Mast cells and the development of allergic airway disease

Murine models have highlighted the importance of T-cells and TH2 cytokines in development of allergen-induced airway disease. In contrast, the role of mast cells for the development of allergic airway disease has been controversial. Recent studies in murine models demonstrate a significant contribution of mast cells during the development of airway hyperresponsiveness and airway inflammation. Furthermore these models have allowed identifying certain mast cell-produced mediators (e.g. histamine and leukotriene B4) to be involved in the recruitment of effector T-cells into the lung. Additionally, mast cell-produced TNF can directly activate TH2 cells and contribute to the development of allergic airway disease. These new findings demonstrate a complex role of mast cells and their mediators, not only as effector cells, but also during sensitization and development of allergic airway disease. Therefore mast cells and certain mast cell-produced mediators might be an interesting target for the prevention and treatment of allergic asthma

Repetitive Activation of the Corticospinal Pathway by Means of rTMS may Reduce the Efficiency of Corticomotoneuronal Synapses

Low-frequency rTMS applied to the primary motor cortex (M1) may produce depression of motor-evoked potentials (MEPs). This depression is commonly assumed to reflect changes in cortical circuits. However, little is known about rTMS-induced effects on subcortical circuits. Therefore, the present study aimed to clarify whether rTMS influences corticospinal transmission by altering the efficiency of corticomotoneuronal (CM) synapses. The corticospinal transmission to soleus α-motoneurons was evaluated through conditioning of the soleus H-reflex by magnetic stimulation of either M1 (M1-conditioning) or the cervicomedullary junction (CMS-conditioning). The first facilitation of the H-reflex (early facilitation) was determined after M1- and CMS-conditioning. Comparison of the early facilitation before and after 20-min low-frequency (1 Hz) rTMS revealed suppression with M1- (−17 ± 4%; P = 0.001) and CMS-conditioning (−6 ± 2%; P = 0.04). The same rTMS protocol caused a significant depression of compound MEPs, whereas amplitudes of H-reflex and M-wave remained unaffected, indicating a steady level of motoneuronal excitability. Thus, the effects of rTMS are likely to occur at a premotoneuronal site—either at M1 and/or the CM synapse. As the early facilitation reflects activation of direct CM projections, the most likely site of action is the synapse of the CM neurons onto spinal motoneuron

Evidence That the Cortical Motor Command for the Initiation of Dynamic Plantarflexion Consists of Excitation followed by Inhibition

At the onset of dynamic movements excitation of the motor cortex (M1) is spatially restricted to areas representing the involved muscles whereas adjacent areas are inhibited. The current study elucidates whether the cortical motor command for dynamic contractions is also restricted to a certain population of cortical neurons responsible for the fast corticospinal projections. Therefore, corticospinal transmission was assessed with high temporal resolution during dynamic contractions after both, magnetic stimulation over M1 and the brainstem. The high temporal resolution could be obtained by conditioning the soleus H-reflex with different interstimulus intervals by cervicomedullary stimulation (CMS-conditioning) and transcranial magnetic stimulation (TMS) of M1 (M1-conditioning). This technique provides a precise time course of facilitation and inhibition. CMS- and M1-conditioning produced an ‘early facilitation’ of the H-reflex, which occurred around 3 ms earlier with CMS-conditioning. The early facilitation is believed to be caused by activation of direct monosynaptic projections to the spinal motoneurons. CMS-conditioning resulted in a subsequent ‘late facilitation’, which is considered to reflect activity of slow-conducting and/or indirect corticospinal pathways. In contrast, M1-conditioning produced a ‘late dis-facilitation’ or even ‘late inhibition’. As the late dis-facilitation was only seen following M1- but not CMS-conditioning, it is argued that cortical activation during dynamic tasks is restricted to fast, direct corticospinal projections whereas corticomotoneurons responsible for slow and/or indirectly projecting corticospinal pathways are inhibited. The functional significance of restricting the descending cortical drive to fast corticospinal pathways may be to ensure a temporally focused motor command during the execution of dynamic movements

