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We establish rigorous upper bounds on the time-averaged heat transport for a model of rotating Rayleigh-Bénard convection between no-slip boundaries at infinite Prandtl numbers and with Ekman pumping. The analysis is based on the asymptotically reduced equations derived for rotationally constrained dynamics with no-slip boundaries, and hence, includes a lower order correction that accounts for the Ekman layer and corresponding Ekman pumping into the bulk. Using the auxiliary functional method, we find that, to leading order, the temporally averaged heat transport is bounded above as a function of the Rayleigh and Ekman numbers Ra and Ek according to Nu ≤ 0.3704Ra2Ek2. Dependent on the relative values of the thermal forcing represented by Ra and the effects of rotation represented by Ek, this bound is both an improvement on earlier rigorous upper bounds and provides a partial explanation of recent numerical and experimental results that were consistent yet surprising relative to the previously derived upper bound of Nu ≲ Ra3Ek4. [ABSTRACT FROM AUTHOR]

We describe methods for proving upper and lower bounds on infinite-time averages in deterministic dynamical systems and on stationary expectations in stochastic systems. The dynamics and the quantities to be bounded are assumed to be polynomial functions of the state variables. The methods are computer-assisted, using sum-of-squares polynomials to formulate sufficient conditions that can be checked by semidefinite programming. In the deterministic case, we seek tight bounds that apply to particular local attractors. An obstacle to proving such bounds is that they do not hold globally; they are generally violated by trajectories starting outside the local basin of attraction. We describe two closely related ways past this obstacle: one that requires knowing a subset of the basin of attraction, and another that considers the zero-noise limit of the corresponding stochastic system. The bounding methods are illustrated using the van der Pol oscillator. We bound deterministic averages on the attracting limit cycle above and below to within 1%, which requires a lower bound that does not hold for the unstable fixed point at the origin. We obtain similarly tight upper and lower bounds on stochastic expectations for a range of noise amplitudes. Limitations of our methods for certain types of deterministic systems are discussed, along with prospects for improvement. [ABSTRACT FROM AUTHOR]

Rationale: Among patients with nontuberculous mycobacterial lung disease is a subset of previously healthy women with a slender body morphotype, often with scoliosis and/or pectus excavatum. We hypothesize that unidentified factors predispose these individuals to pulmonary nontuberculous mycobacterial disease.Objectives: To compare body morphotype, serum adipokine levels, and whole-blood cytokine responses of patients with pulmonary nontuberculous mycobacteria (pNTM) with contemporary control subjects who are well matched demographically.Methods: We enrolled 103 patients with pNTM and 101 uninfected control subjects of similar demographics. Body mass index and body fat were quantified. All patients with pNTM and a subset of control subjects were evaluated for scoliosis and pectus excavatum. Serum leptin and adiponectin were measured. Specific cytokines important to host-defense against mycobacteria were measured in whole blood before and after stimulation.Measurements and Main Results: Patients with pNTM and control subjects were well matched for age, gender, and race. Patients with pNTM had significantly lower body mass index and body fat and were significantly taller than control subjects. Scoliosis and pectus excavatum were significantly more prevalent in patients with pNTM. The normal relationships between the adipokines and body fat were lost in the patients with pNTM, a novel finding. IFN-γ and IL-10 levels were significantly suppressed in stimulated whole blood of patients with pNTM.Conclusions: This is the first study to comprehensively compare body morphotype, adipokines, and cytokine responses between patients with NTM lung disease and demographically matched controls. Our findings suggest a novel, predisposing immunophenotype that should be mechanistically defined. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Caspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro-interleukin-1beta (proIL-1beta), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis. METHODS: Acute and chronic arthritis were induced in caspase 1(-/-) mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated. RESULTS: Surprisingly, caspase 1(-/-) mice, in a model of acute (neutrophil-dominated) arthritis, developed joint swelling to an extent similar to that in wild-type control mice. Joint fluid concentrations of bioactive IL-1beta were comparable in caspase 1(-/-) mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1(-/-) mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1-dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL-1beta concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction. CONCLUSION: Caspase 1 deficiency does not affect neutrophil-dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL-1beta production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present. [ABSTRACT FROM AUTHOR]

