Node Hypertrophy Research Articles

Hypertrophy of lymphoid organs is a possible phenotypic characteristic of R420W mutation of the cardiac ryanodine receptor gene: a study using a knock-in mouse model.

Cardiac ryanodine receptor gene (RyR2) mutations sometimes result in sudden cardiac death due to fatal arrhythmias. N-terminal R420W mutation of RyR2 is known to show similar phenotypes to arrhythmogenic right ventricular cardiomyopathy and to cause juvenile sudden death. We previously reported two sudden death cases with the same R420W mutation. Interestingly, the cases showed hypertrophy of lymphoid organs such as the thymus and mesenteric lymph nodes. The present study examined whether R420W mutation of RYR2 causes hypertrophy of lymphoid organs by generating a mouse model carrying the mutation. Homozygous (RyR2(R420W/R420W)) mice showed significant increases in thymus and spleen weights but not in kidney, heart, and brain weights compared with wild-type mice. The mice also showed remarkable hypertrophy of mesenteric lymph nodes. Immunohistochemical study revealed that RyR2 protein was prominently expressed in epithelial cells of the thymic medulla in the thymus. These findings show that mice with R420W mutation of RyR2 exhibit hypertrophy of lymphoid organs. Sudden unexplained death cases with the mutation may display such findings at autopsy.

Eosinophils control the resolution of inflammation and draining lymph node hypertrophy through the proresolving mediators and CXCL13 pathway in mice.

Resolution of inflammation is critical to restoration of tissue function after an inflammatory response. We previously demonstrated that 12/15-lipoxygenase (12/15-LOX)-expressing eosinophils contribute to this process in murine zymosan-induced peritonitis. In this study, eosinophils promoted resolution by regulating expression of macrophage CXCL13. Microarray analysis revealed that eosinophils significantly increased (∼3-fold) the expression of macrophage CXCL13 by a 12/15-LOX-dependent mechanism. CXCL13 depletion caused a resolution defect, with the reduced appearance of phagocytes carrying engulfed zymosan in the draining lymph nodes. Inflamed lymph node hypertrophy, a critical feature of the resolution process, was reduced by ∼60% in eosinophil-deficient mice, and adoptive transfer of eosinophils or administration of CXCL13 corrected this defect. Administration of the 12/15-LOX-derived mediator lipoxin A4 (LXA4) increased the expression of CXCL13 and restored the defect of lymph node hypertrophy in eosinophil-deficient mice. These results demonstrate that eosinophils control the resolution of inflammation and draining lymph node hypertrophy through proresolving lipid mediators and the CXCL13 pathway in mice.

Deep cervical lymph node hypertrophy: A new paradigm in the understanding of pediatric obstructive sleep apnea

To determine if adenotonsillar hypertrophy is an isolated factor in pediatric obstructive sleep apnea (OSA), or if it is part of larger spectrum of cervical lymphoid hypertrophy. Prospective case control study. A total of 70 screened patients (mean age 7.47 years) underwent polysomnography to confirm OSA, and then underwent MRI of the upper airway. Seventy-six matched controls (mean age 8.00 years) who already had an MRI underwent polysomnography. Volumetric analysis of lymphoid tissue volumes was carried out. Chi-square analysis and Student's t test were used to compare demographic data and lymph node volumes between cohorts. Fisher's Exact test and Chi-square analysis were used to compare sleep data. Patients and controls demonstrated no significant difference in mean age (7.47 vs. 8.00 yrs), weight (44.87 vs. 38.71 kg), height (124.68 vs. 127.65 cm), or body-mass index (23.63 vs. 20.87 kg/m(2)). OSA patients demonstrated poorer sleep measures than controls (P < 0.05) in all polysomnography categories (sleep efficiency, apnea index, apnea-hypopnea index, baseline SpO2, SpO2 nadir, baseline ETCO2, peak ETCO2 , and arousal awakening index). Children with OSA had higher lymphoid tissue volumes than controls in the retropharyngeal region (3316 vs. 2403 mm(3), P < 0.001), upper jugular region (22202 vs. 16819 mm(3), P < 0.005), and adenotonsillar region (18994 vs. 12675 mm(3), P < 0.0001). Children with OSA have larger volumes of deep cervical lymph nodes and adenotonsillar tissue than controls. This finding suggests a new paradigm in the understanding of pediatric OSA, and has ramifications for future research and clinical care.

