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Find video protocols related to scientific articles indexed in Pubmed.
Dectin-2 is a direct receptor for mannose-capped lipoarabinomannan of mycobacteria.
Immunity
PUBLISHED: 08-28-2014
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Mycobacteria possess various immunomodulatory molecules on the cell wall. Mannose-capped lipoarabinomannan (Man-LAM), a major lipoglycan of Mycobacterium tuberculosis, has long been known to have both inhibitory and stimulatory effects on host immunity. However, the direct Man-LAM receptor that explains its pleiotropic activities has not been clearly identified. Here, we report that a C-type lectin receptor Dectin-2 (gene symbol Clec4n) is a direct receptor for Man-LAM. Man-LAM activated bone-marrow-derived dendritic cells (BMDCs) to produce pro- and anti-inflammatory cytokines, whereas it was completely abrogated in Clec4n(-/-) BMDCs. Man-LAM promoted antigen-specific T cell responses through Dectin-2 on DCs. Furthermore, Man-LAM induced experimental autoimmune encephalitis (EAE) as an adjuvant in mice, whereas Clec4n(-/-) mice were resistant. Upon mycobacterial infection, Clec4n(-/-) mice showed augmented lung pathology. These results demonstrate that Dectin-2 contributes to host immunity against mycobacterial infection through the recognition of Man-LAM.
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Small interfering RNA against CD86 during allergen challenge blocks experimental allergic asthma.
Respir. Res.
PUBLISHED: 07-10-2014
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BackgroundCD86-CD28 interaction has been suggested as the principal costimulatory pathway for the activation and differentiation of naïve T cells in allergic inflammation. However, it remains uncertain whether this pathway also has an essential role in the effector phase. We sought to determine the contribution of CD86 on dendritic cells in the reactivation of allergen-specific Th2 cells.MethodsWe investigated the effects of the downregulation of CD86 by short interfering RNAs (siRNAs) on Th2 cytokine production in the effector phase in vitro and on asthma phenotypes in ovalbumin (OVA)-sensitized and -challenged mice.ResultsTreatment of bone marrow-derived dendritic cells (BMDCs) with CD86 siRNA attenuated LPS-induced upregulation of CD86. CD86 siRNA treatment impaired BMDCs¿ ability to activate OVA-specific Th2 cells. Intratracheal administration of CD86 siRNA during OVA challenge downregulated CD86 expression in the airway mucosa. CD86 siRNA treatment ameliorated OVA-induced airway eosinophilia, airway hyperresponsiveness, and the elevations of OVA-specific IgE in the sera and IL-5, IL-13, and CCL17 in the bronchoalveolar lavage fluid, but not the goblet cell hyperplasia.ConclusionThese results suggest that local administration of CD86 siRNA during the effector phase ameliorates lines of asthma phenotypes. Targeting airway dendritic cells with siRNA suppresses airway inflammation and hyperresponsiveness in an experimental model of allergic asthma.
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New pitfalls of high-density postmortem computed tomography.
Leg Med (Tokyo)
PUBLISHED: 05-09-2014
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An 80-year-old female was transferred to the hospital due to a traffic accident. Multiple cranial bone fractures with intracranial hemorrhage and intracranial air were detected. Despite treatment, the patient died after 6h. Twenty-one hours after the patient died, her whole body was scanned by postmortem CT, and a region of high density was detected within the left putamen. The autopsy revealed a cerebral contusion and multiple skull base fractures. Moreover, superabsorbent polymers (SAPs) were found within the left lateral ventricle and adjacent to the putamen, which appeared as a high-density lesion on postmortem CT at the left putamen, where the SAPs were compacted. Both ante- and postmortem conditions should be considered to prevent misdiagnoses based only on postmortem CT.
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Development of non-traumatic osteonecrosis of the femoral head requires toll-like receptor 7 and 9 stimulations and is boosted by repression on nuclear factor kappa B in rats.
Lab. Invest.
PUBLISHED: 05-02-2014
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Non-traumatic osteonecrosis of the femoral head (ONFH) often occurs after corticosteroid therapy in patients with inflammatory diseases. Recent studies suggest that toll-like receptor (TLR) signaling may contribute to the pathogenesis of inflammatory diseases, and that the reason for corticosteroid therapy for inflammatory diseases is related to the anti-inflammatory activities of corticosteroids through the reduction of NF-?B. We hypothesized that the administration of TLR ligands in combination with corticosteroid causes ONFH and that transcription factors may contribute to the pathogenesis of ONFH. The aim of the study was to evaluate (1) the incidence of ONFH in rats after the administration of TLR7 or TLR9 ligands together with methylprednisolone (MPSL) and (2) whether transcription factors contribute to the development of ONFH. Male Wistar rats (n=148) were divided into five groups as follows: Group 1: Saline+MPSL, Group 2: Imiquimod+Saline, Group 3: Imiquimod+MPSL, Group 4: CpG-C+MPSL, Group 5: Imiquimod+BAY11-7082+MPSL. As a result, ONFH was observed in 0 of 12 rats in Group 1, in 1 of 10 in Group 2, in 6 of 12 in Group 3, in 4 of 12 in Group 4, in 0 of 9 in Group 5. MPSL treatment did not significantly affect IRF7 activity, whereas NF-?B activity was significantly repressed in Group 2 and Group 3. Furthermore, the repression in interferon regulatory factor 7 (IRF7) activity by BAY11-7082 interfered with the development of ONFH simultaneously with the MPSL treatment-induced repression in NF-?B activity. In conclusion, in the present study, corticosteroid treatment after the administration of TLR7 or TLR9 ligands caused ONFH. Repression in NF-?B activity by corticosteroid treatment boosted the development of ONFH.Laboratory Investigation advance online publication, 10 November 2014; doi:10.1038/labinvest.2014.134.
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A turn on and a turn off: BLT1 and BLT2 mechanisms in the lung.
Expert Rev Respir Med
PUBLISHED: 04-18-2014
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Leukotriene B4 (LTB4), a potent lipid mediator of inflammation derived from arachidonic acid through the action of 5-lipoxygenase, has been implicated in the pathophysiology of several inflammatory diseases, including asthma and chronic obstructive pulmonary disease. A high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles. A cyclooxygenase metabolite, 12(S)-hydroxyheptadeca-5Z, 8E, 10E-trienoic acid (12-HHT), is an endogenous ligand for BLT2, a low-affinity LTB4 receptor. The recent study indicated that BLT2 has a protective role in allergic airway inflammation, suggesting different functions between BLT1 and BLT2 in the pathogenesis of asthma. Selective BLT1 antagonists may have a potential therapeutic application in patients with asthma, and BLT2 may represent a novel therapeutic target for lung diseases.
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Viral infections in asthma and COPD.
Respir Investig
PUBLISHED: 03-19-2014
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Airway viral infections are associated with the pathogenesis of asthma and COPD. It has been argued that respiratory syncytial virus (RSV) infection in infancy is a probable causal factor in the development of pediatric asthma. RSV infections tend to induce Th2-biased immune responses in the host airways. RSV infection, atopy, and low pulmonary function in neonates may work synergistically toward the development of pediatric asthma. Human rhinovirus (HRV) is a representative virus associated with the exacerbation of asthma in both children and adults. Viral infections trigger innate immune responses including granulocytic inflammation and worsen the underlying inflammation due to asthma and COPD. The innate immune responses involve type-I and -III interferon (IFN) production, which plays an important role in anti-viral responses, and the airway epithelia of asthmatics reportedly exhibit defects in the virus-induced IFN responses, which renders these individuals more susceptible to viral infection. A similarly impaired IFN response is seen in COPD, and several investigators propose that latent adenoviral infection may be involved in COPD development. Persistent RSV infections were detected in a sub-population of patients with COPD and were associated with the accelerated decline of lung function. The virus-induced upregulation of co-inhibitory molecules in the airway epithelium partly accounts for the persistent infections. Experimental animal models for virus-asthma/COPD interactions have shed light on the underlying immune mechanisms and are expected to help develop novel approaches to treat respiratory diseases.
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Polyangiitis overlap syndrome of granulomatosis with polyangiitis (Wegener's granulomatosis) and eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).
BMJ Case Rep
PUBLISHED: 03-01-2014
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Polyangiitis overlap syndrome is defined as systemic vasculitis that cannot be classified into one of the well-defined vasculitic syndromes. In this report, a female patient who presented with vasculitis-like and asthmatic symptoms was diagnosed as having polyangiitis overlap syndrome of granulomatosis with polyangiitis (GPA; formerly known as Wegener's granulomatosis) and eosinophilic granulomatosis with polyangiitis (EGPA; formerly known as Churg-Strauss syndrome). The patient fulfilled the American College of Rheumatology diagnostic criteria for GPA and EGPA. She was successfully treated with immunosuppressants and steroids and has been in remission for 20 months. It is important to establish a proper diagnosis and introduce an appropriate treatment modality in patients with this rare and serious pathology to prevent irreversible organ damage.
