Medicine and surgery in Central Asia

Two cardinal facts exist in connection with Medicine and Surgery in Thibet and they are these:1. There exists no definite Science, such knowledge as there is being derived from the study of old Buddhist and Sanskrit lore.2. It is wholly controlled by religious fanaticism exerted by the influence of the Buddhist Lamas. This latter is illustrated by Photograph X. herewith (page 53.). In it is depicted a house in which sickness has occurred. In the room on the right the patient is in bed, evidently in an emaciated condition, and a priest is in the act of feeling his pulse. Outside in the adjoining room another priest sits amidst charms of all kinds - some (those on the table) being composed of butter and rice, others (on the floor) being made of cotton thread wound around a wooden frame of definite shape. The priest is sitting at his drum which he beats incessantly day and night, being relieved every few hours by another priest, All this is to keep away and drive away the Evil Spirit which is causing the sickness. For this work he receives about 1/- per day plus his food and plenty of "chang" (Thibetan beer). . When the patient is recovering, during one night at a time privately arranged by the priests, they rush about the house as if suddenly become mad and eventually, having exorcised the evil spirit which enters into some of their charms, they rush outside and burn them in a big bonfire and at the same time discharge firearms. This is the end of the case.Unfortunately it must be many years before these things can change. Education they refuse, and as the country is over-run with Lamas any good influence brought to bear upon the layman is speedily destroyed by the action of the Lamas who call down upon the infidel all the worst maledictions possible. He in fear has perforce to amend his ways or else incur their displeasure which they do not omit to arrange shall be in a very tangible form

Resting respiratory tract dendritic cells preferentially stimulate T helper cell Type 2(Th2) responses and require obligatory cytokine signals for induction of Th1 immunity

Consistent with their role in host defense, mature dendritic cells (DCs) from central lymphoid organs preferentially prime for T helper cell type 1 (Th1)-polarized immunity. However, the “default” T helper response at mucosal surfaces demonstrates Th2 polarity, which is reflected in the cytokine profiles of activated T cells from mucosal lymph nodes. This study on rat respiratory tract DCs (RTDCs) provides an explanation for this paradox. We demonstrate that freshly isolated RTDCs are functionally immature as defined in vitro, being surface major histocompatibility complex (MHC) II lo, endocytosishi, and mixed lymphocyte reactionlo, and these cells produce mRNA encoding interleukin (IL)-10. After ovalbumin (OVA)-pulsing and adoptive transfer, freshly isolated RTDCs preferentially stimulated Th2-dependent OVA-specific immunoglobulin (Ig)G1 responses, and antigen-stimulated splenocytes from recipient animals produced IL-4 in vitro. However, preculture with granulocyte/macrophage colony stimulating factor increased their in vivo IgG priming capacity by 2–3 logs, inducing production of both Th1- and Th2-dependent IgG subclasses and high levels of IFN-γ by antigen-stimulated splenocytes. Associated phenotypic changes included upregulation of surface MHC II and B7 expression and IL-12 p35 mRNA, and downregulation of endocytosis, MHC II processing– associated genes, and IL-10 mRNA expression. Full expression of IL-12 p40 required additional signals, such as tumor necrosis factor α or CD40 ligand. These results suggest that the observed Th2 polarity of the resting mucosal immune system may be an inherent property of the resident DC population, and furthermore that mobilization of Th1 immunity relies absolutely on the provision of appropriate microenvironmental costimuli

Gesundheit! Patrick Holt smothers allergies and asthma

Drop the mop and play with Fido is Patrick Holt's recommendation for raising an allergy-free child. Although a tangled web of factors underlies allergies and asthma, Holt believes that preventing lifelong affliction could be simple

Allies or enemies? The effect of regulatory T cells and related T lymphocytes on the profibrotic environment in bleomycin-injured lung mouse models.