Nitric Oxide and TNFα Are Critical Regulators of Reversible Lymph Node Vascular Remodeling and Adaptive Immune Response

Lymph node (LN) vascular growth, at the level of the main arteriole, was recently characterized for the first time during infection. Arteriole diameter was shown to increase for at least seven days and to occur via a CD4+ T cell dependent mechanism, with vascular expansion playing a critical role in regulating induction of adaptive immune response. Here, using intravital microscopy of the inguinal LN during herpes simplex type II (HSV-2) infection, the data provides the first studies that demonstrate arteriole expansion during infection is a reversible vascular event that occurs via eutrophic outward remodeling. Furthermore, using genetic ablation models, and pharmacological blockade, we reveal arteriole remodeling and LN hypertrophy to be dependent upon both endothelial nitric oxide synthase (eNOS) and TNFα expression. Additionally, we reveal transient changes in nitric oxide (NO) levels to be a notable feature of response to viral infection and LN vascular remodeling and provide evidence that mast cells are the critical source of TNFα required to drive arteriole remodeling. Overall, this study is the first to fully characterize LN arteriole vascular changes throughout the course of infection. It effectively reveals a novel role for NO and TNFα in LN cellularity and changes in LN vascularity, which represent key advances in understanding LN vascular physiology and adaptive immune response.

MASTOCYTEMIA ASSOCIATED WITH A VISCERAL MAST CELL TUMOR IN A SUMATRAN TIGER (PANTHERA TIGRIS)

A 6-yr-old male Sumatran tiger (Panthera tigris) with no significant past clinical history was anesthetized for clinical examination after 5 days of lethargy. Clinically, the animal presented with anorexia, pale mucous membranes, and icterus. Hematologic results indicated moderate anemia and severe thrombocytopenia and showed a circulating population of atypical mast cells. The tiger died during anesthesia. On postmortem examination, abdominal hemorrhage associated with marked diffuse hepato-splenomegaly and mesenteric, hepatic, and splenic lymph node hypertrophy were observed. A visceral mast cell tumor was confirmed by histologic examination and toluidine blue staining, with splenic, hepatic, lymphoid, renal, and pulmonary infiltration. Hematologic, postmortem, and histologic findings were consistent with mastocytemia associated with the splenic form of mast cell tumor described in domestic cats.

Expansion of Cortical and Medullary Sinuses Restrains Lymph Node Hypertrophy during Prolonged Inflammation

During inflammation, accumulation of immune cells in activated lymph nodes (LNs), coupled with a transient shutdown in lymphocyte exit, results in dramatic cellular expansion. Counter-regulatory measures to restrain LN expansion must exist and may include re-establishment of lymphocyte egress to steady-state levels. Indeed, we show in a murine model that egress of lymphocytes from LNs was returned to steady-state levels during prolonged inflammation following initial retention. This restoration in lymphocyte egress was supported by a preferential expansion of cortical and medullary sinuses during late inflammation. Cortical and medullary sinus remodeling during late inflammation was dependent on temporal and spatial changes in vascular endothelial growth factor-A distribution. Specifically, its expression was restricted to the subcapsular space of the LN during early inflammation, whereas its expression was concentrated in the paracortical and medullary regions of the LN at later stages. We next showed that this process was mostly driven by the synergistic cross-talk between fibroblastic reticular cells and interstitial flow. Our data shed new light on the biological significance of LN lymphangiogenesis during prolonged inflammation and further underscore the collaborative roles of stromal cells, immune cells, and interstitial flow in modulating LN plasticity and function.