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HMGB1 promotes the development of pulmonary arterial hypertension in rats.
PLoS ONE
PUBLISHED: 01-01-2014
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Pulmonary arterial hypertension (PAH) is characterized by increased pulmonary vascular resistance leading to right ventricular failure and death. Recent studies have suggested that chronic inflammatory processes are involved in the pathogenesis of PAH. However, the molecular and cellular mechanisms driving inflammation have not been fully elucidated.
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Immunoglobulin G4-related lung disease: clinicoradiological and pathological features.
Respirology
PUBLISHED: 09-26-2013
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Immunoglobulin G4 (IgG4)-related disease is a multi-organ disorder that can include the lungs. IgG4-related lung disease can present in various forms; the clinical, radiological and pathological features of patients with this disease have been assessed.
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Cigarette smoke impairs phagocytosis of apoptotic neutrophils by alveolar macrophages via inhibition of the histone deacetylase/Rac/CD9 pathways.
Int. Immunol.
PUBLISHED: 08-29-2013
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Efferocytosis, which is the homeostatic phagocytosis of apoptotic cells, prevents the release of toxic intracellular contents and subsequent tissue damage. Impairment of efferocytosis was reported in alveolar macrophages (AMs) of patients with chronic obstructive pulmonary disease (COPD), a common disease caused by smoking. In COPD, histone deacetylase (HDAC) activity is reduced in AMs. We investigated whether the reduction of HDAC activity is associated with the impairment of efferocytosis. Murine AMs were collected by bronchoalveolar lavage and their ability to efferocytose apoptotic human polymorphonuclear leukocytes was assessed. Pre-treatment of AMs with cigarette smoke extract (CSE) or trichostatin A (TSA), an HDAC inhibitor, suppressed efferocytosis and CSE reduced HDAC activity. TSA inhibited the activity of Rac, a key mediator of efferocytosis. These TSA-induced impairments were restored by treatment of AMs with aminophylline, a potent activator of HDAC. To further elucidate the underlying mechanism, we explored a role of CD9 in TSA-induced impairment of efferocytosis. CD9 is a transmembrane protein of the tetraspanin family that facilitates the uptake of several pathogens and other material. TSA profoundly down-regulated the expression of CD9 on AMs. The expression of CD9 was partly down-regulated by the Rac inhibitor. Pretreatment with an anti-CD9 mAb or CD9 small interfering RNA inhibited efferocytosis, which was attributable to the reduced binding of AMs to apoptotic cells. These results suggest that smoking impairs efferocytosis via inhibition of HDAC/Rac/CD9 pathways. Aminophylline/theophylline is effective in restoring the impairment of efferocytosis and might have benefit for the treatment of patients with COPD.
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Smad2/3 and IRF4 play a cooperative role in IL-9-producing T cell induction.
J. Immunol.
PUBLISHED: 08-02-2013
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IL-9 is a pleiotropic cytokine that can regulate autoimmune and allergic responses. Th9 cells can develop from naive T cells or Th2 cells through stimulation by TGF-? in vitro. In this study, we demonstrated that Smad2 and Smad3 are necessary for IL-9 production from T cells in an OVA-induced asthma model using T cell-specific Smad2- and Smad3-deficient mice. Smad2 and Smad3 were also redundantly essential for TGF-? signaling to induce histone modifications for Il9 transcription. Although Smad2/3 was recruited to the Il9 promoter by TGF-? stimulation, they are not sufficient to activate the Il9 promoter. By the screening the transcription factors, we found that IFN regulatory factor 4 (IRF4) was essential for the Smad2/3-mediated Il9 promoter activation. In addition, Smad2/3 physically interacted with IRF4, and Smad2/3 did not bind to the Il9 promoter and could not induce Th9 in IRF4-deficient T cells. Similarly, IRF4 could not stimulate Il9 transcription in the absence of Smad2/3, and TGF-? enhanced IRF4 recruitment to the Il9 promoter in a Smad2/3-dependent manner. We propose that Smad2/3 and IRF4 cooperatively transactivate the Il9 promoter and play an important role in regulating allergic immune responses by inducing Th9 cells.
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Novel biological activities of allosamidins.
Molecules
PUBLISHED: 04-26-2013
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Allosamidins, which are secondary metabolites of the Streptomyces species, have chitin-mimic pseudotrisaccharide structures. They bind to catalytic centers of all family 18 chitinases and inhibit their enzymatic activity. Allosamidins have been used as chitinase inhibitors to investigate the physiological roles of chitinases in a variety of organisms. Two prominent biological activities of allosamidins were discovered, where one has anti-asthmatic activity in mammals, while the other has the chitinase-production- promoting activity in allosamidin-producing Streptomyces. In this article, recent studies on the novel biological activities of allosamidins are reviewed.
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Leukotriene B4 receptor BLT2 negatively regulates allergic airway eosinophilia.
FASEB J.
PUBLISHED: 04-19-2013
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Leukotriene B4 (LTB4) has been implicated in the pathogenesis of allergic diseases. BLT2, a low-affinity LTB4 receptor, is activated by LTB4 and 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). Although the high-affinity LTB4 receptor BLT1 has been shown to exert proinflammatory roles, the role of BLT2 in allergic inflammation has not been clarified. To study the function of BLT2 in development of asthma, we used mice model of ovalbumin (OVA)-induced allergic airway disease. The 12-HHT levels were elevated in bronchoalveolar lavage (BAL) fluids of OVA-sensitized/challenged wild-type mice. BLT2-deficient mice exhibited enhanced eosinophilia in BAL fluids after OVA exposure. Interleukin (IL)-13 levels in BAL fluids and IL-13-producing CD4(+) T cells in the lungs were elevated in BLT2-deficient mice compared to wild-type mice, whereas the levels of IL-4, IL-5, and interferon (IFN)-? in BAL fluids and serum OVA-specific IgE were comparable. Transfection of BLT2-specific small interfering RNA enhanced IL-13 production in CD4(+) T cells in vitro. Expression of BLT2 mRNA in CD4(+) T cells was significantly reduced in patients with asthma compared to healthy control subjects. These findings indicate that BLT2 has a protective role in allergic airway inflammation and that diminished BLT2 expression in CD4(+) T cells may contribute to the pathophysiology of asthma.
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PI3K-delta mediates double-stranded RNA-induced upregulation of B7-H1 in BEAS-2B airway epithelial cells.
Biochem. Biophys. Res. Commun.
PUBLISHED: 04-04-2013
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Airway viral infection disturbs the health-related quality of life. B7-H1 (also known as PD-L1) is a coinhibitory molecule associated with the escape of viruses from the mucosal immunity, leading to persistent infection. Most respiratory viruses generate double-stranded (ds) RNA during replication. The stimulation of cultured airway epithelial cells with an analog of viral dsRNA, polyinosinic-polycytidylic acid (poly IC) upregulates the expression of B7-H1 via activation of the nuclear factor ?B(NF-?B). The mechanism of upregulation was investigated in association with phosphatidylinositol 3-kinases (PI3Ks). Poly IC-induced upregulation of B7-H1 was profoundly suppressed by a pan-PI3K inhibitor and partially by an inhibitor or a small interfering (si)RNA for PI3K? in BEAS-2B cells. Similar results were observed in the respiratory syncytial virus-infected cells. The expression of p110? was detected by Western blot and suppressed by pretreatment with PI3K? siRNA. The activation of PI3K? is typically induced by oxidative stress. The generation of reactive oxygen species was increased by poly IC. Poly IC-induced upregulation of B7-H1 was attenuated by N-acetyl-L-cysteine, an antioxidant, or by oxypurinol, an inhibitor of xanthine oxidase. Poly IC-induced activation of NF-?B was suppressed by a pan-PI3K inhibitor but not by a PI3K? inhibitor. These results suggest that PI3K? mediates dsRNA-induced upregulation of B7-H1 without affecting the activation of NF-?B.
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Mast cells contribute to double-stranded RNA-induced augmentation of airway eosinophilia in a murine model of asthma.
Respir. Res.
PUBLISHED: 02-26-2013
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Clinical studies showed the contribution of viral infection to the development of asthma. Although mast cells have multiple roles in the pathogenesis of allergic asthma, their role of in the virus-associated pathogenesis of asthma remains unknown. Most respiratory viruses generate double-stranded (ds) RNA during their replication. dsRNA provokes innate immune responses. We recently showed that an administration of polyinocinic polycytidilic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13.
