Improving vasomotor symptoms; psychological symptoms; and health-related quality of life in peri- or post-menopausal women through yoga: An umbrella systematic review and meta-analysis.

OBJECTIVES: Vasomotor symptoms (VMS), commonly reported during menopausal transition, negatively affect psychological health and health-related quality of life (HRQoL). While hormone therapy is an effective treatment, its use is limited by concerns about possible harms. Thus, many women with VMS seek nonhormonal, nonpharmacologic treatment options. However, evidence to guide clinical recommendations is inconclusive. This study reviewed the effectiveness of yoga, tai chi and qigong on vasomotor, psychological symptoms, and HRQoL in peri- or post-menopausal women. DESIGN: MEDLINE, Cochrane Database of Systematic Reviews, EMBASE, CINAHL and the Allied and Complementary Medicine Database were searched. Researchers identified systematic reviews (SR) or RCTs that evaluated yoga, tai chi, or qigong for vasomotor, psychological symptoms, and health-related quality of life (HRQoL) in peri- or post-menopausal women. Data were abstracted on study design, participants, interventions and outcomes. Risk of bias (ROB) was assessed and updated meta-analyses were performed. RESULTS: We identified one high-quality SR (5 RCTs, 582 participants) and 3 new RCTs (345 participants) published after the SR evaluating yoga for vasomotor, psychological symptoms, and HRQoL; no studies evaluated tai chi or qigong. Updated meta-analyses indicate that, compared to controls, yoga reduced VMS (5 trials, standardized mean difference (SMD) -0.27, 95% CI -0.49 to -0.05) and psychological symptoms (6 trials, SDM -0.32; 95% CI -0.47 to -0.17). Effects on quality of life were reported infrequently. Key limitations are that adverse effects were rarely reported and outcome measures lacked standardization. CONCLUSIONS: Results from this meta-analysis suggest that yoga may be a useful therapy to manage bothersome vasomotor and psychological symptoms.

Use of mindfulness, meditation and relaxation to treat vasomotor symptoms.

Postmenopausal women with bothersome vasomotor symptoms (VMS) often seek alternatives to hormone-based treatment due to medication risks or personal preference. We sought to identify the effects of meditation, mindfulness, hypnosis and relaxation on VMS and health-related quality of life in perimenopausal and postmenopausal women. To do this, we conducted an umbrella review supplemented by new randomized, controlled trials (RCTs) published since the most recent good-quality systematic review for eligible interventions. We searched MEDLINE and the Cochrane Database of Systematic Reviews, PubMed, EMBASE, CINAHL and the Allied and Complementary Medicine Databases. We identified five systematic reviews and six new RCTs that met eligibility criteria. In a new meta-analysis examining four RCTs comparing paced respiration with a control group, we found that paced respiration is not associated with a statistically significant decrease in VMS frequency (standardized mean difference (SMD) 0.04, 95% confidence interval (CI) -0.73 to 0.82, I2 = 56.6%, three trials) or severity (SMD 0.06, 95% CI -0.69 to 0.80; I2 = 65.1%, three trials). There was not sufficient new information to conduct meta-analyses that examined the effect of mindfulness or hypnosis on our outcomes of interest. No effect on VMS or quality of life was found between various relaxation or mindfulness interventions.

What is the physiological function of mast cells?

Under physiological conditions, skin mast cells preferentially localize around nerves, blood vessels and hair follicles. This observation, which dates back to Paul Ehrlich, intuitively suggests that these enigmatic, multifacetted protagonists of natural immunity are functionally relevant to many more aspects of tissue physiology than just to the generation of inflammatory and vasodilatory responses to IgE-dependent environmental antigens. And yet, for decades, mainstream-mast cell research has been dominated by a focus on the -undisputedly prominent and important - mast cell functions in type I immune responses and in the pathogenesis and management of allergic diseases. Certainly, it is hard to believe that the very large and rather selectively distributed number of mast cells in normal, uninflamed, non-infected, non-traumatized mammalian skin or mucosal tissue simply hanging around there lazily day and night, just wait for the odd allergen or parasite-associated antigen to come by so the mast cell can finally swing into action. Indeed, the past decade has witnessed a renaissance of mast cell research 'beyond allergy', along with a more systematic exploration of the surprisingly wide range of physiological functions that mast cells may be involved in. The current debate sketches many exciting horizons that have recently come into our vision during this intriguing, ongoing search.