Lymph Node Yield and Oncologic Outcome after Colorectal Cancer Resection

When performing mesorectal and mesocolic excision for rectal and colon cancer, it is crucial to encompass the draining nodal basins for staging and, possibly, therapeutic purposes. During the past 15 years, colorectal cancer investigators have demonstrated a relationship between the number of lymph nodes examined in the surgical specimen and oncologic outcome. However, the nature of this relationship has not been clearly elucidated. Early explanations for this finding were based on the concept of understaging. The hypothesis was that with fewer nodes examined, the pathologist was less likely to identify metastatic nodes and the patient would be given an inappropriate diagnosis of stage I or II rather than stage III cancer. However, the linear relationship between the total number of lymph nodes in the specimen and the number of metastatic lymph nodes argues against understaging as the primary explanation. If understaging was the cause of this phenomenon, the number of positive nodes would plateau at a certain number of total lymph nodes examined. Yet, multiple investigators have been unable to demonstrate that there is a number above which examination of additional lymph nodes does not identify more metastatic nodes. Many authors have hypothesized that maximal surgical clearance of metastatic lymph nodes offers therapeutic effect. Although this may be intuitive, mesenteric lymph node recurrence is a very uncommon phenomenon, and this hypothesis remains unsupported. Kanemitsu et al. have attempted to use their results to support the practice of central vascular pedicle ligation. However, they state that it is standard practice in Japan to resect apical nodes if the stage is T2 or higher; in this study there is no control group without proximal ligation. As a result, such an assumption cannot be supported by these data nor is there conclusive evidence elsewhere in the existing colorectal cancer literature that proximal pedicle ligation improves oncologic outcome or is necessary for adequate lymph node yields. In a study, conducted by this author, of a consecutive series of surgical specimens at a single center, apical vessel ligation was not universally performed; yet 96 % of the specimens were found to contain more than 12 lymph nodes. Meticulous surgical technique and careful pathologic examination is paramount to achieve high lymph node yields. Many protocols have been advocated to maximize nodal yield, including the use of in vivo or ex vivo dye injection, fat clearance, and multiple rounds of gross examination. However, one cannot categorically state that specific surgical or pathologic methods are necessary to achieve such yields in all cases, because this has not been adequately studied in a prospective, controlled fashion. Kanemitsu et al. have elegantly demonstrated that, in a broad population of stage II colorectal cancer patients, the threshold of 12 lymph nodes examined is associated with superior predictive capacity for prognosis in individual patients. Moreover, they acknowledge that this association is not straightforward. However, their discussion focuses on improved staging and clearing of micrometastatic disease, neither of which has been proven causal despite almost two decades of investigation. Biologic explanations need to be examined further. Age, tumor size, depth of penetration, location, use of radiation, and gene mutations have been associated with lymph node yield. These findings suggest a host–tumor interaction that may result in stimulation of the immune system and, as a consequence, larger and thus easier to identify mesenteric lymph nodes. It does not stretch the imagination to consider that such an interaction would have implications for tumor recurrence. Our understanding of the biology of lymph node hypertrophy or proliferation in the presence of a colorectal Society of Surgical Oncology 2012

Lymph Node Hypertrophy following Leishmania major Infection Is Dependent on TLR9

Control of the protozoan parasite Leishmania major is dependent on establishing a robust T cell response. An early event in the development of an effective T cell response is the expansion (or hypertrophy) of the lymph node draining the site of infection, although the mechanisms involved in this response are not completely understood. In this study, we show that lymph node hypertrophy following L. major infection in mice is associated with increased recruitment of lymphocytes to the lymph node from the blood, and that CD62L-deficient mice, which are unable to recruit cells to the lymph node, develop a chronic infection with L. major. Injection of L. major-activated dendritic cells promoted lymph node hypertrophy, and this correlated with an increase in the expression of CCR7 on dendritic cells, although the upregulation of CCR7 occurred on the bystander (uninfected) dendritic cells rather than those containing parasites. We found that increased CCR7 expression was TLR9-dependent, that TLR9(-/-) dendritic cells migrated less efficiently to the draining lymph node, and that TLR9(-/-) mice exhibited a deficit in lymph node expansion following L. major infection, as well as increased susceptibility. Taken together, to our knowledge, these results are the first to demonstrate that activation of dendritic cells via TLR9 is essential for the induction of lymph node hypertrophy in leishmaniasis.