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Low-dose salbutamol suppresses airway responsiveness to histamine but not methacholine in subjects with asthma.
Respir Investig
PUBLISHED: 02-07-2013
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Airway hyperresponsiveness is a cardinal feature of asthma. Although the modulation of cholinergic neuroeffector transmission may play a role in airway responsiveness, in vivo evidence remains scarce. It is well known that histamine causes bronchoconstriction partly via vagal reflex, whereas methacholine does not. To investigate the significance of modulating neuroeffector transmission, we compared the effect of low-dose salbutamol-a ?2-adrenoceptor agonist-on airway responsiveness to histamine with that to methacholine.
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Acute brainstem compression by intratumoral hemorrhages in an intracranial hypoglossal schwannoma.
Leg Med (Tokyo)
PUBLISHED: 01-10-2013
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A 77-year-old female in the hospital was found tachycardic and hypothermic by a nurse, and the patients respiration subsequently ceased. Forensic autopsy revealed an intracranial cystic tumor that would have compressed the brainstem. On microscopic examination, the tumor was diagnosed as an Antoni A schwannoma growth, and recent multiple intratumoral hemorrhages in the intracranial schwannoma were observed, suggesting the sudden enlargement of the intracranial schwannoma due to intratumoral hemorrhaging. Accordingly, we diagnosed the cause of death as brainstem compression induced by the intratumoral hemorrhaging in the intracranial schwannoma. Meanwhile, a rhinopharyngeal tumor was also detected by the autopsy, which was compatible with an antemortem diagnosis of a dumbbell-shaped hypoglossal schwannoma.
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Pyridone 6, a pan-JAK inhibitor, ameliorates allergic skin inflammation of NC/Nga mice via suppression of Th2 and enhancement of Th17.
J. Immunol.
PUBLISHED: 09-28-2011
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Atopic dermatitis (AD) is a common pruritic inflammatory disease triggered by a defective skin barrier and immunodysregulation. AD has been considered a typical example of a Th2 response associated with allergic disease. In the early phases of the disease, symptoms include IgE hyperproduction, eosinophil accumulation, and mast cell activation; in the chronic phase, a Th1-dominant immune response is also observed at the sites of AD skin lesions. The role of IL-17-producing Th (Th17) cells in AD has not been established. In the current study, we found that pyridone 6 (P6), a pan-JAK inhibitor, delayed the onset and reduced the magnitude of skin disease in an AD-like skin-disease model of NC/Nga mice. P6 reduced IFN-? and IL-13, whereas it enhanced IL-17 and IL-22 expression. In vitro, P6 also inhibited both Th1 and Th2 development, whereas it promoted Th17 differentiation from naive T cells when present within a certain range of concentrations. This was probably because P6 strongly inhibited STAT1, STAT5, and STAT6 phosphorylation, whereas STAT3 phosphorylation was less efficiently suppressed by P6 at the same concentration. Furthermore, IL-22 protects keratinocytes from apoptosis induced by IFN-?, and administration of IL-17 and IL-22 partially ameliorated skin diseases in NC/Nga mice. These results suggested that the JAK inhibitor P6 is therapeutic for AD by modulating the balance of Th2 and Th17.
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A case of diffuse large B-cell lymphoma of the lung demonstrating diffuse ground-glass shadows.
Ann Thorac Cardiovasc Surg
PUBLISHED: 08-17-2011
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We report a case of 77-year-old woman suffering from breathlessness on exertion and dry cough. Chest computed tomography (CT) showed diffuse ground-glass shadows. A video-assisted thoracoscopic lung biopsy resulted in the diagnosis of diffuse large B-cell lymphoma (DLBCL). Gene rearrangement analysis using polymerase chain reaction (PCR) technique was performed on the cells in bronchoalveolar lavage (BAL) fluid, and showed the clonality of the immunoglobulin heavy chain (IgH) gene, supporting the diagnosis. DLBCL should be considered in the differential diagnosis of diffuse ground-glass shadows in the chest CT, and gene rearrangement analysis may have an impact on the diagnosis of pulmonary DLBCL.
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Inhalative administration of insulin using a new bubble jet atomization device.
Fukuoka Igaku Zasshi
PUBLISHED: 08-10-2011
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In this study, we attempted to perform inhalative administration of insulin using a new "bubble jet" atomization device based on ink jet printing technology and developed by Canon Inc. The aim of this study was to confirm the usefulness of the new device for achieving a hypoglycemic effect by insulin inhalation in normal rats.
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IL-6 induced by double-stranded RNA augments allergic inflammation via suppression of Foxp3+ T-cell/IL-10 axis.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 07-28-2011
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Activation of innate immunity against viruses in the respiratory tracts affects the development of asthma. Most respiratory viruses generate double-stranded (ds)RNA during their replication. We recently showed that a low-dose administration of polyinosinic polycytidylic acid (poly IC), a mimetic of viral dsRNA, during allergen sensitization augments airway eosinophilia and hyperresponsiveness in mice via enhanced production of IL-13 from T cells. However, a phenotype of asthma under severer load of dsRNA remains unknown. d-galactosamine (d-GalN) is known as a strong sensitizer of poly IC. Mice were treated with poly IC plus d-GalN during allergen sensitization. A sublethal dose of poly IC/d-GalN augmented airway eosinophilia and CD4(+) T-cell accumulation in the lungs but not airway hyperresponsiveness. The augmented inflammation was associated with decreased IL-10 in the bronchoalveolar lavage fluid and decreased Foxp3(+) regulatory T cells in the lungs. Serum IL-6 was prominently higher in the mice treated with poly IC/d-GalN than in that with poly IC alone or d-GalN alone. Poly IC/d-GalN did not affect IL-17-producing T cells in the lungs. Poly IC/d-GalN failed to augment airway eosinophilia after anti-IL-10 receptor monoclonal antibody treatment during allergen challenge. Finally, anti-IL-6 receptor monoclonal antibody treatment before poly IC/d-GalN completely prevented the decrease of IL-10 and Foxp3(+) regulatory T cells and the augmentation of airway inflammation. These results indicate that enhanced production of IL-6 by poly IC/d-GalN induces the augmentation of allergic inflammation via suppression of Foxp3(+) regulatory T-cell/IL-10 axis. IL-6 may be a target for preventing asthma augmentation related to severe virus infection.
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A subacute epidural haematoma extending over the occipital region and posterior cranial fossa due to a laceration in the transverse sinus.
Int. J. Legal Med.
PUBLISHED: 06-27-2011
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A 6-year-old male was found dead on his stomach with massive reddish vomiting from his mouth and nose. Postmortem cranial CT revealed an epidural haematoma in the left occipital region, but the cause and origin of the haematoma were unclear. An autopsy revealed that the epidural haematoma expanded over the left temporal region and the left side of the occipital region and posterior cranial fossa, and its origin was a laceration in the left transverse sinus induced by diastases in the left lambdoidal and occipitomastoid sutures. A pathohistological examination revealed that one portion of the haematoma was an early-stage hemorrhage, while the other portion extended approximately 1 week after the hemorrhage. Moreover, approximately 1 week elapsed after the laceration of the transverse sinus. Thus, we believe that the primary haematoma was induced by the laceration in the transverse sinus approximately 1 week before death, but the haematoma ceased to enlarge due to hemostasis. However, later, the size of the haematoma rapidly increased again due to rebleeding from the laceration, which led to intracranial hypertension. Consequently, we diagnosed the direct cause of death as choking due to vomit aspiration that resulted from intracranial hypertension induced by a subacute epidural haematoma.
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Characterization of the immunophenotype of the tumor budding and its prognostic implications in squamous cell carcinoma of the lung.
Lung Cancer
PUBLISHED: 06-24-2011
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Tumor budding is morphologically defined as infiltration by small clusters of cancer cells. While the biological properties of budding cells in adenocarcinoma (decreased expression of adhesion molecules and of differentiation markers) have been elucidated, those of the cells in squamous cell carcinoma (SqCC) of the lung still remain to be clarified. We examined the clinicopathological data of 217 patients with SqCC of the lung. Furthermore we evaluated the immunohistochemical properties of the budding cells. Tumor budding was observed in 83 (38.2%) patients. A statistically significant difference was observed in overall 5-year survival rates between the cases showing tumor budding and the cases not showing budding (45.6% vs. 64.0%, p<0.001). As compared with cancer cells forming solid nests, budding cells (BCs) exhibited reduced expression levels of the cellular adhesion molecules (E-cadherin; p=0.004, ?-catenin; p=0.002) and increased expression levels of laminin-5?2 (p=0.001). On the other hand, no significant differences in the staining scores for differentiation markers (p63 and podoplanin) were found between BCs and cancer cells forming nests. Multivariate analysis revealed that tumor budding was a significant independent prognostic factor in patients with SqCC of the lung (p=0.022). Tumor budding is an independent adverse prognostic factor in patients with SqCC of the lung. Although budding cells in SqCC exhibited reduced expression levels of the cellular adhesion molecules, the expression levels of specific differentiation markers were retained, suggesting that the budding mechanism in SqCC may differ, at least in part, from that in adenocarcinoma.
