggest that driving with a left ventricular assist device is safe for stable patients and driving can be resumed 3 months after LVAD implantation after careful patient assessment.     

Chronic AMPK activation evokes the slow, oxidative myogenic program and triggers beneficial adaptations in mdx mouse skeletal muscle

A therapeutic approach for Duchenne muscular dystrophy (DMD) is to up-regulate utrophin in skeletal muscle in an effort to compensate for the lack of dystrophin. We previously hypothesized that promotion of the slow, oxidative myogenic program, which triggers utrophin up-regulation, can attenuate the dystrophic pathology in mdx animals. Since treatment of healthy mice with the AMP-activated protein kinase (AMPK) activator 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) enhances oxidative capacity and elicits a fast-to-slow fiber-type transition, we evaluated the effects of chronic AMPK stimulation on skeletal muscle phenotype and utrophin expression in mdx mice. Daily AICAR administration (500 mg/kg/day, 30 days) of 5-7-week-old mdx animals induced an elevation in mitochondrial cytochrome c oxidase enzyme activity, an increase in myosin heavy-chain type IIa-positive fibers and slower twitch contraction kinetics in the fast, glycolytic extensor digitorum longus muscle. Utrophin expression was significantly enhanced in response to AICAR, which occurred coincident with an elevated β-dystroglycan expression along the sarcolemma. These adaptations were associated with an increase in sarcolemmal structural integrity under basal conditions, as well as during damaging eccentric contractions ex vivo. Notably, peroxisome proliferator-activated receptor γ co-activator-1α (PGC-1α) and silent information regulator two ortholog 1 protein contents were significantly higher in muscle from mdx mice compared with wild-type littermates and AICAR further increased PGC-1α expression. Our data show that AICAR-evoked muscle plasticity results in beneficial phenotypic adaptations in mdx mice and suggest that the contextually novel application of this compound for muscular dystrophy warrants further study.     

Association of a Monoamine Oxidase-A Gene Promoter Polymorphism With ADHD and Anxiety in Boys With Autism Spectrum Disorder

The aim of the present study was to examine the association between a variable number tandem repeat (VNTR) functional polymorphism in the promoter region of the MAO-A gene and severity of ADHD and anxiety in boys with ASD. Parents and teachers completed a DSM-IV-referenced rating scale for 5- to 14-year-old boys with ASD (n = 43). Planned comparisons indicated that children with the 4- versus 3-repeat allele had significantly (p < 05) more severe parent-rated ADHD inattention and impulsivity, and more severe teacher-rated symptoms of generalized anxiety. Our results support a growing body of research indicating that concomitant behavioral disturbances in children with ASD warrant consideration as clinical phenotypes, but replication with independent samples is necessary to confirm this preliminary finding.     

Blunted rostral anterior cingulate response during a simplified decoding task of negative emotional facial expressions in alcoholic patients

BACKGROUND: Alcoholism is characterized by deficits in emotional functioning as well as by deficits in cognitive functioning. However, most brain imaging research on alcoholism has focused on cognition rather than emotion. METHOD: We used an event-related functional magnetic imaging approach to examine alcoholics' brain blood oxygenation level dependent (BOLD) response to evaluation of emotional stimuli and to compare their response to that of nonalcoholic controls. The task used was a simplified variant of a facial emotion-decoding task in which subjects determined the intensity level of a target emotion displayed as a facial expression. Facial expressions of happy, sad, anger, disgust, and fear were used as stimuli. RESULTS: Alcoholics and controls did not differ in accurately identifying the intensity level on the simple emotional decoding task but there were significant differences in their BOLD response during evaluation of facial emotion. In general, alcoholics showed less brain activation than nonalcoholic controls. The greatest differences in activation were during decoding of facial expressions of fear and disgust during which alcoholics had significantly less activation than controls in the affective division of the anterior cingulate cortex (ACC). Alcoholics also had significantly less activation than controls in the affective division of the ACC, while viewing sad faces. Only to facial expressions of anger did the alcoholics show significant activation in the affective ACC and in this case, their BOLD response did not significantly differ from that of the controls. CONCLUSION: Alcoholics show a deficit in the function of the affective division of the ACC during evaluation of negative facial emotions that can serve as cues for flight or avoidance. This deficit may underlie some of the behavioral dysfunction in alcoholism.     

Dynamic changes in CREB phosphorylation and neuroadaptive gene expression in area V1 of adult monkeys after monocular enucleation

Our understanding of the molecular events that emerge after change in sensory input remains elusive, especially with regard to mature area V1. Here, we characterized P-CREB expression in area V1 of monkeys at multiple time-points after monocular enucleation (ME) to assess the possible contribution of CREB in visually deprived neocortex. Immunoblot assays and immunostainings showed that P-CREB is dynamically regulated in adult area V1, reaching a peak level between 5 and 30 days after ME, and becoming reduced at the 90-day post-ME time-point. This striking temporal increase in P-CREB level was paralleled by a concomitant increase of two CREB-regulated pro-survival effectors, namely Bcl-2 and Bcl-w. We present our results in the context of recent advances about adult visual neocortex and propose that ME induces a multifaceted CREB-mediated response that favors intrinsic stability of neurons and facilitates mature cortical networks to reorganize over a prolonged period.     