Gut barrier dysfunction in the ApcMin/+ mouse model of colon cancer cachexia

Background: The Apc Min/+ mouse, an animal model of colorectal cancer and cachexia, has a heterologous mutation in the Apc tumor suppressor gene, predisposing the mouse to intestinal and colon tumor development. This mouse develops intestinal polyps by ~ 4 weeks of age, and loses body weight gradually between ~ 14 and ~ 20 weeks of age. The strengths of this cachexia model derive from several features that mimic human cancer, including a gradual increase in tumor burden, chronic inflammation, and anemia. Little is known about the role of gut barrier dysfunction and endotoxemia in the development of cancer cachexia. We sought to determine how gut permeability and resultant endotoxemia change with the progression of cachexia. Methods: Intestinal gut barrier integrity was assessed by permeability to FITC-dextran (MW av = 4000 kDa; FD4). Plasma glucose and triglycerides were measured by enzymatic assays, IL-6 by enzyme-linked immunosorbent assay, and endotoxin by the limulus amoebocyte assay. Body temperature was measured using a rectal probe. Results: Progression of cachexia was accompanied by development of gut barrier dysfunction (permeability to FD4), hypertrophy of mesenteric lymph nodes, and an increase in plasma endotoxin concentration. Changes in blood glucose and glucose tolerance, plasma IL-6, triglycerides, and body temperature were characteristic of endotoxemia. Conclusion: We propose a role for gut barrier dysfunction (GBD) and subsequent endotoxemia in the development of inflammation and progression of cachexia in the Apc Min/+ mouse.

Paciente VIH positivo con tuberculosis sistémica y lesiones osteolíticas de la calvaria, semejando mieloma múltiple

Varón de 33 años, soltero, sin ocupación fija, promiscuo, con historia de relaciones homosexuales, ingesta crónica de alcohol, consumo de tabaco, marihuana, pasta básica y clorhidrato de cocaína, desde los 18 años. Infectado por el virus de la inmunodeficiencia humana, recibía tratamiento irregular con terapia antirretroviral de gran actividad (Targa) entre 2006 y 2008, regularizada en los últimos 12 meses. Por presentar bacilo ácido alcohol resistente (BAAR) pansensible en esputo, inició en junio 2008 tratamiento antituberculoso [2RHZE/4(HR)2)], retirándosele la medicación 6 meses después por presentar BAAR pulmonar negativo. En marzo de 2009, percibió dolor lumbar intenso, dificultad para caminar, hipertrofia de ganglios cervicales, tos, fiebre. Un cultivo de secreción ganglionar cervical descubrió M. tuberculosis resistente a rifampicina. La imagenología mostró lesiones osteolíticas múltiples en cráneo y vértebras dorsolumbares y tumefacciones renitentes en cuero cabelludo, antebrazo derecho y parrilla costal izquierda. Tras descartarse mieloma múltiple y metástasis cancerosas, se añadió tratamiento antituberculosis multidrogo resistente al Targa, notándose dos meses después involución de las tumefacciones renitentes, de la fiebre y mejoría del estado general. Tras 16 meses de tratamiento supervisado, el paciente aumentó 7 kg de peso, habiendo desaparecido la sintomatología que presentaba. Se discute la fisiopatología de las lesiones osteolíticas cráneo-vertebrales en un paciente con coinfección por el virus de la inmunodeficiencia humana y tuberculosis.