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A case of multiple squamous cell papillomas of the trachea.
Ann Thorac Cardiovasc Surg
PUBLISHED: 05-21-2011
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We report a case of 68-year-old woman suffering from breathlessness on exertion with stridor. A chest computed tomography showed a tumor arising from the posterior wall of the trachea. The diagnosis was squamous cell papilloma of the surgically removed tumor, which had caused the asphyxiation. After removal of the tumor, the patient received radical therapy: semiconductor laser transpiration. Polymerase chain reaction (PCR) detected human papilloma virus (HPV) type 6, thought to be the cause of the respiratory papilloma.
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[A case of squamous cell carcinoma of the lung with bilateral diffuse uveal melanocytic proliferation (BDUMP) diagnosed by visual disturbance].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 04-13-2011
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A 50-year-old man presented with visual disturbance at a local ophthalmology clinic. He was given a diagnosis of uveitis and treated with oral corticosteroids; however, his visual disturbance did not improve and he was admitted to our hospital. A chest CT scan showed a pulmonary nodule in the upper lobe of the right lung, and right hilar and mediastinal lymphadenopathy. Transbronchial biopsy yielded a diagnosis of squamous cell carcinoma, and an ophthalmologic examination revealed bilateral diffuse uveal melanocytic proliferation (BDUMP). BDUMP is a rare manifestation of paraneoplastic syndrome, and the characteristics of the condition have not yet been clarified in detail. BDUMP carries a very poor visual prognosis, and in the present case, the patients visual disturbance progressed rapidly despite systemic chemotherapy and corticosteroid therapy.
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Perspectives on a new educational system for dental hygiene students in Japan.
J Dent Educ
PUBLISHED: 04-05-2011
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The purpose of this article is to report changes to dental hygiene education in Japan and to evaluate the successful implementation of these changes in 2010. The legislative change that began in 2005 revised the length of education for dental hygiene students from two years to three or four years (the mandate was three years), which has led to a dramatic change in program curriculum. After a five-year moratorium, a new curriculum has been established for dental hygiene education in Japan. The new curriculum provides students the requisite knowledge to effectively perform the latest dental hygiene procedures. Although the change of the educational system from the present mandatory three-year to the new four-year programs poses many administrative problems, we believe this shift will ultimately provide a more thorough and in-depth education for students.
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The transcription factor E4BP4 regulates the production of IL-10 and IL-13 in CD4+ T cells.
Nat. Immunol.
PUBLISHED: 03-10-2011
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The immunoregulatory cytokine interleukin 10 (IL-10) is expressed mainly by T helper type 2 (T(H)2) cells but also by T(H)1 cells during chronic infection. Here we observed plasticity in the expression of IL-10 and IL-13 after chronic T(H)1 stimulation; furthermore, the expression of Il10 and Il13 was regulated by the transcription factor E4BP4. Chronically stimulated E4BP4-deficient (Nfil3(-/-); called E4bp4(-/-) here) T(H)1 cells, regulatory T cells (T(reg) cells) and natural killer T cells (NKT cells) had attenuated expression of IL-10 and IL-13. Enforced expression of E4bp4 initiated the production of IL-10 and IL-13 by conventional T(H)1 cells. E4bp4(-/-) T(H)2 cells showed impairment of IL-10 production with no effect on IL-13. Our results indicate that E4BP4 has multiple functions in controlling the plasticity of IL-13 in T(H)1 cells and IL-10 in T(H)1 cells, T(H)2 cells, T(reg) cells and NKT cells.
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A zinc chelator TPEN attenuates airway hyperresponsiveness and airway inflammation in mice in vivo.
Allergol Int
PUBLISHED: 02-25-2011
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Zinc is an essential element required for the cell metabolism, including gene transcription, signal transduction, immunity, and apoptosis. The pathophysiological role of zinc in asthma, however, is not entirely clear. Mast cells have been implicated in atopic asthma, and zinc deprivation has been reported to reduce mast cell activation. Here, we investigate the effects of a zinc chelator, N,N,N,N-tetrakis (2-pyridyl-methyl) ethylenediamine (TPEN), on asthmatic responses in mouse models of ovalbumin (OVA)-induced airway hyperresponsiveness and allergic airway inflammation.
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Preparation of allosamidin and demethylallosamidin photoaffinity probes and analysis of allosamidin-binding proteins in asthmatic mice.
Bioorg. Med. Chem.
PUBLISHED: 02-23-2011
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Allosamidins, metabolites of Streptomyces with strong inhibitory activities toward family 18 chitinases, show a variety of biological activities in various organisms. We prepared photoaffinity and biotinylated probes of allosamidin and demethylallosamidin, the N-demethyl derivative that shows much stronger anti-asthmatic activity than allosamidin. Mild acid hydrolysis of allosamidins afforded mono-amine derivatives, which were amidated to prepare probes with a photoactivatable aryl azide and/or biotin moieties. The derivatives with an N-acyl group at C-2 of the D-allosamine residue at the non-reducing end of allosamidins inhibited Trichoderma chitinase as strongly as the original compounds. Since the target of allosamidins in asthma is unclear, photoaffinity probes were used to analyze allosamidin-binding proteins in bronchoalveolar lavage (BAL) fluid in IL-13-induced asthmatic mice. Ym1, a chitinase-like protein, was identified as the main allosamidin-binding protein among proteins whose expression was upregulated by IL-13 in BAL fluid. Binding of allosamidins with Ym1 was confirmed by the experiments with photoaffinity probes and recombinant Ym1.
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IL-13 suppresses double-stranded RNA-induced IFN-? production in lung cells.
Biochem. Biophys. Res. Commun.
PUBLISHED: 12-16-2010
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Acute asthma exacerbations are frequently associated with respiratory viral infections. Although impaired production of type III IFNs (IFN-?s) is related to the severity of asthma exacerbation, the mechanisms underlying deficient IFN-? production in asthma are poorly understood. Airway epithelial cells were stimulated in vitro with a synthetic mimetic of viral double-stranded RNA (dsRNA). IL-13, a crucial cytokine responsible for asthma pathogenesis, suppressed dsRNA-induced expression of IFN-?s, and JAK inhibitor AG490 prevented the suppression by IL-13. IL-13 per se did not affect IFN-? production or the expressions of membrane dsRNA receptor TLR3 and of cytoplasmic receptors RIG-I and MDA5. IL-13-deficient mice exhibited more enhanced IFN-? expression after intratracheal instillation of dsRNA than wild-type mice, whereas IFN-? expression after dsRNA was absent in the mouse lungs of the OVA-induced asthma model. These findings suggest that IL-13 may be a putative cytokine suppressing IFN-? production against airway viral infections in asthmatics.
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Effects of a Janus kinase inhibitor, pyridone 6, on airway responses in a murine model of asthma.
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-17-2010
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Th2 cytokines and their downstream Janus kinase (JAK)-signal transducer and activation of transcription (STAT) pathways play a critical role in allergic asthma. We studied the effects of a pan-JAK inhibitor, pyridone 6 (P6), on asthmatic responses in a mouse model and investigated the mechanism for its biological effects. Mice were sensitized and challenged by ovalbumin (OVA). P6 treatment during the challenge phase suppressed eosinophilia in bronchoalveolar lavage (BAL) fluids but did not affect airway hyperresponsiveness (AHR). To improve the efficacy of the JAK inhibitor, P6 was encapsulated in polylactic-coglycolic acid nanoparticles (P6-PLGA). P6-PLGA treatment just before OVA challenge suppressed both airway eosinophilia and AHR. Although the IL-13 levels in BAL fluids and the OVA-specific IgE levels in serum after the challenge phase treatment with P6-PLGA were similar to those after a sham treatment, the eotaxin levels in BAL fluids and lung mCLCA3/Gob-5 expression were decreased in P6-PLGA-treated mice. Interestingly, the local IL-13 levels and serum OVA-specific IgE were decreased, while IL-17-producing T cells were increased by P6-PLGA treatment during the sensitization plus challenge phases. In vitro, P6 strongly suppressed the differentiation of Th2 from naive CD4 T cells, but it partly enhanced Th17 differentiation. P6 potently suppressed IL-13-mediated STAT6 activation and mCLCA3/Gob-5 expression in mouse tracheal epithelial cells. These findings suggest that the JAK inhibitor P6 suppresses asthmatic responses by inhibiting Th2 inflammation and that application of PLGA nanoparticles improves the therapeutic potency of P6.