Idiopathic pulmonary fibrosis (IPF) is characterized by permanent scarring of lung tissue and declining lung function, and is an incurable disease with increase in prevalence over the past decade. The current consensus is that aberrant wound healing following repeated injuries to the pulmonary epithelium is the most probable cause of IPF, with various immune inflammatory pathways having been reported to impact disease pathogenesis. While the role of immune cells, specifically T lymphocytes and regulatory T cells (Treg), in IPF pathogenesis has been reported and discussed recently, the pathogenic or beneficial roles of these cells in inducing or preventing lung fibrosis is still debated. This lack of understanding could be due in part to the difficulty in obtaining diseased human lung tissue for research purposes. For this reason, many animal models have been developed over the years to attempt to mimic the main clinical hallmarks of IPF: among these, inducing lung injury in rodents with the anti-cancer agent bleomycin has now become the most commonly studied animal model of IPF. Pulmonary fibrosis is the major side effect when bleomycin is administered for cancer treatment in human patients, and a similar effect can be observed after intra-tracheal administration of bleomycin to rodents. Despite many pathophysiological pathways of lung fibrosis having been investigated in bleomycin-injured animal models, one central facet still remains controversial, namely the involvement of specific T lymphocyte subsets, and in particular Treg, in disease pathogenesis. This review aims to summarize the major findings and conclusions regarding the involvement of immune cells and their receptors in the pathogenesis of IPF, and to elaborate on important parallels between animal models and the human disease. A more detailed understanding of the role of Treg and other immune cell subsets in lung injury and fibrosis derived from animal models is a critical basis for translating this knowledge to the development of new immune-based therapies for the treatment of human IPF

Protection against neonatal respiratory viral infection via maternal treatment during pregnancy with the benign immune training agent OM‐85

Objectives Incomplete maturation of immune regulatory functions at birth is antecedent to the heightened risk for severe respiratory infections during infancy. Our forerunner animal model studies demonstrated that maternal treatment with the microbial-derived immune training agent OM-85 during pregnancy promotes accelerated postnatal maturation of mechanisms that regulate inflammatory processes in the offspring airways. Here, we aimed to provide proof of concept for a novel solution to reduce the burden and potential long-term sequelae of severe early-life respiratory viral infection through maternal oral treatment during pregnancy with OM-85, already in widespread human clinical use. Methods In this study, we performed flow cytometry and targeted gene expression (RT-qPCR) analysis on lungs from neonatal offspring whose mothers received oral OM-85 treatment during pregnancy. We next determined whether neonatal offspring from OM-85 treated mothers demonstrate enhanced protection against lethal lower respiratory infection with mouse-adapted rhinovirus (vMC0), and associated lung immune changes. Results Offspring from mothers treated with OM-85 during pregnancy display accelerated postnatal seeding of lung myeloid populations demonstrating upregulation of function-associated markers. Offspring from OM-85 mothers additionally exhibit enhanced expression of TLR4/7 and the IL-1β/NLRP3 inflammasome complex within the lung. These treatment effects were associated with enhanced capacity to clear an otherwise lethal respiratory viral infection during the neonatal period, with concomitant regulation of viral-induced IFN response intensity. Conclusion These results demonstrate that maternal OM-85 treatment protects offspring against lethal neonatal respiratory viral infection by accelerating development of innate immune mechanisms crucial for maintenance of local immune homeostasis in the face of pathogen challenge

Genetic partitioning of interleukin-6 signalling in mice dissociates Stat3 from Smad3-mediated lung fibrosis

Idiopathic pulmonary fibrosis (IPF) is a fatal disease that is unresponsive to current therapies and characterized by excessive collagen deposition and subsequent fibrosis. While inflammatory cytokines, including interleukin (IL)-6, are elevated in IPF, the molecular mechanisms that underlie this disease are incompletely understood, although the development of fibrosis is believed to depend on canonical transforming growth factor (TGF)-β signalling. We examined bleomycin-induced inflammation and fibrosis in mice carrying a mutation in the shared IL-6 family receptor gp130. Using genetic complementation, we directly correlate the extent of IL-6-mediated, excessive Stat3 activity with inflammatory infiltrates in the lung and the severity of fibrosis in corresponding gp130757F mice. The extent of fibrosis was attenuated in B lymphocyte-deficient gp130757F;µMT−/− compound mutant mice, but fibrosis still occurred in their Smad3−/− counterparts consistent with the capacity of excessive Stat3 activity to induce collagen 1α1 gene transcription independently of canonical TGF-β/Smad3 signalling. These findings are of therapeutic relevance, since we confirmed abundant STAT3 activation in fibrotic lungs from IPF patients and showed that genetic reduction of Stat3 protected mice from bleomycin-induced lung fibrosis