Terapia floral em gatos domésticos (Felis catus, Linnaeus, 1758) portadores do complexo da doença respiratória felina: estudo clínico e hematológico

A terapia floral é considerada, atualmente, prática médica alternativa utilizada em diversas situações clínicas, constituindo possibilidade a mais de prevenção e cura de muitas doenças de natureza física e emocional. Este estudo objetivou pesquisar o efeito das essências do Sistema Brasileiro de Florais Compostos de Joel Aleixo num mesmo grupo de gatos domésticos com sinais clínicos sugestivos de Doença Respiratória Felina (DRF), tratados em diferentes momentos (M0, M1, M2, M3). Foram utilizados 20 gatos domésticos, de ambos os sexos, sem raça definida, com idade média de 5,63 ± 3,02 anos criados em gatil na UFRPE. Os animais foram submetidos ao tratamento com os florais por via oral em duas etapas. Na primeira etapa com os florais Desintus Total e Helminthus Total por 14 dias, e na segunda etapa com os florais Antibius e Regius por 28 dias. Os resultados observados, quanto aos aspectos clínicos, foram redução de secreção nasal, secreção ocular e estertores pulmonares; desaparecimento de sinais clínicos como fezes alteradas, úlceras na cavidade oral, pêlos eriçados e permanência da hipertrofia dos linfonodos. Quanto aos aspectos hematológicos houve interferência nas variáveis relacionadas ao hemograma (hemoglobina, VCM, CHCM, leucócitos, linfócitos e monócitos). Conclui-se que a terapia floral mostrou-se eficaz em gatos domésticos com sinais sugestivos de DRF criados nas mesmas condições de manejo.

Immune-modifying properties of topical vitamin D: Focus on dendritic cells and T cells

Topical creams containing the active form of vitamin D (1,25-dihydroxyvitamin D 3; 1,25(OH) 2D 3) or analogues of this compound are currently used with some success to treat skin conditions including psoriasis and vitiligo. As well as targeting inflammatory processes in the skin, topical application of 1,25(OH) 2D 3 also affects the function of immune cells in the skin and draining lymph nodes. Topically applied 1,25(OH) 2D 3 reduces the number of dendritic cells in the skin, resulting in suppressed immunity and in particular reduced contact hypersensitivity (CHS) responses. Topical 1,25(OH) 2D 3 may also promote the migration of dendritic cells from the skin to the draining lymph nodes. Skin application of 1,25(OH) 2D 3 prevented the inflammatory effects of UVB irradiation on lymph node hypertrophy, when cell numbers were examined 4 days after skin treatment. In contrast, when 1,25(OH) 2D 3 was applied to UVB irradiated skin, there was no reversal in the suppression of CHS responses caused by UVB irradiation. Instead, 1,25(OH) 2D 3 had an additive effect with UVB to suppress CHS responses to a greater degree than UVB alone. In these studies, 1,25(OH) 2D 3 was applied to the treated skin of BALB/c mice immediately following UVB irradiation. Finally, topical 1,25(OH) 2D 3 also enhanced the number and suppressive activity of CD4+CD25+ regulatory T cells in the lymphatic tissue draining skin.

Castleman's disease—A case report

Castleman's disease is a rare clinicopathological entity characterized by non-neoplastic lymph node hypertrophy. Its incidence and etiology is unknown. It has been found in association with Kaposi's sarcoma thus necessitating investigations for HIV. Although its localized variety is benign other types can be multifocal with adverse systemic manifestations. A case report of a 42 yrs old female with a slowly enlarging highly vascular mass in the left iliac fossa is presented which lead to a histological diagnosis of this rare condition (see picture). Furthermore its clinical features, its types, relevant investigations and current treatment modalities are discussed.