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[A case of non-small cell lung cancer with hemodialysis which responded to docetaxel monotherapy].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 11-12-2010
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A 56-year-old man receiving hemodialysis treatment was hospitalized for examination of a mass in the right middle lobe. Chest computed tomography showed a right hilar mass shadow accompanied by pleural effusion. Non-small cell lung cancer (NSCLC) was diagnosed by cytological examination of the pleural effusion. No epidermal growth factor receptor (EGFR) mutation was found. He was treated with 6 courses of docetaxel as first-line chemotherapy. Docetaxel was administered on the same day as hemodialysis. Adverse events, including hematotoxicity, were managed safely and no delay in administration occurred. This chemotherapy resulted in a partial response. Because docetaxel is metabolized in the liver and does not affect renal function, it can be administered as a standard regimen. This suggests that docetaxel monotherapy is an efficient therapy for non-small cell lung cancer patients receiving hemodialysis.
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Essential role of B7-H1 in double-stranded RNA-induced augmentation of an asthma phenotype in mice.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 08-27-2010
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Clinical and epidemiological studies have shown the contribution of viral infection to the development of allergic asthma. Many RNA viruses, pathogenic for the respiratory tract, generate double-stranded (ds)RNA during their replication. Typical innate immune responses triggered by dsRNA involve the endosomal and cytoplasmic pathways. The former is mediated by Toll/IL-1R domain-containing adaptor inducing IFN-? (TRIF), and the latter by IFN-? promoter stimulator 1 (IPS-1). We explored the effect of polyinocinic polycytidilic acid, a synthetic dsRNA, on the development of an asthma phenotype in mice. Administration of dsRNA during ovalbumin sensitization augmented airway eosinophilia and airway hyperresponsiveness after an antigen challenge, which was associated with enhanced induction of IL-13-producing CD8(+) T cells. The augmentation was induced in IPS-1-deficient mice but not in TRIF-deficient mice. The interactions between dendritic cells (DCs) and T cells are regulated by B7-family costimulatory molecules, including B7-H1 (also known as PD-L1), a putative ligand for programmed death-1 (PD-1). Treatment of bone marrow-derived DCs with dsRNA enhanced B7-H1 expression in a TRIF-dependent manner. Additionally, dsRNA increased B7-H1 expression on DCs in the draining lymph nodes of ovalbumin-sensitized mice. The augmentation of the asthma phenotype was prevented by the treatment of mice with anti-B7-H1 mAb but not with anti-PD-1 mAb. The augmentation was not induced in B7-H1-deficient mice. These results suggest that dsRNA-triggered activation of the innate immune system in sensitization leads to augmentation of the asthma phenotype via IL-13 mainly from CD8(+) T cells. B7-H1 plays a crucial role in the process without requiring interaction with PD-1.
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[Drug dependency and drug-related sudden death].
Nippon Rinsho
PUBLISHED: 08-19-2010
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Abuse of many substances is one of the serious problems in Japan, and we often encounter an autopsy case where the individual died in association with the administration of them. Although their intoxication is mainly diagnosed on the basis of their serum concentrations, it is difficult to diagnose as their poisoning when their concentrations are less than lethal level. Moreover, the mechanism of death induced by them is still unclear. Therefore, forensic autopsy should be performed in the case where drug-related death is suspicious not only so as to make a precise diagnosis but also so as to elucidate the mechanism of the drug-related deaths, leading to the efficient therapy for drug intoxication.
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The enhancer HS2 critically regulates GATA-3-mediated Il4 transcription in T(H)2 cells.
Nat. Immunol.
PUBLISHED: 06-23-2010
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GATA-3 is a master regulator of T helper type 2 (T(H)2) differentiation. However, the molecular basis of GATA-3-mediated T(H)2 lineage commitment is poorly understood. Here we identify the DNase I-hypersensitive site 2 (HS2) element located in the second intron of the interleukin 4 locus (Il4) as a critical enhancer strictly controlled by GATA-3 binding. Mice lacking HS2 showed substantial impairment in their asthmatic responses and their production of IL-4 but not of other T(H)2 cytokines. Overexpression of Gata3 in HS2-deficient T cells failed to restore Il4 expression. HS2 deletion impaired the trimethylation of histone H3 at Lys4 and acetylation of histone H3 at Lys9 and Lys14 in the Il4 locus. Our results indicate that HS2 is the target of GATA-3 in regulating chromosomal modification of the Il4 locus and is independent of the Il5 and Il13 loci.
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T cell treatment with small interfering RNA for suppressor of cytokine signaling 3 modulates allergic airway responses in a murine model of asthma.
Am. J. Respir. Cell Mol. Biol.
PUBLISHED: 05-27-2010
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CD4(+) T cells, particularly T helper (Th) 2 cells, play a pivotal role in the pathophysiology of allergic asthma. Suppressor of cytokine signaling (SOCS) proteins control the balance of CD4(+) T cell differentiation. Mice that lack SOCS3 in T cells by crossing SOCS3-floxed mice with Lck-Cre-transgenic mice have reduced allergen-induced eosinophilia in the airways. Here, we studied the effects of SOCS3 silencing with small interfering (si) RNA in primary CD4(+) T cells on Th2 cell differentiation and on asthmatic responses in mice. Th2 cells were generated from ovalbumin (OVA)-specific T cell receptor-transgenic mice in vitro and transferred into recipient mice. Transfection of SOCS3-specific siRNA attenuated Th2 response in vitro. Adoptive transfer of SOCS3-siRNA T cells exhibited markedly suppressed airway hyperresponsiveness and eosinophilia after OVA challenge, with a concomitant decrease in OVA-specific CD4(+) T cell accumulation in the airways. To investigate the mechanism of this impaired CD4(+) T cell accumulation, we inactivated SOCS3 of T cells by crossing SOCS3-floxed (SOCS3(flox/flox)) mice with CD4-Cre transgenic mice. CD4-Cre × SOCS3(flox/flox) mice exhibited fewer IL-4-producing cells and more reduced eosinophil infiltration in bronchoalveolar lavage fluids than control mice in a model of OVA-induced asthma. Expression of CCR3 and CCR4 in CD4(+) T cells was decreased in CD4-Cre × SOCS3(flox/flox) mice. CCR4 expression was also decreased in CD4(+) T cells after transfer of SOCS3 siRNA-treated T cells. These findings suggest that the therapeutic modulation of SOCS3 expression in CD4(+) T cells might be effective in preventing the development of allergic asthma.
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[A case of interstitial pneumonia with smoldering adult T-cell leukemia].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 05-04-2010
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A 66-year-old woman was admitted because of dry cough and dyspnea. Computed tomography showed ground-glass opacities and traction bronchiectasis in both lung fields. Then, ATL cells appeared in her peripheral blood, and the number of lymphocytes in BALF increased. Inverse PCR for HTLV-1 clonality of the peripheral blood revealed a polyclonal pattern, and she was given a diagnosis of smoldering adult T-cell leukemia. Using BALF flow cytometry, both CD4- and CD25-positive cells accounted for only 0.8%. Secondary interstitial pneumonia was diagnosed and we started therapy with prednisolone and cyclophosphamide. BALF flow cytometry may be useful in the differential diagnosis of ATL lung lesions.
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Massive retroperitoneal haemorrhage after extracorporeal shock wave lithotripsy (ESWL).
Int. J. Legal Med.
PUBLISHED: 04-07-2010
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A 76-year-old male suffering from nephrolithiasis developed a shock syndrome 5 days after extracorporal shock wave lithotripsy (ESWL). CT scan of the abdomen showed massive haemorrhage around the right kidney. Although nephrectomy was performed immediately, the haemorrhage could not be controlled. Numerous units of erythrocytes were transfused, but the patient died. The autopsy revealed massive retroperitoneal haemorrhage around the right kidney. The kidney showed a subcapsular haematoma and a rupture of the capsule. The right renal artery was dissected. The inferior vena cava was lacerated. Accordingly, a hemorrhagic shock as the cause of death was determined, which might mainly have resulted from the laceration of the inferior vena cava due to ESWL. ESWL seems to be a relatively non-invasive modality, but one of its severe complications is perirenal hematoma. The injuries of the blood vessels might have been caused by excessive shock waves. Subsequently, anticoagulation therapy had been resumed 3 days after EWSL, which might have triggered the haemorrhage. Physicians should note that a haemorrhage after an ESWL can occur and they should pay attention to the postoperative management in aged individuals especially when they are under anticoagulation therapy.