Optimierung des Kartoffelanbaus im ökologischen Landbau hinsichtlich der Weiterverarbeitung zu Pommes frites und Chips

Voraussetzungen für einen erfolgreichen Anbau von Verarbeitungskartoffeln sind außer einem hohen Ertrag vor allem die von der Kartoffel verarbeitenden Industrie geforderten produktspezifischen Qualitäten für Pommes frites und Chips. Für die Verarbeitung zu Pommes frites muss z.B. ein hoher Anteil großfallender Knollen realisiert werden oder bei Chipskartoffeln bestehen strenge Vorgaben für die Gehalte an reduzierenden Zuckern. Um hohe Zuckergehalte zu vermeiden, erfolgt die Kartoffellagerung bei 8°C, was erhöhte Ansprüche an die Lagerfähigkeit bedeutet. In dem gemeinsam von der Universität Kassel (FG Ökologischer Land- und Pflanzenbau, Projektleitung), der FAL (Institut für ökologischen Landbau), der Universität Kiel (Institut für Pflanzenbau und Pflanzenzüchtung) und der BFEL (Institut für Getreide-, Kartoffel- und Stärketechnologie) bearbeiteten Projekt wurden daher Strategien für die Erzeugung qualitativ hochwertiger Verarbeitungskartoffeln geprüft. Der Sortenwahl kommt die entscheidende Bedeutung zu. So können für eine Verarbeitung zu Pommes frites die Sorten Agria und Marena empfohlen werden, die bei hohen Erträgen marktfähiger Ware (>50 mm) eine gute Qualität zur Ernte und nach Lagerung zeigten. Für die Verarbeitung zu Chips ist die Sorte Marlen geeignet, die sich als relativ lagerstabil erwies. In Abhängigkeit der Ausreife der Kartoffeln kann der Richtwert für die reduzierenden Zucker nach Lagerung schnell überschritten werden. Hier stellen die 4°C-Sorten Sempra und Verdi eine Alternative dar, wobei deren Ertragsniveau nicht zufriedenstellend war. Die weiteren Ergebnisse belegen, dass alle pflanzenbaulichen Möglichkeiten hinsichtlich einer guten Nährstoff- und Wasserversorgung sowie der Pflanzgutvorbereitung ausgeschöpft werden sollten, um hohe Erträge mit der notwendigen Sortierung bei ansprechender Rohstoffqualität zu erzielen. Als Vorfrucht eignen sich insbesondere Leguminosen (Körnererbsen mit anschl. Zwischenfrucht oder Kleegras). Das Kleegrasmanagement (Schnitt- oder Mulchnutzung) hat keinen wesentlichen Einfluss auf den Ertrag, die Sortierung und die Produktqualität. Auf leichten Böden empfiehlt sich der Einsatz einer qualitätsfördernden Düngung von Kalium – entweder über Stallmist oder mit den im Ökologischen Landbau zugelassenen mineralischen Kaliumdüngern. Eine gleichmäßige Wasserversorgung muss auf leichten Standorten über Beregnung sichergestellt werden, die auch zu einer verbesserten N-Ausnutzung organischer Dünger beitragen kann. Der Einsatz N-haltiger organischer Dünger (Horngrieß) wies im Vergleich zu Stallmist eine bessere Wirkung auf. Pflanzenbauliche Maßnahmen hatten zwar einen Einfluss auf die Verarbeitungsqualität, diese wurde aber stärker von der Witterung und dem davon abhängigen Wachstumsverlauf beeinflusst. Zusammenfassend kann festgehalten werden, dass der Anbau von Verarbeitungskartoffeln unter Einbeziehung der standort- und betriebsspezifischen Gegebenheiten erfolgreich betrieben werden kann

Changes in corticospinal transmission following 8 weeks of ankle joint immobilization

