Association between thymoma and persistent hypothermia: a case report

<p>Abstract</p> <p>Introduction</p> <p>Thymomas are rare, slow-growing tumours that present in a variety of ways such as incidental findings on chest radiographs following symptoms of cough and dyspnoea. Thymomas may also present with symptoms due to intrathoracic spread such as superior vena cava obstruction, or with symptoms of an associated paraneoplastic disorder. Such paraneoplastic disorders are typified by the generation of autoantibodies directed against a variety of self antigens including myasthenia gravis, neuromyotonia, and hypogammaglobulinaemia.</p> <p>Significant hypothermia in association with thymoma has been described previously in one published case report. The basis for hypothermia in that case was not clear, but was postulated to relate to abnormal central thermal regulation and was resolved completely following treatment with intravenous gammablobulin, thus suggesting an autoimmune aetiology.</p> <p>Case presentation</p> <p>We present the case of an 88-year-old man with Type A thymoma and persistent hypothermia. An extensive investigation of the hypothermia revealed no aetiology other than the thymoma itself. Symptoms of hypothermia were treated effectively with passive and active external rewarming. The patient's dyspnoea was much improved by intercostal drainage of a left-sided pleural effusion and talc pleurodesis. He was not offered definitive treatment for the thymoma in view of its relatively favourable prognosis, and because his symptoms were well controlled at the time of discharge.</p> <p>Conclusion</p> <p>We suggest that the possibility of thymoma be investigated once the more common causes of hypothermia have been excluded in an appropriate clinical context. To the best of our knowledge, this is only the second published case report describing such an association.</p

TGF-β Isoform Specific Regulation of Airway Inflammation and Remodelling in a Murine Model of Asthma

The TGF-β family of mediators are thought to play important roles in the regulation of inflammation and airway remodelling in asthma. All three mammalian isoforms of TGF-β, TGF-β1–3, are expressed in the airways and TGF-β1 and -β2 are increased in asthma. However, there is little information on the specific roles of individual TGF-β isoforms. In this study we assess the roles of TGF-β1 and TGF-β2 in the regulation of allergen-induced airway inflammation and remodelling associated with asthma, using a validated murine model of ovalbumin sensitization and challenge, and isoform specific TGF-β neutralising antibodies. Antibodies to both isoforms inhibited TGF-β mediated Smad signalling. Anti-TGF-β1 and anti-TGF-β2 inhibited ovalbumin-induced sub-epithelial collagen deposition but anti-TGF-β1 also specifically regulated airway and fibroblast decorin deposition by TGF-β1. Neither antibody affected the allergen-induced increase in sub-epithelial fibroblast-like cells. Anti- TGF-β1 also specifically inhibited ovalbumin-induced increases in monocyte/macrophage recruitment. Whereas, both TGF-β1 and TGF-β2 were involved in regulating allergen-induced increases in eosinophil and lymphocyte numbers. These data show that TGF-β1 and TGF-β2 exhibit a combination of specific and shared roles in the regulation of allergen-induced airway inflammation and remodelling. They also provide evidence in support of the potential for therapeutic regulation of specific subsets of cells and extracellular matrix proteins associated with inflammation and remodelling in airway diseases such as asthma and COPD, as well as other fibroproliferative diseases

Localisation of TGF-β₁, -β₂ and -β₃ in normal and OVA challenged mouse airways.

<p>Representative images from control lungs (A, E and I) and OVA sensitised and challenged mice 3–7 d (B, C, F, G, J and K) and 12 d (D, H and L) after final OVA challenge, immunostained (brown) for TGF-β₁ (A-D), TGF-β₂ (E-H) and TGF-β₃ (I-L). Different cell populations are indicated by arrows; BE - bronchial epithelial cell, F - fibroblast-like cell, G - goblet cell, M - macrophage, Pmn - polymorphonuclear cell, ATII - type II alveolar epithelial cell. Representative images are shown from n = 6–8 animals per experimental group. Scale bar represents 50 µm.</p

TGF-β isoform shared and selective effects on allergen-induced inflammation.

<p>Graphs show total BAL cell numbers and the relative contributions of monocytes/macrophages, eosinophils, lymphocytes and neutrophils isolated from animals 12 days following final challenge. Each bar represents the mean ± SEM of values from 9–14 animals per group. *, P<0.05. **, P<0.01. ***, P<0.001. Photomicrographs show staining of lung sections for the macrophage and macrophage progenitor surface antigen, F4/80, demonstrating inhibition of macrophage accumulation (arrows) around the airways of animals treated with antibodies to TGF-β₁ compared with sections from animals treated with control IgG or anti-TGF-β₂. Scale bar represents 50 µm.</p

TGF-β isoform shared regulation of allergen-induced sub-epithelial collagen deposition.

<p>Control (A) and OVA sensitised and challenged (B) mouse airways 12 days following final challenge demonstrating allergen-induced increase in sub-epithelial collagen deposition depicted by blue staining of the thickened airway wall using a modified Martius Scarlet Blue stain. Scale bar represents 50 µm. (C) Quantification of the area of collagen staining demonstrating OVA-induced increase in sub-epithelial collagen deposition and its inhibition by treatment with antibodies to TGF-β₁ or -β₂. Each value represents the mean ± SEM of measurements from 7–10 animals per group. **, P<0.001 compared with relative control. ⁺, P<0.02 and ⁺⁺, P<0.01 compared with OVA control groups.</p

TGF-β isoform specific regulation of allergen-induced sub-epithelial decorin deposition.

<p>Control (A) and OVA sensitised and challenged (B) mouse airways 12 days following final challenge demonstrating allergen-induced increase in sub-epithelial decorin deposition depicted by brown staining of the thickened airway wall by immunohistochemistry. Scale bar represents 50 µm. (C) Quantification of the area of decorin staining demonstrating OVA-induced increase in sub-epithelial decorin deposition and its inhibition by treatment with antibodies to TGF-β₁ but not TGF-β₂. Each value represents the mean ± SEM of measurements from 9–10 animals per group. *, P<0.001 compared with relative control. ⁺, P<0.01 compared with OVA control and not significantly different to the saline anti-TGF-β₁ group.</p

Treatment with isoform specific TGF-β antibodies inhibits signalling via the Smad pathway.

<p>(A-C) Representative images of airways stained for phosphorylated Smad 2/3 (brown) from saline sensitised and challenged mice treated with irrelevant IgG (A), anti-TGF-β₁ (B) or anti-TGF-β₂ (C) 12 days after final challenge. Phosphorylated Smad 2/3 localises to the nucleus. Note the reduction in intensity of staining and number of positive cells in the airways of animals treated with TGF-β antibodies (B-C) compared with controls (A). Scale bar represents 25 µm. (D) Quantification of the proportion of bronchial epithelial cells negative for phosphorylated Smad 2/3 in IgG controls and saline (Sal) or ovalbumin (Ova) sensitised and challenged animals treated with TGF-β antibodies. Each value represents the mean ± SEM of measurements from 9–10 animals per group. * P<0.05 or ** P<0.001 compared with control.</p