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[Heparin-induced thrombocytopenia and disseminated intravascular coagulation in a patient with drug-induced pneumonia].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 02-27-2010
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An 82-year-old woman was admitted to the hospital with dyspnea and fatigue. She had been given amlodipine, furosemide, candesartan, pravastatin and roxatidine acetate for two months in an other hospital. Chest CT showed patchy consolidations throughout the entire lungs. We suspected drug-induced pneumonia, and treated her with prednisolone under mechanical ventilation. The pulmonary consolidations eventually improved, but on the 15th hospital day the patient developed thrombocytopenia and disseminated intravascular coagulation (DIC). Heparin flushes had been performed since the first hospital day. After these were stopped, her platelet count became normal and the patient recovered from DIC. The clinical course, and the fact that testing for heparin-induced thrombocytopenia (HIT) antibodies was positive, supported the diagnosis of HIT and DIC. We report a rare case of HIT and DIC during treatment for drug-induced pneumonia.
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Molecular-biological analysis of the effect of methamphetamine on the heart in restrained mice.
Leg Med (Tokyo)
PUBLISHED: 01-06-2010
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In order to investigate the interaction in the heart between the administration of methamphetamine (MAP) and restraint of the body following it, we administrated MAP intraperitoneally to mice and restrained them, and then determined the level of mRNA expression of 22 genes in the heart using quantitative RT-PCR method. The mRNA expressions of Nfkbiz, Nr4a1 and Dusp1 changed significantly after the administration of MAP, suggesting the induction of an inflammatory condition such as damage to the myocardium. Moreover, the serum concentrations of inflammatory cytokines such as tumor necrosis factor-alpha, interleukin (IL)-1 beta and IL-6 were significantly increased by the administration of MAP. On the other hand, the mRNA expressions of Rgs2 and Rasd1 were changed by both the administration of MAP and body restraint without interaction, which indicated that these insults affected the circulatory system additively or synergistically. From these results, it is likely that the administration of MAP, followed by body restraint, might cause acute myocardial damage due to the direct myocardial toxic effect of MAP, myocardial hypoxia and/or severe hypertension, which is one of the mechanisms for sudden death in MAP abusers who were restrained due to their excited state.
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Demethylallosamidin, a chitinase inhibitor, suppresses airway inflammation and hyperresponsiveness.
Biochem. Biophys. Res. Commun.
PUBLISHED: 09-06-2009
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Acidic mammalian chitinase is upregulated in response to allergen exposure in the lung. We investigated the effects of chitinase inhibitors, allosamidin (Allo) and demethylallosamidin (Dma), on asthmatic responses. Mice were subjected to IL-13 instillation into the airways or to ovalbumin sensitization plus exposure with or without treatment of Allo or Dma. Airway hyperresponsiveness (AHR) and inflammation were evaluated. Allo and Dma attenuated airway eosinophilia and the upregulation of eotaxin after IL-13 instillation, while Dma, but not Allo, suppressed AHR in IL-13-induced asthma. Allo or Dma suppressed the elevated chitinase activity in BAL fluids after IL-13 to similar levels. The bronchoprotective PGE(2) levels in BAL fluids were elevated after IL-13 instillation. Allo, but not Dma, suppressed the overproduction of PGE(2) and the expression of COX-2 and PGE synthase-1 induced by IL-13. In ovalbumin-induced asthma, Dma suppressed AHR more strongly than Allo. These findings suggest that Dma attenuates asthmatic responses induced by IL-13 without affecting PGE(2) synthesis. Dma may have potential as therapeutic agents for asthma.
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[A case of rapidly growing inflammatory myofibroblastic tumor in the lung].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 06-25-2009
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We report a case of a 28-year-old man with a dry cough and chest pain. Chest X-ray film showed a huge mass in the right lung field. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a huge mass which occupied most of the right thoracic cavity and invaded the superior vena cava, heart atrium and right pulmonary vein. Positron emission tomography (PET) showed metastasis of bone, right adrenal grand and lymph nodes. A tumor specimen was biopsied percutaneously, and the diagnosis was pathologically confirmed as an inflammatory myofibroblastic tumor. Immunohistochemical staining also showed an overexpression of ALK in the tumor. He was treated with a non-steroid anti-inflammation drug and steroid, but they were ineffective. He underwent chemotherapy with bleomicin, etoposide and cisplatin. After two cycles of chemotherapy, the tumor slightly reduced in size, but was eventually refractory to the regimen finally. He also underwent with paclitaxel and carboplatin. At present, if operative extirpation is not possible, there is no way to treat an inflammatory myofibroblastic tumor. In the future, new therapy incorporating ALK inhibitors would be expected to treat those cases of IMT in which local recurrences and distant metastases occur.
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[A case of secondary pulmonary alveolar proteinosis associated with myelodysplastic syndrome, complicated with disseminated M. abscessus infection].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 06-25-2009
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A 27-year-old man was admitted to our hospital complaining of a persistent high fever since August 2007. Chest radiography showed infiltration shadows in the right lower lung field. Chest CT revealed scattered small nodular shadows and patchy consolidations in the right lower lobe. He was diagnosed as secondary pulmonary alveolar proteinosis (sPAP) associated with myelodysplastic syndrome (MDS), confirmed by video-assisted thoracic surgery (VATS) and bone marrow aspiration. Sera were negative for anti-granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibody. He developed a subcutaneous abscess and meningitis caused by M. absessus after VATS. After a long-course of antibiotic therapy, an allogenic peripheral blood stem cell transplantation was performed. But he died of graft versus host disease and M. abscessus sepsis 87 days after transplantation.
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[Case of solitary fibrous tumor of the pleura completely resected eleven years after detection].
Nihon Kokyuki Gakkai Zasshi
PUBLISHED: 06-12-2009
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A 65-year-old woman was referred to our hospital for investigation of increased opacity in the right lower lung field of the chest X-ray. Chest CT demonstrated a large tumor in the right thoracic cavity. A preoperative needle biopsy was performed. The microscopic appearance revealed many spindle cells. An immunohistochemical study was positive for CD34 and vimentin. Solitary fibrous tumor of the pleura was strongly suspected and the operation was performed. The tumor arose from the visceral pleura and was pedunculated. The resected specimen was positive for CD34 and vimentin. The tumor was diagnosed as solitary fibrous tumor of the pleura. Although this case was diagnosed 11 years after detection, the tumor was completely resected. Solitary fibrous tumors are usually cured with complete resection, but long-term clinical follow up is needed because of the possibility of recurrence and metastasis.
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Pulmonary suppressor of cytokine signaling-1 induced by IL-13 regulates allergic asthma phenotype.
Am. J. Respir. Crit. Care Med.
PUBLISHED: 03-19-2009
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Th2 cytokines play an important role in allergic diseases. These cytokines activate signal transduction pathways, including Janus kinase/signal transducer and activator of transcription (STAT) signaling. Although the suppressor of cytokine signaling (SOCS) family protein, a negative regulator of the Janus kinase/STAT signaling pathway, contributes to helper T cell differentiation during immune responses, the role of SOCS proteins within the structural cells of a target organ has not been clarified in allergy.
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Pulmonary fat embolization as a diagnostic finding for heat exposure.
Leg Med (Tokyo)
PUBLISHED: 02-20-2009
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The aim of this study was to examine whether the detection of pulmonary fat embolization is valid as a significant indicator of heat exposure in forensic autopsies. In 54 cases where there was no evidence of fracture, burn or pancreatitis, 25 cases (46.3%) showed pulmonary fat embolization, the degree of which was pathohistologically classified as slight in all cases. Among the 25 cases where the pulmonary fat embolization was detected, the individual had died under a high ambient temperature in 14 cases (56%). Based on logistic regression analysis, pulmonary fat embolization was found to be associated with a high ambient temperature, but not associated with coronary arteriosclerosis, fatty infiltration in the liver, severe infectious diseases, intracranial hemorrhage or the detection of methamphetamine in the blood. Further investigations are necessary before these findings can be applied in forensic autopsy cases; however, it is likely that the detection of pulmonary fat embolization is valuable as one of the diagnostic findings indicating antemortem heat exposure.
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Matrix metalloproteinases in blood from patients with LAM.