Joint immobilization has previously been shown to modulate corticospinal excitability. The present study investigated changes in the excitability of distinct fractions of the corticospinal pathway by means of conditioning the H-reflex with transcranial magnetic stimulation (TMS) of the primary motor cortex (Hcond). This method allows assessment of transmission in fast (monosynaptic) and slow(er) (polysynaptic) corticospinal pathways.Methods: 9 subjects underwent 8 weeks of unilateral ankle joint immobilization during daytime, 7 subjects served as controls. The measures obtained before and after immobilization included stretch- and H-reflexes assessing excitability of the spinal reflex circuitries, TMS recruitment curves estimating overall changes in corticospinal excitability, and Hcond.Results: TMS recruitment curves showed an overall increase in corticospinal excitability following immobilization. Importantly, Hcond revealed significant facilitation of conditioned reflexes, but only for longer conditioning intervals, suggesting that immobilization increased excitability only of slower, indirect corticospinal pathways. No changes were observed in the control group. Immobilization had no significant effects on spinal reflex measures.Conclusions: 8 weeks of ankle joint immobilization was accompanied by pathway-specific modulation of corticospinal transmission.Significance: It is particularly interesting that fast corticospinal projections were unaffected as these are involved in controlling many, if not most, movements in humans

Soluble Triggering Receptor Expressed on Myeloid Cells 1 Is Released in Patients with Stable Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is increasingly recognized as a systemic disease that is associated with increased serum levels of markers of systemic inflammation. The triggering receptor expressed on myeloid cells 1 (TREM-1) is a recently identified activating receptor on neutrophils, monocytes, and macrophage subsets. TREM-1 expression is upregulated by microbial products such as the toll-like receptor ligand lipoteichoic acid of Gram-positive or lipopolysaccharides of Gram-negative bacteria. In the present study, sera from 12 COPD patients (GOLD stages I–IV, FEV1 51 ± 6%) and 10 healthy individuals were retrospectively analyzed for soluble TREM-1 (sTREM-1) using a newly developed ELISA. In healthy subjects, sTREM-1 levels were low (median 0.25 ng/mL, range 0–5.9 ng/mL). In contrast, levels of sTREM-1 in sera of COPD patients were significantly increased (median 11.68 ng/mL, range 6.2–41.9 ng/mL, P<.05). Furthermore, serum levels of sTREM-1 showed a significant negative correlation with lung function impairment. In summary, serum concentrations of sTREM-1 are increased in patients with COPD. Prospective studies are warranted to evaluate the relevance of sTREM-1 as a potential marker of the disease in patients with COPD

Isolated Schistosoma mansoni eggs prevent allergic airway inflammation

Chronic helminth infection with Schistosoma (S.) mansoni protects against allergic airway inflammation (AAI) in mice and is associated with reduced Th2 responses to inhaled allergens in humans, despite the presence of schistosome-specific Th2 immunity. Schistosome eggs strongly induce type 2 immunity and allow to study the dynamics of Th2 versus regulatory responses in the absence of worms. Treatment with isolated S. mansoni eggs by i.p. injection prior to induction of AAI to ovalbumin (OVA)/alum led to significantly reduced AAI as assessed by less BAL and lung eosinophilia, less cellular influx into lung tissue, less OVA-specific Th2 cytokines in lungs and lung-draining mediastinal lymph nodes and less circulating allergen-specific IgG1 and IgE antibodies. While OVA-specific Th2 responses were inhibited, treatment induced a strong systemic Th2 response to the eggs. The protective effect of S. mansoni eggs was unaltered in mu MT mice lacking mature (B2) B cells and unaffected by Treg cell depletion using anti-CD25 blocking antibodies during egg treatment and allergic sensitization. Notably, prophylactic egg treatment resulted in a reduced influx of pro-inflammatory, monocyte-derived dendritic cells into lung tissue of allergic mice following challenge. Altogether, S. mansoni eggs can protect against the development of AAI, despite strong egg-specific Th2 responses

Treatment with Helicobacter pylori-derived VacA attenuates allergic airway disease

