RESUMO
The non-imprinted in Prader-Willi/Angelman syndrome (NIPA) proteins are highly conserved receptors or transporters. Translocation of NIPA genes were found in patients with Prader-Willi syndrome, and loss-of-function of the NIPA1 gene was identified in hereditary spastic paraplegia. The family of NIPA-like domain containing (NPAL) proteins is closely related to the NIPA proteins, but to date nothing is known about their function. Here, we could demonstrate that both human NPAL3 and mouse NPAL3 are ubiquitously expressed and encode highly conserved proteins. To further elucidate the function of the Npal3 gene, knockout (Npal3(-/-)) mice were generated. Intensive phenotypic analyses revealed that disruption of the Npal3 gene results in a pleiotropic phenotype. The function of the nervous system was impaired in both mutant males and females which could be demonstrated in behavioral tests. In addition, in NPAL3 mutants the number of NK cells was decreased and changes in IgM, IgG(2), and IgA were observed, indicating that the immune system is also affected. Interestingly, increased IgE levels as well as impaired lung functions were observed in mutant males but not in mutant females. It should be noted that the human Npal3 gene is located at 1p36.12-->p35.1, and atopic diseases were previously linked to this genomic region. Thus, the Npal3(-/-) mice could serve as a valuable model system for studying atopic diseases.
Assuntos
Comportamento Animal , Imunoglobulina E/sangue , Pulmão/fisiologia , Proteínas de Membrana/genética , Sequência de Aminoácidos , Animais , Proteínas de Transporte de Cátions , Membrana Celular/metabolismo , Sequência Conservada , Evolução Molecular , Feminino , Expressão Gênica , Humanos , Imunoglobulina E/imunologia , Masculino , Proteínas de Membrana/química , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Fenótipo , Filogenia , Alinhamento de SequênciaRESUMO
Exposure to ionizing radiation (IR) results in the formation of DNA double strand breaks, resulting in the activation of phosphatidylinositol 3'-kinase-like kinases ATM, ATR and DNK-PKcs. A physiologically important downstream target is the minor histone H2A variant, H2AX, which is rapidly phosphorylated on Ser 139 of the carboxyl tail after IR. Recent work suggests that phosphorylated H2AX (gamma-H2AX) plays an important role in the recruitment and/or retention of DNA repair and checkpoint proteins such as BRCA1, MRE11/RAD50/NBS1 complex, MDC1 and 53BP1. H2AX-/- mouse embryonic fibroblasts are radiation sensitive and demonstrate deficits in repairing DNA damage compared to their wildtype counterparts. Cells treated with peptide inhibitors of gamma-H2AX demonstrate increased radiosensitivity following radiation compared with untreated irradiated cells. Analysis of the kinetics of gamma-H2AX clearance after IR or other DNA damaging agents reveals a correlation between increased gamma-H2AX persistence and unrepaired DNA damage and cell death. These data highlight the potential of post-translational modifications of chromatin as a therapeutic target for enhancing the efficacy of radiotherapy. Therapies that either block gamma-H2AX foci formation by inhibiting upstream kinase activity or that directly inhibit H2AX function may interfere with DNA damage repair processes and warrant further investigation as potential radiosensitizing agents. Agents that increase persistence of gamma-H2AX after IR are likely to increase unrepaired DNA damage.
Assuntos
Histonas/efeitos da radiação , Neoplasias/genética , Neoplasias/radioterapia , Radioterapia , Antineoplásicos/farmacologia , Biomarcadores , Dano ao DNA/genética , DNA de Neoplasias/efeitos dos fármacos , DNA de Neoplasias/efeitos da radiação , HumanosRESUMO
Acute cricoarytenoid arthritis is a frequent complication of rheumatoid arthritis and the most frequent otolaryngologic manifestation of the disease. Over 25% of rheumatoid arthritis cases have discomfort from this problem. Other etiologies can produce cricoarytenoid arthritis. Symptoms range from mild discomfort through hoarseness to complete airway obstruction requiring emergency tracheotomy. Chronic cricoarytenoid arthritis may result in joint ankylosis and vocal fold fixation. Single periarticular triamcinolone injections may bring rapid and dramatic relief of the symptomatology of nonankylosed acute cricoarytenoid arthritis for periods of up to one year if other medical management is adequate. Six cases illustrate the problem and the efficacy of this treatment methodology. Findings, pathology and pertinent literature are discussed. Specific criteria for considering this technique are outlined. This form of therapy has not been described previously.
Assuntos
Artrite/tratamento farmacológico , Cartilagens Laríngeas , Doenças da Laringe/tratamento farmacológico , Triancinolona/administração & dosagem , Doença Aguda , Adulto , Artrite/cirurgia , Feminino , Humanos , Injeções , Intubação Intratraqueal , Neoplasias Laríngeas/cirurgia , Masculino , Pessoa de Meia-Idade , Triancinolona/uso terapêuticoRESUMO
From 1998 to 2012, 42 dogs with spirocercosis referred to pathology Department of Veterinary Faculty, Tehran University. Frequency of spirocercosis was higher in October, November, December, January, February, March months. Averagely, the cases were 4.73 years old of age, so that 59.3 % of them were male. The major pathological findings were located in distal part of esophagus (57 %, n = 24), stomach (24 %, n = 10), and aorta (9.5 %, n = 4), respectively. In addition, 7 % (n = 3) were in esophagus and stomach, 2 % (n = 1) in esophagus and aorta, 42 % (n = 18) indicated pulmonary lesions with hyperemia, atelectasis, edema and pneumonia. In 35 % (n = 15) of cases were with hepatic lesions hyperemia and fatty change. However, 26 % (n = 11) cases demonstrated renal lesions with hyperemia, interstitial nephritis, and 24 % (n = 10) encompassed urinary bladder lesions with hyperemia and adhesive cystitis. Furthermore, sudden death occurred in 7 % (n = 3) as well as cachexia in 7 % (n = 3) cases. Some spirocercosis cases (12 %, n = 5) were accompanied by distemper disease, mixed mammary gland tumor (2 %, n = 1) and parasitic dermatitis due to demodicosis (9.5 %, n = 4). Presumably some of pathological findings were related or emerged by other sort of diseases such as distemper.
RESUMO
The German Mouse Clinic (GMC) is a large scale phenotyping center where mouse mutant lines are analyzed in a standardized and comprehensive way. The result is an almost complete picture of the phenotype of a mouse mutant line--a systemic view. At the GMC, expert scientists from various fields of mouse research work in close cooperation with clinicians side by side at one location. The phenotype screens comprise the following areas: allergy, behavior, clinical chemistry, cardiovascular analyses, dysmorphology, bone and cartilage, energy metabolism, eye and vision, host-pathogen interactions, immunology, lung function, molecular phenotyping, neurology, nociception, steroid metabolism, and pathology. The German Mouse Clinic is an open access platform that offers a collaboration-based phenotyping to the scientific community (www.mouseclinic.de). More than 80 mutant lines have been analyzed in a primary screen for 320 parameters, and for 95% of the mutant lines we have found new or additional phenotypes that were not associated with the mouse line before. Our data contributed to the association of mutant mouse lines to the corresponding human disease. In addition, the systemic phenotype analysis accounts for pleiotropic gene functions and refines previous phenotypic characterizations. This is an important basis for the analysis of underlying disease mechanisms. We are currently setting up a platform that will include environmental challenge tests to decipher genome-environmental interactions in the areas nutrition, exercise, air, stress and infection with different standardized experiments. This will help us to identify genetic predispositions as susceptibility factors for environmental influences.