Respir Med
PUBLISHED: 02-10-2009
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Pulmonary lymphangioleiomyomatosis (LAM) is characterized by the proliferation of abnormal smooth muscle cells (LAM cells) and destruction of alveolar structure. Immunohistochemical studies suggest that excess matrix metalloproteinases (MMPs) synthesized by LAM cells function in the proteolytic mechanisms of this disease. We postulated MMP levels in the blood are elevated in LAM patients. Serum samples were collected from 36 LAM patients and 25 controls, and gelatinolytic activities were semi-quantified by gelatin zymography. The reliability of serum data for MMP-9 was confirmed by the measurement of MMP-9 concentration in plasma by enzyme-linked immunosorbent assay as well as by gelatin zymography. Serum levels of MMP-9 (0.7+/-0.1 AU), but not MMP-2, were significantly elevated in LAM patients compared with controls (0.1+/-0 AU). Plasma and serum levels of MMP-9 significantly correlated. These results suggest the involvement of MMP-9 in LAM.
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Electrolyte analysis of pleural effusion as an indicator of drowning in seawater and freshwater.
J Forensic Leg Med
PUBLISHED: 01-31-2009
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It is important for forensic pathologists to determine the diagnosis of drowning as well as the site of drowning. In a previous study, we propose that analysis of electrolytes in pleural effusion from rats may be useful for determining whether drowning has occurred in seawater or freshwater. To test this proposal, we measured the concentration of sodium, potassium and chloride ions and total protein in pleural effusion from 40 autopsy cases: 24 involving seawater drowning, 9 freshwater drowning and 7 no drowning. The concentrations of sodium and chloride ions in pleural effusion showed a significant difference between seawater drowning and freshwater drowning. The concentration of potassium ions and total protein showed no difference between each group, although they increased in proportion to the postmortem interval in cases of both seawater and freshwater drowning. These results are almost same as our previous study and, thus, the quantitative analysis of electrolytes in pleural effusion may be useful for determining whether drowning has occurred in seawater or freshwater.
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Frequency of Foxp3+CD4CD25+ T cells is associated with the phenotypes of allergic asthma.
Respirology
PUBLISHED: 01-23-2009
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A forkhead/winged-helix family transcriptional repressor, Foxp3, is highly expressed on CD4(+)CD25(+) T regulatory cells. The role of Foxp3(+)CD4(+)CD25(+) T regulatory cells in asthma remains to be elucidated. Using mouse models and peripheral blood mononuclear cells (PBMC) from subjects with allergic asthma, we aimed to explore whether Foxp3(+)CD4(+)CD25(+) T regulatory cells associate with asthma phenotypes.
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Effects of thirty-times chewing per bite on secretion of glucagon-like peptide-1 in healthy volunteers and type 2 diabetic patients.
Endocr. J.
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Glucagon-like peptide 1 (GLP-1) is secreted from the small intestine to the blood in response to glucose intake during a meal; however, it is not known whether mastication affects GLP-1 secretion. Here, we examined the relationship between mastication and GLP-1 secretion, along with postprandial blood glucose and insulin concentrations. We compared the levels of blood glucose, serum insulin, and plasma active GLP-1 concentrations after young healthy volunteers ate a test meal either by usual eating (control) or in one of three specified ways: 1. unilateral chewing, 2. quick eating, 3. 30-times chewing per bite. Ten volunteers participated in each of the three groups. Plasma active GLP-1 concentrations did not change by unilateral chewing or quick eating, but did increase by the third method, without affecting the concentrations of blood glucose or serum insulin. Next, we tested whether 30-times chewing per bite increased plasma active GLP-1 concentrations in 15 patients with type 2 diabetes mellitus, but there was no difference in results between usual eating and 30-times chewing per bite. This is a pilot trial with a small number of subjects, but is the first study to investigate the relationships between various styles of mastication and the GLP-1 secretion in young healthy volunteers and type 2 diabetic patients.
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Effects of tiotropium on lung function in severe asthmatics with or without emphysematous changes.
Pulm Pharmacol Ther
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The effects of tiotropium, an inhaled long-acting anti-cholinergic agent, on lung function were investigated in obstructed severe asthmatics with and without emphysematous changes despite maximal recommended treatments with high-dose of inhaled glucocorticoids and inhaled long-acting ?(2)-agonists. We conducted a double-blind, placebo-controlled study of an inhaled single-dose of tiotropium in 18 asthmatics with emphysema and 18 without emphysema in a crossover manner. The primary efficacy outcome was the relative change in forced expiratory volume in 1 s (FEV(1)) from baseline to 60 min, and the secondary outcome was a relative change in FEV(1) from baseline to 12 h. Subsequently, the patients were treated with tiotropium inhaled once daily for 12 weeks in an open label manner, and lung function and symptoms were evaluated. At baseline, patients with or without emphysema had a mean FEV(1) of 55.9% before tiotropium and 56.8% before placebo, or 77.4% before tiotropium and 77.6% before placebo of the predicted value and were taking a mean dose of inhaled glucocorticoids of 1444 or 1422 ?g/day. Among patients with emphysema, the increase from baseline FEV(1) was 12.6 percentage points higher at 60 min after tiotropium than after placebo. Among patients without emphysema, the increase from baseline FEV(1) was 5.4 percentage points higher at 60 min after tiotropium than after placebo. Tiotropium resulted in improved lung function and symptoms in asthmatics with and without emphysema. These findings suggest that tiotropium will provide a new strategy for the treatment of bronchial asthma and of overlapping asthma and COPD.
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EGFR mutations and human papillomavirus in lung cancer.
Lung Cancer
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Our previous study reported a frequent detection of human papillomavirus (HPV) genome in primary lung adenocarcinomas of the recurrent patients who were responsive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor, suggesting that HPV presence in lung cancer may be related to a genetic background related to EGFR mutations. The present study examined the association between the HPV presence and mutations in exons 19 and 21 of EGFR gene in Japanese lung cancer patients. Thirteen (31%) out of 42 cases had EGFR mutations. Although these mutations were tended to be observed in females, non-smokers, or adenocarcinomas, there was no statistically significant associations. HPV DNA was found in 7/42 (17%) lung tumors. The frequency of HPV presence did not differ in histological types. The presence of HPV DNA was significantly related to EGFR mutations (P=0.021), especially in adenocarcinomas of the lung (P=0.014). HPV-positive lung tumors accounted for 38% and 7% of those with and without EGFR mutations, respectively. Our results suggest that EGFR mutations are associated with HPV presence in Japanese patients with lung cancer.
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The elevation of serum napsin A in idiopathic pulmonary fibrosis, compared with KL-6, surfactant protein-A and surfactant protein-D.
BMC Pulm Med
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Napsin A, an aspartic protease, is mainly expressed in alveolar type-II cells and renal proximal tubules and is a putative immunohistochemical marker for pulmonary adenocarcinomas. This study sought to determine whether napsin A could be measured in the serum to evaluate its relationship to idiopathic pulmonary fibrosis (IPF) and determine whether renal dysfunction might affect serum napsin A levels.
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Prediction of peoples origin from degraded DNA--presentation of SNP assays and calculation of probability.
Int. J. Legal Med.
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The characterization of externally visible traits by DNA analysis is already an important tool when investigating ancient skeletal remains and may gain similar importance in future forensic DNA analysis. This, however, depends on the different legal regulations in the different countries. Besides eye or hair color, the population origin can provide crucial information in criminal prosecution. In this study, we present the analysis of 16 single-nucleotide polymorphisms (SNPs) combined to two robust SNaPshot assays with a detection threshold of 25-pg DNA. This assay was applied to 891 people from seven different populations (West Africa, North Africa, Turkey, Near East, Balkan states, North Europe, and Japan) with a thorough statistical evaluation. The prediction model was validated by an additional 125 individuals predominantly with an ancestry from those same regions. The specificity of these SNPs for the prediction of all population origins is very high (>90 %), but the sensitivity varied greatly (more than 90 % for West Africa, but only 25 % for the Near East). We could identify West Africans with a certainty of 100 %, and people from North Africa, the Balkan states, or North Europe nearly with the same reliability while determination of Turks or people from the Near East was rather difficult. In conclusion, the two SNaPshot assays are a powerful and reliable tool for the identification of people with an ancestry in one of the above listed populations, even from degraded DNA.
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Molecular-biological analysis of acute lung injury (ALI) induced by heat exposure and/or intravenous administration of oleic acid.