Interleukin mRNA changes in mast cells stimulated by TSL-1 antigens.

In this work we analyzed by RT-PCR, the mRNA changes for IL-4, IL-10, TNF and IFN (induced by TSL-1 antigens in a rat mast cell line (HRMC) with mucosal characteristics. The data obtained showed an increase of 65 and 52% in mRNA expression for IL-4 and TNF respectively and a decrease of 59 and 55% in mRNAs for IFN gamma and IL-10. Our results suggest that TSL-1 antigens induce the release from MC of regulatory molecules, such as IL-4 by an IgE independent mechanism. Our data also provides important information related to the ability of MC to participate not only in the effector phase against the infectious agents, but also in the orchestration of the immune response by the host against parasites.

Submandibular gland peptide-T (SGP-T) inhibits intestinal anaphylaxis.

A novel peptide, submandibular gland peptide-T (SGP-T), which reduces allergen-induced hypotension, was examined for effects on intestinal anaphylaxis. Hooded-Lister rats were sensitized to egg albumin and prepared for the measurement of in vivo myoelectric activity of the jejunum. The disruption of migrating myoelectric complexes (MMCs) that occurs upon intraluminal, duodenal challenge with antigen of sensitized rats was inhibited by 75% upon intravenous treatment with 100 micrograms/kg of SGP-T. In addition, SGP-T reduced the number of rats experiencing anaphylactic diarrhea and disrupted MMCs, but the peptide did not alter antigen-provoked release of rat mast cell protease II. The mechanism of action of SGP-T remains to be determined, but it apparently does not act directly on mast cells to exert its antianaphylactic action. These results emphasize that modulation of immediate hypersensitivity reactions is only one of several gastrointestinal activities that are affected by growth factors and peptides released from salivary glands.

Nitric oxide synthesis inhibition increases epithelial permeability via mast cells.

In this study, we assessed the involvement of mast cells and mast cell-derived mediators in the enhanced epithelial permeability associated with nitric oxide synthesis inhibition. Permeability of the small bowel was assessed by measuring the clearance of a small marker (51Cr-labeled EDTA) from blood to lumen in the presence of the nitric oxide synthesis inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). L-NAME caused a very rapid (10 min) increase in epithelial permeability, reaching peak values (sixfold increase) within 20 min. Two mast cell stabilizers, doxantrazole and lodoxamide, greatly attenuated the rise in mucosal permeability. Rat mast cell protease II activity (marker of mucosal mast cell degranulation) was increased significantly only in the plasma of L-NAME-treated animals. Chronic dexamethasone administration depleted rats of mucosal mast cells and also prevented the L-NAME-induced rise in mucosal permeability. The increase in epithelial permeability was mediated by a number of mediators: platelet-activating factor caused the early rise in epithelial permeability, and histamine caused the later increase in epithelial permeability. Superoxide dismutase attenuated the L-NAME-induced rise in epithelial permeability, suggesting an important and continuous role for superoxide. Transepithelial flux of 51Cr-EDTA across rat intestinal epithelial cell monolayers did not increase in the presence of L-NAME, suggesting that inhibition of nitric oxide does not directly cause epithelial permeability alterations, whereas the in vivo data implicate a potential role for the mast cell. In conclusion, nitric oxide synthesis inhibition activates mast cells in the mucosa and consequently increases epithelial permeability.

Pulmonary immune responses to Nippostrongylus brasiliensis: isotype-specific antibodies in bronchoalveolar lavage fluids of rats.