Pulmonary delivery of cationic gold nanoparticles boost antigen-specific CD4+ T Cell Proliferation

To address how surface charge affects the fate of potential nanocarriers in the lung, gold nanoparticles (AuNPs) coated with polyvinyl alcohol containing either positively (NH2) or negatively (COOH) charged functional groups were intra-nasally instilled in mice, and their uptake by antigen presenting cell populations (APC) in broncho-alveolar lavage (BAL) fluid, trachea, and lung parenchyma, as well as trafficking to the lung draining lymph nodes (LDLNs) was assessed by flow cytometry. Furthermore, CD4+ T cell proliferation in LDLNs was investigated following instillation. All APC subpopulations preferentially captured positively-charged AuNPs compared to their negatively-charged counterparts. Uptake of AuNPs up-regulated expression of co-stimulatory molecules on all APC populations. Furthermore, positively-charged AuNPs induced enhanced OVA-specific CD4+ T cell stimulation in LDLNs compared to negatively-charged AuNPs, or polymer alone. Our findings demonstrate surface charge as a key parameter determining particle uptake by APC, and down-stream immune responses depend on the presence of particle core-bound polymer

Transplacental innate immune training via maternal microbial exposure: role of XBP1-ERN1 axis in dendritic cell precursor programming

We recently reported that offspring of mice treated during pregnancy with the microbial-derived immunomodulator OM-85 manifest striking resistance to allergic airways inflammation, and localized the potential treatment target to fetal conventional dendritic cell (cDC) progenitors. Here, we profile maternal OM-85 treatment-associated transcriptomic signatures in fetal bone marrow, and identify a series of immunometabolic pathways which provide essential metabolites for accelerated myelopoiesis. Additionally, the cDC progenitor compartment displayed treatment-associated activation of the XBP1-ERN1 signalling axis which has been shown to be crucial for tissue survival of cDC, particularly within the lungs. Our forerunner studies indicate uniquely rapid turnover of airway mucosal cDCs at baseline, with further large-scale upregulation of population dynamics during aeroallergen and/or pathogen challenge. We suggest that enhanced capacity for XBP1-ERN1-dependent cDC survival within the airway mucosal tissue microenvironment may be a crucial element of OM-85-mediated transplacental innate immune training which results in postnatal resistance to airway inflammatory disease

Size-dependent accumulation of particles in lysosomes modulates dendritic cell function through impaired antigen degradation

Introduction: Nanosized particles may enable therapeutic modulation of immune responses by targeting dendritic cell (DC) networks in accessible organs such as the lung. To date, however, the effects of nanoparticles on DC function and downstream immune responses remain poorly understood. Methods: Bone marrow–derived DCs (BMDCs) were exposed in vitro to 20 or 1,000 nm polystyrene (PS) particles. Particle uptake kinetics, cell surface marker expression, soluble protein antigen uptake and degradation, as well as in vitro CD4⁺ T-cell proliferation and cytokine production were analyzed by flow cytometry. In addition, co-localization of particles within the lysosomal compartment, lysosomal permeability, and endoplasmic reticulum stress were analyzed. Results: The frequency of PS particle–positive CD11c⁺/CD11b⁺ BMDCs reached an early plateau after 20 minutes and was significantly higher for 20 nm than for 1,000 nm PS particles at all time-points analyzed. PS particles did not alter cell viability or modify expression of the surface markers CD11b, CD11c, MHC class II, CD40, and CD86. Although particle exposure did not modulate antigen uptake, 20 nm PS particles decreased the capacity of BMDCs to degrade soluble antigen, without affecting their ability to induce antigen-specific CD4⁺ T-cell proliferation. Co-localization studies between PS particles and lysosomes using laser scanning confocal microscopy detected a significantly higher frequency of co-localized 20 nm particles as compared with their 1,000 nm counterparts. Neither size of PS particle caused lysosomal leakage, expression of endoplasmic reticulum stress gene markers, or changes in cytokines profiles. Conclusion: These data indicate that although supposedly inert PS nanoparticles did not induce DC activation or alteration in CD4⁺ T-cell stimulating capacity, 20 nm (but not 1,000 nm) PS particles may reduce antigen degradation through interference in the lysosomal compartment. These findings emphasize the importance of performing in-depth analysis of DC function when developing novel approaches for immune modulation with nanoparticles.