Essential Role of Osteopontin in Smoking-Related Interstitial Lung Diseases

Smoking-related interstitial lung diseases are characterized by the accumulation of macrophages and Langerhans cells, and fibrotic remodeling, which are linked to osteopontin (OPN) expression. Therefore, OPN levels were investigated in bronchoalveolar lavage (BAL) cells in 11 patients with pulmonary Langerhans cell histiocytosis (PLCH), 15 patients with desquamative interstitial pneumonitis (DIP), 10 patients with idiopathic pulmonary fibrosis, 5 patients with sarcoidosis, 13 otherwise healthy smokers, and 19 non-smoking controls. Furthermore, OPN overexpression was examined in rat lungs using adenoviral gene transfer. We found that BAL cells from patients with either PLCH or DIP spontaneously produced abundant amounts of OPN. BAL cells from healthy smokers produced 15-fold less OPN, and those cells from non-smoking healthy volunteers produced no OPN. BAL cells from patients with either idiopathic pulmonary fibrosis or sarcoidosis produced significantly less OPN, as compared with patients with PLCH. These data were confirmed by immunochemistry. Nicotine stimulation increased production of both OPN and granulocyte-macrophage colony stimulating factor by alveolar macrophages from smokers. Nicotinic acetylcholine receptor expression resembled the pattern of spontaneous OPN production and was dramatically increased in both PLCH and DIP. OPN overexpression in rat lungs induced lesions similar to PLCH with marked alveolar and interstitial accumulation of Langerhans cells. Our findings suggest a pathogenetic role of increased OPN production in both PLCH and DIP by promoting the accumulation of macrophages and Langerhans cells.Cigarette smoke is linked to a variety of lung diseases including chronic obstructive pulmonary disease, lung cancer, and interstitial lung diseases. Respiratory bronchiolar interstitial lung disease, desquamative interstitial pneumonitis (DIP), and pulmonary Langerhans cell histiocytosis (PLCH) belong to the group of smoking-related interstitial lung diseases.^1,2,3 Cigarette smoke is a complex mixture of more than 4000 compounds and is known to cause systemic and pulmonary effects.⁴ However, the underlying mechanisms as to how cigarette smoking leads to the changes observed in smoking-related interstitial lung diseases are largely unknown.^1,2,3Cigarette smoke induces inflammation, oxidative stress, and tissue injury, and has an important effect on the number, distribution, and activation state of macrophages and Langerhans cells.^5,6 There is a strong epidemiological link between PLCH and smoking. PLCH is characterized by the accumulation of activated Langerhans cells originating from the distal bronchiole walls.^1,2,3,7 The accumulations of Langerhans cells are poorly demarcated and extend to the adjacent alveoli, which often contain an abundance of pigmented macrophages. These areas show morphological changes similar to DIP.^7,8 In DIP, the predominant feature is the accumulation of alveolar macrophages, densely filling the alveolar lumen, combined with moderate fibrotic interstitial remodeling.^1,2As measured by bronchoalveolar lavage (BAL) in healthy individuals, cigarette smoking induces a 5- to 10-fold increase in alveolar macrophages in a dose-response curve.^9,10,11 It was shown that concentrations of granulocyte-macrophage colony stimulating factor (GMCSF) in patients with PLCH are increased,¹² but the mechanisms that lead to the expansion of the pulmonary macrophage pool and fibrosis in smokers are poorly understood.^1,2,3 Based on the findings of a microarray study, Woodruff et al¹³ have recently proposed that alveolar macrophages from smokers exhibit a distinctive macrophage activation state that is accompanied by increased OPN expression. Osteopontin is a glycoprotein found in the extracellular matrix of bone.¹⁴ However, multiple studies have reported cytokine properties of OPN in cell-mediated immunity.¹⁴ Further, OPN exhibits a strong chemotactic activity for macrophages, monocytes, Langerhans cells, and dendritic cells.^15,16,17In the context of these findings we speculated that OPN might be involved in the pathogenesis of smoking-related lung interstitial diseases. We found abundant OPN production by alveolar macrophages from patients with PLCH and DIP. Alveolar macrophages from both healthy smokers and patients with DIP and PLCH show up-regulated nicotine receptor expression as a sign of chronic nicotine stimulation. Further, nicotine directly induced OPN and GMCSF in alveolar macrophages. Our data provides evidence for a role of osteopontin in the pathogenesis of smoking- related interstitial lung diseases.