SURTO DE FEBRE CATARRAL MALIGNA EM BOVINOS NO ESTADO DO RIO GRANDE DO NORTE

MALIGNANT CATARRHAL FEVER IN CATTLE FROM RIO GRANDE DO NORTE, BRAZIL This study describes the clinical, epidemiological, and histopathological aspects of three cases of acute malignant catarrhal fever in cattle from a rural property in the municipality of Mossoro, Rio Grande do Norte. The main symptoms observed in the affected animals were anorexia, fever, cornea opacity, mucopurulent nasal discharge, and incoordination. Hematological analysis revealed leukopenia with relative monocytosis. Prior to these three cases, six other animals had died with similar symptoms. Postmortem findings included ulcers in oral and nasal mucosa, lesions in the tongue and palate, edema of glottis, hyperemia of esophagus and trachea mucosa, hypertrophy and congestion of lymph nodes, cerebral and cerebellar congestion. Histopathological examination showed generalized vasculitis, necrosis of vessel wall, and perivascular infiltration of mononuclear cells in several organs. A definitive diagnosis of malignant catarrhal fever was provided by the clinical and histopathological changes observed.

A case of a periarticular abscess and suppurative arthritis of the atlanto‐occipital joint

SummaryThis Case Report describes a periarticular abscess and a suppurative arthritis of the atlanto‐occipital joint in an adult horse. The horse showed a painful swelling localised on the atlanto‐occipital region and ataxia in all 4 limbs. During hospitalisation, the horse developed recumbency, dysphagia, facial paralysis and seizures. Ultrasonography of the atlanto‐occipital region enabled a tentative diagnosis to be made, which was later confirmed at autopsy. Culture of the abscess revealed a Staphylococcus aureus. However, the horse had a history of recurrent fever, hypertrophy and abscessation of the submandibular lymph nodes, neck pain and dyspnoea for 2 months, which was suggestive of strangles.

Impaired Mast Cell-Driven Immune Responses in Mice Lacking the Transcription Factor NFATc2

The three calcium-dependent factors NFATc1, c2, and c3 are expressed in cells of the immune system and play pivotal roles in modulating cellular activation. With regard to NFATc2, it was reported that NFATc2-deficient mice display increased immune responses in several models for infection and allergy in vivo. This led to the assumption that NFATc2 is involved in the maintenance of immune homeostasis. Using the synthetic TLR7 agonist imiquimod as an adjuvant in epicutaneous peptide immunization, we observed that both the inflammatory reaction and the peptide-specific CTL response are severely impaired in NFATc2-deficient mice. Detailed analyses revealed that early production of proinflammatory cytokines, lymph node hypertrophy, and migration of Langerhans cells are strongly reduced in NFATc2-deficient animals. With the aid of mast cell-deficient mice and reconstitution experiments using mast cells derived from either NFATc2-deficient mice or wild-type controls, we were able to show that NFATc2 expressed in mast cells is critical for the initiation of inflammation, migration of Langerhans cells, and the development of full-blown CTL responses following epicutaneous immunization. Thus, NFATc2 is an important factor controlling mast cell accessory function at the interface of innate and adaptive immunity.

Alterações histopatológicas em girinos de rã-touro alimentados com rações comerciais de diferentes níveis protéicos

Realizaram-se necropsia e exame histopatológico de girinos de rã-touro (Rana catesbeiana) alimentados com rações comerciais formuladas com 32, 36, 45 ou 55% de proteína bruta (PB) visando estabelecer a relação entre o nível de proteína bruta da ração e a sanidade do animal. Na necropsia, os girinos não apresentaram externamente nenhuma alteração aparente, no entanto, o fígado dos animais, em todos os níveis de proteína bruta, apresentou-se de cor palha e manchado. Na análise histopatológica, observaram-se fígados com rarefação e degeneração celular protéica, intestinos com colite e achatamento das microvilosidades; baço com hiperplasia linfocitária; coração sem nenhuma alteração; rins com glomerulonefrite e áreas de tubulonefroses; gastrite mononuclear e hiperplasia e hipertrofia dos linfonodos regionais. Em todos os órgãos, verificou-se depósito de hemossiderina. Essas lesões sugerem quadro degenerativo nutricional, com desenvolvimento de processos inflamatórios, se difundindo para todos os órgãos. Os resultados sugerem que os animais foram alimentados com rações com proteínas de baixo valor biológico, portanto, de má qualidade, o que comprometeu a sanidade e o desempenho dos animais. Estudos complementares são necessários para compreensão do comportamento bioquímico de rãs-touro na fase de girino visando à nutrição adequada desses animais.