BACKGROUND: Asthma is an incurable heterogeneous disease with variations in clinical and underlying immunological phenotype. New approaches could help to support existing therapy concepts. Neonatal infection of mice with Helicobacter pylori or administration of H. pylori-derived extracts or molecules after birth have been shown to prevent the development of allergic airway disease later in life. This study evaluated the potential therapeutic efficacy of H. pylori vacuolating cytotoxin A (VacA) in allergic airway inflammation and investigated the underlying immunological mechanisms for its actions. METHODS: Murine models of allergic airway diseases, and murine and human in vitro models were used. RESULTS: In both an acute model and a therapeutic house dust mite model of allergic airway disease, treatment with H. pylori-derived VacA reduced several asthma hallmarks, including airway hyperresponsiveness, inflammation and goblet cell metaplasia. Flow cytometry and ELISA analyses revealed induction of tolerogenic dendritic cells (DC) and FoxP3 positive regulatory T cells (Tregs), and a shift in the composition of allergen-specific immunoglobulins. Depletion of Tregs during treatment with VacA reversed treatment-mediated suppression of allergic airway disease. Human monocyte derived DCs (moDC) that were exposed to VacA induced Tregs in co-cultured naïve autologous T cells, replicating key observations made in vivo. CONCLUSION: H. pylori-derived VacA suppressed allergic airway inflammation via induction of Tregs in both allergic airway disease models. These data suggest that the immunomodulatory activity of VacA could potentially be exploited for the prevention and treatment of allergic airway disease

Barriers for Sports and Exercise Participation and Corresponding Barrier Management in Cystic Fibrosis

Background Nowadays physical activity (PA)/exercise is an important component of cystic fibrosis (CF) therapy. The aim of the study was to assess the barriers to PA and the barrier management and to explore the effect of supervision on the barriers and barrier management during an exercise program. Methods In total, 88 people with CF (pwCF) of the ages 6 to 50 years old (mean 24.2 ± 7.9 yrs) participated in the partially supervised 12-month exercise program and filled in a structured and validated questionnaire about barriers to sports and barrier management at baseline. Results Physical barriers were more relevant than psychosocial barriers and no trend could be seen in the situational and preventive counter strategies. When divided in subgroups, the less active pwCF (7500 steps/day), physical barriers, and psychosocial barriers showed no significant differences. However physical barriers showed a tendency to have a higher value in the less active group compared to the more active group (p > 0.05). Stratified by age or FEV1%pred between the subgroups, no differences could be seen regarding barriers and counter strategies. Conclusions Physical barriers seemed to have a higher priority when it comes to not participating in PA/exercise. Supervision over 6 months during an exercise program did not show a beneficial effect on barriers and barrier management. Besides the motivational aspect of sport counselling, the volitional aspect seemed to be more important to incorporate more PA into daily life. Individual barriers and their concrete counter strategies should be discussed with the patient with CF. Sport counselling is needed permanently and should be part of the CF routine care

Modulating local airway immune responses to treat allergic asthma: lessons from experimental models and human studies

With asthma affecting over 300 million individuals world-wide and estimated to affect 400 million by 2025, developing effective, long-lasting therapeutics is essential. Allergic asthma, where Th2-type immunity plays a central role, represents 90% of child and 50% of adult asthma cases. Research based largely on animal models of allergic disease have led to the generation of a novel class of drugs, so-called biologicals, that target essential components of Th2-type inflammation. Although highly efficient in subclasses of patients, these biologicals and other existing medication only target the symptomatic stage of asthma and when therapy is ceased, a flare-up of the disease is often observed. Therefore, it is suggested to target earlier stages in the inflammatory cascade underlying allergic airway inflammation and to focus on changing and redirecting the initiation of type 2 inflammatory responses against allergens and certain viral agents. This focus on upstream aspects of innate immunity that drive development of Th2-type immunity is expected to have longer-lasting and disease-modifying effects, and may potentially lead to a cure for asthma. This review highlights the current understanding of the contribution of local innate immune elements in the development and maintenance of inflammatory airway responses and discusses available leads for successful targeting of those pathways for future therapeutics