Leg Med (Tokyo)
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The aim of this study was to molecular-biologically investigate the interaction between heat exposure and pulmonary fat embolization in regards to the development of acute lung injury (ALI). Ten-week-old Wistar male rats were divided into four groups: (1) oleic acid injected into caudal vein after heat exposure, (2) oleic acid injected without heat exposure, (3) soybean oil injected after heat exposure, and (4) soybean oil injected without heat exposure, and then mRNA expression of eight inflammatory mediators related to ALI/acute respiratory distress syndrome (ARDS) and heat shock protein 70 (Hsp70) in lung was determined 1h after the injection. mRNA expression of interleukin 1 beta (Il1b), tumor necrosis factor alpha (Tnfa), vascular endothelial growth factor A (Vegfa), transforming growth factor beta 1 (Tgfb1) and Hsp70 was significantly increased by heat exposure, while that of Il1b, interleukin 6 (Il6), Tnfa, macrophage inflammatory protein 2 (Mip2) and granulocyte macrophage-colony stimulating factor (Gm-csf) was significantly elevated by the injection of oleic acid. Moreover, the expressions of inflammatory cytokines and chemokines in lung almost paralleled their mRNA expressions. In particular, IL-1? expression was synergistically elevated by heat exposure followed by injection of oleic acid. Additionally, IL-6 expression tended to increase under the same conditions as well. It is likely that heat exposure itself injures lung tissue within a short time, and that more than two conditions which induce ALI/ARDS interact with each other synergistically, exacerbating the development of ALI/ARDS.
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The blood concentration and organ distribution of haloperidol at therapeutic and toxic doses in severe fatty liver disease.
Leg Med (Tokyo)
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The aim of this study was to investigate the difference between the pharmacokinetics of haloperidol in normal rats and in rats with fatty liver disease. A therapeutic dosage (0.1 mg/kg) and a toxic dose (15 mg/kg) of haloperidol were administrated to normal 9-week-old male rats or those with severe fatty liver disease, and the blood concentration of haloperidol was determined 15 min, 1, 2, and 3 h following haloperidol administration. The concentration of haloperidol in the organs was determined 1, 2, and 3 h after the haloperidol administration. Additionally, the volume of the portal vein blood flow was measured 3 h after haloperidol administration. When given at the therapeutic dosage, the concentrations of haloperidol in both the blood and organs of the rats with fatty liver disease were significantly higher than those in the normal rats. However, when given at the toxic level, the blood and organ haloperidol concentrations 1 h after administration tended to be lower in the rats with fatty liver disease than those in the normal rats; these lower haloperidol levels returned to be the levels in the normal rats 3 h after the administration of haloperidol. The volume of the portal vein blood flow significantly increased following the toxic haloperidol dose as compared with the volume pre-administration and following the therapeutic haloperidol dose in the normal rats. However, the volume did not change after the toxic or the therapeutic dose of haloperidol compared with pre-administration in rats with severe fatty liver disease, although it was significantly higher than in the normal rats. The pathway for haloperidol metabolism might have been saturated before the administration of haloperidol in rats with fatty liver disease; thus, it is possible that the blood concentration of haloperidol tends to be much higher in individuals with severe fatty liver disease than in those with normal livers in an inverse proportion to the dosage of haloperidol.
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The 3 enhancer CNS2 is a critical regulator of interleukin-4-mediated humoral immunity in follicular helper T cells.
Immunity
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A main role for interleukin-4 (IL-4) is in humoral immunity, and follicular helper CD4(+) T (Tfh) cells may be an intrinsic IL-4 source. Here we demonstrate that conserved noncoding sequence 2 (CNS2) is an essential enhancer element for IL-4 expression in Tfh cells but not in Th2 cells. Mice with a CNS2 deletion had a reduction in IgG1 and IgE production and in IL-4 expression in Tfh cells. Tracking of CNS2 activity via a GFP reporter mouse demonstrated that CNS2-active cells expressed several markers of Tfh cells: CXCR5, PD-1, and ICOS; the transcriptional master regulator Bcl6; and the cytokines IL-21 and IL-4. These CNS2-active cells were mainly localized in B cell follicles and germinal centers. The GFP(+) Tfh cells were derived from GFP(-) naive T cells after in vivo systemic immunization. These results indicate that CNS2 is an essential enhancer element required for IL-4 expression in Tfh cells controlling humoral immunity.
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Molecular biological analysis of cardiac effect of high temperature in rats.
Leg Med (Tokyo)
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The aim of this study was to investigate direct effects of heat exposure on the heart molecular-biologically and pathohistologically, using rats exposed to high temperatures. The mRNA expression of natriuretic peptide type A (Nppa), natriuretic peptide type B (Nppb), actin alpha 1 skeletal muscle (Acta1), myosin heavy polypeptide 6 cardiac muscle alpha (Myh6) and myosin heavy polypeptide 7 cardiac muscle alpha (Myh7) was determined in the hearts of the rats. Whereas the expression of Nppa and Nppb rapidly increased immediately after the heat exposure, the expression of Acta1 was gradually reduced, which indicated cardiac overload. Moreover, the expression of Myh6 and Myh7 in the heart increased 4h after the heat exposure, which suggested the involvement of a compensatory mechanism. Immunohistochemical staining with anti-fibronectin antibody showed that positive cardiomyocytes could be detected sparsely 4h after the heat exposure, and they could be clearly observed 8h after the heat exposure. Our results showed that hyperthermia causes myocardial damage shortly after the exposure to heat and that the ventricle was more vulnerable to hyperthermia-induced damage than the atrium. Cardiac dysfunction may be induced not only by hypercytokinemia but also by the direct effect of heat exposure at the early period of heat stroke, which may be one of the mechanisms by which heat causes death. Elucidating the mechanism of death from heat stroke could lead to not only diagnostic improvement but also the prevention of death from heat stroke.
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Low dose CP-690,550 (tofacitinib), a pan-JAK inhibitor, accelerates the onset of experimental autoimmune encephalomyelitis by potentiating Th17 differentiation.
Biochem. Biophys. Res. Commun.
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Th17 cells, which have been implicated in autoimmune diseases, require STAT3 signaling activated by IL-6 or IL-23 for their development. Other Th1 and Th2 cytokines such as IL-2, IFN-? and IL-4 strongly suppress Th17 development. Recently, CP-690,550 (tofacitinib), originally developed as a JAK3 inhibitor, has been shown to be effective in phase III clinical trials of rheumatoid arthritis and collagen-induced arthritis (CIA) models, but the precise mechanism of the effect, especially with respect to Th17 cells, is poorly understood. To our surprise, a low dose CP-690,550 was found to accelerate the onset of experimental autoimmune encephalomyelitis (EAE) at a concentration that suppressed CIA. At an early stage after immunization, more IL-17 production was observed in 15mg/kg body weight CP-690,550-treated mice than in untreated mice. In vitro, CP-690,550 inhibited both Th1 and Th2 development, while promoting Th17 differentiation at 10-50nM concentrations. Enhancement of Th17 by CP-690,550 is probably due to suppression of IL-2 signaling, because anti-IL-2 antibodies cancel the Th17-promoting effect of CP-690,550. CP-690,550 selectively inhibited IFN--induced STAT1, IL-4-induced STAT6 and IL-2-induced STAT5 at 3-30nM, while suppression of IL-6-induced STAT3 phosphorylation required a concentration greater than 100nM. In HEK293T cells, CP-690,550 less effectively suppressed JAK1-mediated STAT3 phosphorylation compared with JAK3. These results suggest that CP-690,550 has a different effects among JAKs and STATs, thereby affecting helper T cell differentiation, and murine autoimmune disease models.
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Role of mast cells and basophils in IgE responses and in allergic airway hyperresponsiveness.
J. Immunol.
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We established a diphtheria toxin (DT)-based conditional deletion system using Il4 enhancer elements previously shown to be specific for IL-4 production in mast cells (MCs) or basophils (Mas-TRECK and Bas-TRECK mice). DT treatment of Bas-TRECK mice resulted in specific deletion of basophils, whereas both MCs and basophils were deleted in Mas-TRECK mice. DT-treated Mas-TRECK mice had impaired passive cutaneous anaphylaxis, IgE-mediated passive systemic anaphylaxis, and IgE-mediated chronic allergic inflammation, whereas DT-treated Bas-TRECK mice had impaired IgE-mediated chronic allergic inflammation. Using these mice, we also sought to tease out the role of MCs and basophils in airway hyperresponsiveness (AHR). Although MC deletion resulted in a slight increase in basal Ag-specific IgE levels and significant increases in basal IgE levels, we found that this deletion markedly impaired the AHR effector phase and was accompanied by decreased histamine levels. By contrast, basophil deletion had no effect on the AHR effector phase or on IgE production induced by systemic OVA immunization. Our results, using these newly established Mas-TRECK and Bas-TRECK models, demonstrated an indispensable role for MCs as effector cells in AHR.
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