In situ imaging reveals different responses by naïve and memory CD8 T cells to late antigen presentation by lymph node DC after influenza virus infection

Pulmonary influenza infection causes prolonged lymph node hypertrophy while processed viral antigens continue to be presented to virus-specific CD8 T cells. We show that naïve, but not central/memory, nucleoprotein (NP)-specific CD8 T cells recognized antigen-bearing CD11b(+) DC in the draining lymph nodes more than 30 days after infection. After these late transfers, the naïve CD8 T cells underwent an abortive proliferative response in the mediastinal lymph node (MLN), where large clusters of partially activated cells remained in the paracortex until at least a week after transfer. A majority of the endogenous NP-specific CD8 T cells that were in the MLN between 30 and 50 days after infection also showed signs of a continuing response to antigen stimulation. A high frequency of endogenous NP-specific CD8 T cells in the MLN indicates that late antigen presentation may help shape the epitope dominance hierarchy during reinfection.

Identification of a novel mutation V2321M of the cardiac ryanodine receptor gene of sudden unexplained death and a phenotypic study of the gene mutations

Mutations of the cardiac ryanodine receptor (RyR2) gene cause catecholaminergic polymorphic ventricular tachycardia, which sometimes results in a finding of sudden unexplained death (SUD) at autopsy. We found a novel mutation (V2321M) in exon 46 of the RyR2 gene in a SUD case. V2321M was localized in a highly conservative site of the RyR2 gene, but was not found in 400 reference alleles. We previously reported two SUD cases with R420W mutations in exon 14 of the RyR2 gene. We examined possible phenotypic characteristics of all three of these cases of SUD with the RyR2 gene mutations. All cases displayed mesenteric lymph node hypertrophy as well as tendencies for aortic narrowing. By contrast, only one of the 14 SUD cases without RyR2 mutations displayed these phenotypes. This study supports the concept that postmortem genetic testing of RyR2 mutations should be considered in autopsy examinations of SUD cases. It also raises the possibility that some cases with RyR2 mutations may display phenotypic changes in lymphoid and cardiovascular organs.

Tumour necrosis factor-alpha blockade suppresses murine allergic airways inflammation.

Asthma is a heterogeneous disease that has been increasing in incidence throughout western societies and cytokines, including proinflammatory tumour necrosis factor alpha (TNF-alpha), have been implicated in the pathogenesis of asthma. Anti-TNF-alpha therapies have been established successfully in the clinic for diseases such as rheumatoid arthritis and Crohn's disease. TNF-alpha-blocking strategies are now being trialled in asthma; however, their mode of action is poorly understood. Based on the observation that TNF-alpha induces lymph node hypertrophy we have attempted to investigate this as a mechanism of action of TNF-alpha in airway inflammation by employing two models of murine airway inflammation, that we have termed short and long models, representing severe and mild/moderate asthma, respectively. The models differ by their immunization schedules. In the short model, characterized by eosinophilic and neutrophilic airway inflammation the effect of TNF-alpha blockade was a reduction in draining lymph node (DLN) hypertrophy, eosinophilia, interleukin (IL)-5 production and immunoglobulin E (IgE) production. In the long model, characterized by eosinophilic inflammation, TNF-alpha blockade produced a reduction in DLN hypertrophy and IL-5 production but had limited effects on eosinophilia and IgE production. These results indicate that anti-TNF-alpha can suppress DLN hypertrophy and decrease airway inflammation. Further investigations showed that anti-TNF-alpha-induced inhibition of DLN hypertrophy cannot be explained by preventing l-selectin-dependent capture of lymphocytes into the DLN. Given that overall TNF blockade was able to suppress the short model (severe) more effectively than the long model (mild/moderate), the results suggest that TNF-alpha blocking therapies may be more effective in the treatment of severe asthma.