Background Adipokines are involved in the regulation of many inflammatory processes and are present at very high concentrations in cord blood of term infants. Objective We analysed data of a large prospective birth cohort study to examine whether adiponectin and leptin concentration in cord blood are determinants of wheezing disorders in children within the first 2 years of life. Methods Seven hundred and forty mothers and their newborns were included in this analysis. Adiponectin and leptin concentrations were measured in cord blood. The cumulative incidence of physician-reported asthma or obstructive bronchitis was recorded during a 2-year follow-up. Results During the first 2 years of life, asthma or obstructive bronchitis was reported by the caring paediatricians for 157 (19.6%) of the children. We found a strong interaction of cord blood adiponectin and history of atopic disease in the mother with respect to the risk of physician-reported asthma or obstructive bronchitis ( P=0.006). Compared with children with cord blood levels in the middle quintile (reference category), the odds ratios for physician-reported asthma or obstructive bronchitis in the bottom quintile and top quintile were 0.14 [95% confidence interval (CI) 0.02–0.90] and 2.12 (95% CI 0.67–6.66), respectively ( P for trend=0.0003), among children of mothers with a history of atopy. This association was independent of other established risk factors. Leptin levels in cord blood were not associated with risk of asthma or obstructive bronchitis. Conclusions In children of mothers with a history of atopy, concentrations of adiponectin in cord blood could play an important role in determining risk of wheezing disorders in early childhood. [ABSTRACT FROM AUTHOR]

OBJECTIVE: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha. METHODS: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha(-/-) mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis. RESULTS: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively). CONCLUSION: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha. [ABSTRACT FROM AUTHOR]

The role of leptin in the immune system has been well established. While adipocytes represent the major source, leptin production by lymphocytes, infiltrating at the site of inflammation, was recently demonstrated. However, the significance of this locally released leptin remains unresolved. In the present study, two models in which absence of leptin-signalling is associated with protection were employed: the model of ConA-induced hepatitis and the CD4+CD45Rbhigh transfer model of colitis. For the ConA model, scid mice were reconstituted with either WT or leptin-deficient ( ob/ob) CD4+ T cells. Eight weeks post transfer, ConA was injected and serum ALT, TNFα, leptin as well as liver mononuclear cell activation and histological signs of inflammation were evaluated. No difference between recipients of WT or ob/ob cells was observed for any of the parameters evaluated. In the second model, either WT or ob/ob CD4+CD45Rbhigh cells were transferred into scid mice. No histological differences were detected, although recipients of ob/ob cells showed higher weight loss compared to recipients of WT cells. Spontaneous production of IL-6 from colon cultures obtained from recipients of ob/ob cells was reduced compared to recipients of WT cells, whereas stimulation of lamina propria lymphocytes with leptin resulted in a higher IFNγ release in recipients of ob/ob cells compared to recipients of WT cells. In conclusion, the present study provides evidence that T cell-derived leptin does not play a major role in the regulation of the inflammatory process, indicating that the adipose tissue is the critical player in the immune-modulating effects of leptin. [ABSTRACT FROM AUTHOR]