Larvae of Nippostrongylus brasiliensis have an obligatory migratory phase through the lungs of rats during their development. Since earlier studies have shown that this migration is associated with accumulation of Fc receptor bearing effector cells in the bronchoalveolar spaces, we have analysed antibody reactivity in bronchoalveolar lavage fluids (BALF) during development of immune responses against N. brasiliensis. The development of parasite specific antibodies in bronchoalveolar spaces was similar to that in the serum, but was of a lower titre. A secondary infection resulted in an anamnestic response. Isotype analysis showed that IgG, IgA and IgM antibodies were present in BALF and they recognized several proteins of the parasite ranging from 16-290 kDa. Immunoblot analysis on two-dimensional electrophoretic separated parasitic proteins identified stage specific differences in the BALF antibody responses. IgG was the predominant class of antibody in BALF and when compared with serum, IgM antibody responses were weak. Thus, infection with N. brasiliensis resulted in the appearance of site-, stage- and isotype-specific antibody responses in the lungs of rats.

Pulmonary inflammation and immune responses during the course of Nippostrongylus brasiliensis infection: lymphocyte subsets in bronchoalveolar lavage fluids of rats.

Quantitative measurements were made of different phenotypes of lymphocytes in bronchoalveolar lavage fluid (BALF) of rats during the course of a primary or secondary infection with Nippostrongylus brasiliensis. These changes were compared with those in the peripheral blood to understand the site-specificity of the responses. Following infection, there was a significant increase in both B and T lymphocytes in BALF. The CD4:CD8 ratio was significantly altered with a decreased ratio on day 2 and increased ratio on days 16 and 32 post infection (p.i.). Two colour analysis showed that during larval migration through the lungs (day 2 p.i.) there was a significant increase in CD8+, CD4+ OX22+ and CD4+ OX22- cells in BALF. As infection progressed in time, CD4+ OX22- cells were increased significantly. Compared to primary infection, a secondary infection resulted in increased recovery of CD4+ OX22- cells in BALF. These changes were not readily appreciated in the peripheral blood, suggesting site-specific compartmentalization of lymphocyte responses in the lung. The functional significance of these dynamic changes in lymphocyte subsets in the airspaces following infection remains to be identified.

IgE antibody responses in bronchoalveolar spaces of rats infected with Nippostrongylus brasiliensis.

IgE levels in the bronchoalveolar lavage fluids (BALF) of rats increased significantly following infection with Nippostrongylus brasiliensis. This increase corresponded with a concurrent increase in serum IgE levels. However, a comparison of IgE to albumin ratio in both BALF and serum suggested local accumulation and/or production of IgE in the bronchoalveolar spaces rather than leakage from serum. Subsequent analysis of BALF showed presence of heat-labile PCA activity with highest anti-worm titer (1:64) on Days 11-16 postinfection (pi). Secondary infection resulted in up to a fourfold increase in PCA activity compared to primary infection. Immunoblot analysis showed that these parasite-specific IgE antibodies in BALF recognized many proteins of adult worms ranging from 16-290 kDa. IgE antibodies in serum and BALF showed similarities in their reactivities toward adult worm antigens. However, the IgE antibody reactivities to different antigens varied significantly among different days pi. Depletion of IgG from BALF and serum resulted in more intense binding by IgE antibodies to antigens than when IgG was not depleted. Concurrent with the elevated levels of IgE antibodies, there was a significant increase in the levels of histamine in BALF, suggesting activation of mast cells. Thus, following N. brasiliensis infection there is an abundance of parasite-specific IgE antibodies in the lower respiratory tract and IgE-mediated pathways of inflammation appeared to be activated in the lungs.

In vitro translation of mRNA from rat peritoneal and intestinal mucosal mast cells.

We isolated RNA from in vivo-derived rat peritoneal (PMC) and intestinal mucosal mast cells (IMMC) and assessed the in vitro translation products of these two mast cell types using rabbit reticulocyte lysate and wheat germ systems. The translated polypeptides were analyzed by one- and two-dimensional gel electrophoresis. Fluorographic analyses established that polypeptides with a spectrum of molecular size and pI were produced by both PMC and IMMC. Immunoprecipitation studies with anti-rat mast cell protease (RMCP) I antibodies detected a band at 31 kD from products of PMC RNA assessed by one-dimensional electrophoresis, whereas anti-RMCP II antibodies precipitated a band of 27 kD from products of IMMC RNA. This is the first report of translation products of IMMC and of the translated precursors of RMCP I and RMCP II.

Removal of the submandibular glands increases the acute hypotensive response to endotoxin.

We investigated the roles of the submandibular glands and of their sympathetic innervation on the acute hypotensive response induced by the i.v. injection of endotoxin (10 mg/kg; Salmonella typhosa) into rats anesthetized with sodium pentobarbital. Endotoxin given to unoperated and sham-operated rats induced a transient 30-40 mm Hg drop in blood pressure. Rats that had their submandibular glands removed (sialadenectomy) or bilateral resection of the superior cervical ganglia (ganglionectomy), exhibited significantly larger drops in blood pressure (approximately 65 mm Hg) that were maintained for the 60 min of the experiment. This increased responsiveness to endotoxin in sialadenectomized and ganglionectomized animals was not related to changes in haematocrit, white blood cell counts, or neutrophil activity. Pretreatment of rats with pentoxifylline (PTX) produced substantial protection against the hypotensive effects of endotoxin in ganglionectomized and sialadenectomized rats, although this xanthine did not affect the responses of sham-operated rats. These results suggest that the submandibular gland elaborates a factor that protects against acute hypotension induced by endotoxin and that this factor is under the control of the cervical sympathetic nervous system.

Decentralization of the superior cervical ganglia and the immediate hypersensitivity response.

Bilateral decentralization of the superior cervical ganglia protects against pulmonary inflammation when measured 8 hr after induction of anaphylaxis in rats sensitized to the nematode, Nippostrongylus brasiliensis. Since anaphylactic shock produces immediate perturbations to the cardiovascular and respiratory systems, we examined whether bilateral decentralization of the superior cervical ganglia modified the responses of these two systems during the first 4 hr of the anaphylactic response. With the exception of the bronchioles, decentralization did not protect against anaphylaxis-associated increases in extravasation of albumin, and the small changes in respiratory function induced by anaphylaxis were unaffected by the denervation. Decentralization did not alter anaphylaxis-induced reductions in blood flow to the gastrointestinal tract; however, blood flow to the kidneys and spleen of decentralized rats was restored more rapidly to normal values. These results suggest that the protective effect of decentralization on the late phase pulmonary inflammation of anaphylaxis is unrelated to early changes in respiratory mechanics, although the protection may be facilitated by the more rapid re-establishment of normal cardiovascular homeostasis.

Role for the submandibular gland in modulating pulmonary inflammation following induction of systemic anaphylaxis.

Previous studies have shown that bilateral decentralization of the superior cervical ganglia (SCG; decentralization) attenuates allergen-induced pulmonary inflammatory responses in male rats sensitized to the nematode Nippostrongylus brasiliensis. The present report examines the neuronal and glandular mechanisms mediating the protection against pulmonary inflammation afforded by decentralization. Tissues and organs innervated by the SCG are responsible for this protection since, in a manner similar to decentralization, bilateral removal of the SCG (ganglionectomy) reduced anaphylaxis-induced accumulation of inflammatory cells in bronchoalveolar lavage fluid. Removal of the submandibular gland (sialadenectomy) did not modify the severity of the pulmonary inflammation, but concurrent sialadenectomy and decentralization abolished the protective effect of decentralization. Thus, we postulate that cervical sympathetic nerves tonically inhibit release of anti-inflammatory factors from submandibular glands. No relationship was found between noradrenaline and serotonin content of submandibular glands and the degree of protection against pulmonary inflammation offered by decentralization and ganglionectomy. Both decentralization and ganglionectomy appeared to increase the level of transcripts that encode immunomodulatory growth factors (nerve growth factor and epidermal growth factor) in submandibular glands, but these denervations evidently did not modify the transcripts for TGF beta 2. Systemic inflammatory events are regulated by the central nervous system at a level superior to the SCG probably through modulation of immunoregulatory factors in submandibular glands.