A considerable amount of research has focused on elucidating the mechanisms by which cytokines synthesized by cells of the innate immune system participate in the life-threatening multiple-organ failure of endotoxic shock. We show here that alphabeta T cells, which are archetypes of the adaptive cellular immune response, suppress the proinflammatory cascade triggered during the early stages of lipopolysaccharide (LPS)-induced endotoxemia. The absence of alphabeta T cells led to the fulminant death of LPS-challenged mice, coinciding with a massive release of the proinflammatory cytokines tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma and a marked reduction in the synthesis of the immunosuppressive cytokine transforming growth factor (TGF)-beta. Cytotoxic T lymphocyte antigen (CTLA)-positive alphabeta T cells emerging shortly after LPS challenge appear to control TGF-beta synthesis. The neutralization of either TGF-beta or CTLA4 resulted in similar increases in IFN-gamma and TNF-alpha serum concentrations in LPS-challenged mice. These observations suggest that suppressor alphabeta T lymphocytes protect against the proinflammatory cascade unleashed during the innate stages of endotoxemia. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GC) are well known inhibitors of tumour necrosis factor (TNF) production. We investigated the role of endogenous GC in the regulation of TNF production in mice treated with lipopolysaccharide (LPS) using a pretreatment with dexamethasone (DEX) to down-regulate the hypothalamus-pituitary adrenal axis (HPA). Short-term DEX pretreatment (up to 12 h before LPS) inhibited TNF production, but earlier (24-48 h) pretreatments potentiated it. This up-regulating effect was not observed in adrenalectomized mice or when GC synthesis was inhibited with cyanoketone (CK). This effect could not be explained only by the suppression of LPS-induced corticosterone (CS) levels induced by DEX, since a 48-h pretreatment potentiated TNF production without affecting LPS-induced CS levels. On the other hand, mice chronically pretreated with DEX were still responsive to its inhibitory effect on TNF production, thus ruling out the possibility of a decreased responsiveness to GC. [ABSTRACT FROM AUTHOR]

Chlorpromazine (CPZ) has been previously shown to protect against endotoxin [lipopolysacchar- ide (LPS)] lethality and inhibit the release of tumour necrosis factor in vivo. We investigated at the cellular level whether this was due to direct inhibition of tumour necrosis factor-α (TNF-α) synthesis, using LPS-stimulated THP-1 human monocytic leukemia cells. We also studied the effect of CPZ on human TNF-α action by assessing TNF-α cytotoxicity on mouse fibrosarcoma L929 cells. CPZ (1–100 μM) inhibited TNF-α production in THP-1 cells in a dose dependent manner by a maximum of 80%. This effect was comparable to that of two well-known inhibitory drugs, dexamethasone and cyclicAMP. Inhibition was also evident at the mRNA level. On the other hand CPZ (10–25 μM) also inhibited TNF-α activity: in fact it reduced the cytotoxicity of TNF-α on L929 cells (EC50 was increased four times) and could provide protection even as a post- treatment. CPZ inhibited TNF-induced apoptosis in L929 cells, as detected by analysis of nuclear morphology. However, since we showed that apoptosis was very limited, and was not the main mode of cell death in our conditions, this could not explain the overall protection. Since CPZ did not interfere with either the oligomerization state of TNF-α or its receptor binding, our data suggest that it reduced cytotoxicity by inhibiting some steps in the TNF-α signalling pathways. [ABSTRACT FROM AUTHOR]

We have previously shown that chlorpromazine (CPZ) inhibits tumour necrosis factor (TNF) production and protects against endotoxic shock in mice. In this paper we investigated the effect of pretreatment with CPZ, 4 mg/kg i.p. 30 min before, compared with dexamethasone (DEX; 3 mg/ kg) on the induction of other endotoxin (lipopolysaccharide; LPS)-induced cytokines in the serum of mice, i.e. interleukin-lα (IL-lα), IL-6 and IL-b, and TNF. We also studied the effect of CPZ on serum and spleen-associated TNF. Both DEX and CPZ inhibited TNF production, whereas induction of IL-b and IL-6 was inhibited by DEX but not by CPZ. DEX did not affect IL-l0, while CPZ potentiated its induction. CPZ also inhibited spleen-associated TNF induction in LPS- treated mice, suggesting an effect on the synthesis of TNF. CPZ inhibited TNF induction by Gram-positive bacteria (heat-killed Staphylococcus epidermidis) and by anti-CD3 monoclonal antibodies. Intraperitoneal administration of CPZ also inhibited the induction of brain-associated TNF induced by intra-cerebroventricular injection of LPS. Therefore, CPZ is a more specific inhibitor of TNF production than DEX; in particular, CPZ increased the induction of 1L-l0, which is a `protective' cytokine known to inhibit LPS toxicity and TNF production. CPZ inhibited TNF production in vivo, irrespective of the TNF stimulus used to induce TNF. Finally, CPZ did not induce the `rebound' effect of DEX that, when given 24 hr before LPS, potentiates TNF production, but it did inhibit TNF production after 24 hr. [ABSTRACT FROM AUTHOR]