Inhibition of neutrophil chemotaxis and activation following decentralization of the superior cervical ganglia.

Recent studies have shown that bilateral decentralization (sympathectomy) of the superior cervical ganglia (SCG) of rats sensitized to the parasite Nippostrongylus brasiliensis attenuated the development of pulmonary inflammation following allergen challenge. Sympathectomy inhibited total leukocyte infiltration into lung lavage fluids, particularly neutrophil infiltration. To define the effects of decentralization of the SCG on neutrophil responses, peripheral blood neutrophils of rats were isolated and tested in in vitro chemotaxis and phagocytosis assays. Neutrophils from rats that were sympathectomized 7 days previously displayed a marked reduction in chemotaxis to N-formyl-methionyl-leucyl-phenylalanine and leukotriene B4 compared to neutrophils from sham-operated or unoperated groups. Although the degree of chemotaxis was greater in blood neutrophils from parasite-infected rats than from uninfected rats, sympathectomy markedly reduced the chemotactic responses of both groups. In addition, neutrophils of sympathectomized rats were unresponsive to lipopolysaccharide-induced metabolic activation as assessed by in vitro phagocytosis and oxidative reduction of nitroblue tetrazolium. Thus, decentralization of the SCG of rats affects the chemotactic responses and functions of neutrophils. Understanding the role of the sympathetic nervous system in modulating the behavior of neutrophils will shed light on the interactions between the nervous and immune systems.

Mast cell response to formaldehyde. 1. Modulation of mediator release.

To examine the effects of the atmospheric pollutant formaldehyde on functionally distinct mast cells, peritoneal mast cells (PMC), intestinal mucosal mast cells (IMMC) and mouse bone-marrow-derived mast cells (BMMC) were incubated with various concentrations of formaldehyde. Pretreatment for 30 min with up to 100 micrograms/ml formaldehyde was not cytotoxic to mast cells. Formaldehyde (1-10 micrograms/ml) alone induced low levels of histamine release (< 10%) from IMMC and BMMC. Antigen-induced histamine release was significantly increased in both PMC pretreated with low concentrations of formaldehyde (5-20 micrograms/ml) and BMMC pretreated with 10 micrograms/ml formaldehyde but decreased in PMC pretreated with a higher concentration (100 micrograms/ml) of formaldehyde. By contrast, antigen-induced histamine release was decreased in IMMC pretreated with formaldehyde in a dose-dependent manner. Histamine release stimulated with A23187 was also increased in PMC pretreated with a low concentration (10 micrograms/ml) of formaldehyde but decreased in those pretreated with a higher concentration (100 micrograms/ml) of formaldehyde. Pretreatment with 10 micrograms/ml formaldehyde significantly enhanced beta-hexosaminidase release from PMC stimulated with antigen or A23187. Compared to sham-treated PMC, PMC pretreated with formaldehyde expressed a markedly depressed natural cytotoxicity for the tumor target WEHI-164 (an assay of tumor necrosis factor alpha activity). These results suggest that formaldehyde modifies various mast cell functions through alterations in cellular metabolism. Such effects may be important in respiratory and other diseases associated with formaldehyde exposure.

Mast cell response to formaldehyde. 2. Induction of stress-like proteins.

Previously we established that immediately after pretreatment with low concentrations (5-10 micrograms/ml) of formaldehyde antigen- and ionophore-induced histamine secretion was enhanced from peritoneal mast cells (PMC) isolated from rats infected with Nippostrongylus brasiliensis. In contrast to immediately following pretreatment with low concentrations of formaldehyde, 3 h after a 30-min treatment with formaldehyde (10, 50 and 100 micrograms/ml) antigen-induced histamine secretion from PMC was significantly depressed, and 35S-methionine incorporation was also decreased. To further explore the effects of formaldehyde on mast cells, we investigated protein biosynthesis of PMC following formaldehyde treatment and compared this with the effects of hydrogen peroxide (H2O2) or heat treatment. One- and two-dimensional SDS-PAGE were used to assess the effects. Formaldehyde treatment induced the synthesis of 70- and 72-kD stress-like proteins in rat PMC. Pretreatment of PMC with 50 microM H2O2 and heat (45 degrees C) also induced proteins with the same molecular weight. Two-dimensional SDS-PAGE analysis established that formaldehyde-induced 70-kD proteins had the same pI values as 70-kD heat shock proteins previously observed in mammalian cells. These results suggest that formaldehyde, H2O2 and heat shock induce stress proteins in rat PMC. It will be important to establish whether or not these stress proteins are responsible for the functional alterations observed in the mast cells.

Pathology of pulmonary parasitic migration: morphological and bronchoalveolar cellular responses following Nippostrongylus brasiliensis infection in rats.

Nippostrongylus brasiliensis has an obligatory migratory phase through the lungs during its development in rats. This migration is associated with marked tissue damage and pronounced cellular reaction. Given that cells from the lower respiratory tract, especially alveolar macrophages, can adhere to and kill larvae of N. brasiliensis in vitro, we studied the time course of morphological changes associated with parasitic migration. Compared to a primary infection, a secondary infection resulted in significant changes in the pulmonary tissue characterized by an early acute inflammation leading to granulomatous reaction in the parenchyma and a leucocytosis in the bronchoalveolar lavage fluids with an anamnestic increase in absolute numbers of neutrophils, alveolar macrophages, eosinophils, and lymphocytes. Scanning electron microscopy showed that inflammatory cells, especially alveolar macrophages, granulocytes, lymphocytes, erythrocytes, and platelets, adhered to the larvae following secondary infection and this adhesion was associated with disruption of cuticular surface in some larvae. Secondary infection also resulted in retention of larvae in granulomatous lesions in the lungs even up to 21 days postinfection. There was mast cell and type II pneumocyte hyperplasia and these cells appeared to be activated. Thus, the histopathological changes in lungs correlated with the bronchoalveolar cellular responses and further document the inflammatory and immunological reactions during the migration of N. brasiliensis larvae.

Mast cell heterogeneity: protein composition, biosynthesis and mRNA characterization.

Proteins of rat peritoneal mast cells (PMC), rat intestinal mast cells (IMMC) and human skin mast cells (SMC) were compared by two-dimensional electrophoresis. PMC and IMMC had many similarities in distribution of their neutral/acidic proteins but marked differences in the more abundant, granule-associated basic proteins. SMC proteins showed a unique distribution. Distributions of the products of in vitro translation of PMC and IMMC RNA were different from those of proteins isolated directly from these cells which, together with results of pulse-chase labelling experiments, shows evidence for processing of certain mast cell proteins including rat mast cell proteases I and II.

Marked antiinflammatory effects of decentralization of the superior cervical ganglia.

Intravenous challenge with parasite antigens in Nippostrongylus brasiliensis-sensitized rats resulted in anaphylactic shock and, in some animals, death. Surviving animals showed significant drop in mean arterial blood pressure, cardiac output, and blood flow to the trachea, bronchioles, and mesentery. After anaphylaxis, changes in the cellular and protein composition in bronchoalveolar lavage fluids (BALF) were assessed. 8 h after antigen challenge, there was significant influx of inflammatory cells and an increase in the levels of histamine and serum-derived immunoglobulins (IgG and IgM) in BALF. Chemotactic activity for neutrophils was also present in BALF. Once we established this anaphylaxis-induced model of pulmonary inflammation, we sought to determine whether or not the superior cervical ganglia (SCG) modulate this inflammation. We performed bilateral superior cervical ganglionectomy or decentralization of the SCG. Our results show that decentralization significantly reduced mortality (by 68%) after anaphylaxis. Furthermore, the increases in levels of serum-derived proteins, histamine, and influx of cells (especially neutrophils) observed in BALF after anaphylaxis were attenuated by both decentralization and ganglionectomy. By contrast, hemodynamic parameters in the respiratory tract and the presence of neutrophil chemotactic activity in BALF were not influenced by decentralization. Thus, the severity of pulmonary inflammation initiated by systemic anaphylaxis is depressed by bilateral ganglionectomy or decentralization of SCG.