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1.
J Am Anim Hosp Assoc ; 58(6): 288-291, 2022 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-36315860

RESUMO

A 6 yr old spayed female Chihuahua was referred for a 10 mo history of chronic respiratory compromise. Decreased serum thyroxine and thyroid-stimulating hormone concentrations had been confirmed at a primary clinic, but no treatment was initiated. Serum biochemistries revealed elevated alkaline phosphatase and cholesterol concentrations. An adrenocorticotropic hormone-stimulating test revealed elevated preserum and postserum cortisol concentrations. Fluoroscopy revealed marked epiglottic retroversion (ER) during inhalation. Enlarged bilateral adrenal glands were found on abdominal ultrasonography. Based on these findings, ER and hyperadrenocorticism (HAC) were diagnosed and surgical correction of the ER was planned. Trilostane administration was initiated before surgery to reduce the risk of thrombosis due to HAC. Seven days after the initiation of trilostane therapy, clinical signs of chronic respiratory compromise were resolved. The patient had remained clinically stable without recurrence of respiratory compromise for at least 15 mo at the time of this case report. This case suggests that HAC could contribute to the development of clinical signs of ER, which could potentially be successfully controlled by medical treatment of HAC.


Assuntos
Hiperfunção Adrenocortical , Doenças do Cão , Cães , Feminino , Animais , Doenças do Cão/diagnóstico , Hiperfunção Adrenocortical/tratamento farmacológico , Hiperfunção Adrenocortical/veterinária , Hiperfunção Adrenocortical/diagnóstico , Hormônio Adrenocorticotrópico/uso terapêutico , Di-Hidrotestosterona/uso terapêutico , Hidrocortisona/uso terapêutico , Ultrassonografia
2.
Physiol Rep ; 9(9): e14859, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33991461

RESUMO

Exercise ameliorates nonalcoholic fatty liver disease (NAFLD) by inducing phenotypic changes in Kupffer cells (KCs). p62/Sqstm1-knockout (p62-KO) mice develop NAFLD alongside hyperphagia-induced obesity. We evaluated (1) the effects of long-term exercise on the foreign-body phagocytic capacity of KCs, their surface marker expression, and the production of steroid hormones in p62-KO mice; and (2) whether long-term exercise prevented the development of non-alcoholic steatohepatitis (NASH) in p62-KO mice fed a high-fat diet (HFD). In experiment 1, 30-week-old male p62-KO mice were allocated to resting (p62-KO-Rest) or exercise (p62-KO-Ex) groups, and the latter performed long-term exercise over 4 weeks. Then, the phenotype of their KCs was compared to that of p62-KO-Rest and wild-type (WT) mice. In experiment 2, 5-week-old male p62-KO mice that were fed a HFD performed long-term exercise over 12 weeks. In experiment 1, the phagocytic capacity of KCs and the proportion of CD68-positive cells were lower in the p62-KO-Rest group than in the WT group, but they increased with long-term exercise. The percentage of CD11b-positive KCs was higher in the p62-KO-Rest group than in the WT group, but lower in the p62-KO-Ex group. The circulating dehydroepiandrosterone (DHEA) concentration was higher in p62-KO-Ex mice than in p62-KO-Rest mice. In experiment 2, the body mass and composition of the p62-KO-Rest and p62-KO-Ex groups were similar, but the hepatomegaly, hepatic inflammation, and fibrosis were less marked in p62-KO-Ex mice. The DHEA concentration was higher in p62-KO-Ex mice than in WT or p62-KO-Rest mice. Thus, long-term exercise restores the impaired phagocytic capacity of KCs in NAFLD obese mice, potentially through greater DHEA production, and prevents the development of NASH by ameliorating hepatic inflammation and fibrogenesis. These results suggest a molecular mechanism for the beneficial effect of exercise in the management of patients with NAFLD.


Assuntos
Hiperfagia/complicações , Células de Kupffer/metabolismo , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Obesidade/complicações , Condicionamento Físico Animal/métodos , Animais , Antígenos CD/metabolismo , Antígenos de Diferenciação Mielomonocítica/metabolismo , Células Cultivadas , Desidroepiandrosterona/metabolismo , Hiperfagia/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Atividade Motora , Hepatopatia Gordurosa não Alcoólica/etiologia , Hepatopatia Gordurosa não Alcoólica/genética , Obesidade/genética , Fenótipo , Proteína Sequestossoma-1/genética
3.
J Med Chem ; 61(12): 5257-5268, 2018 06 28.
Artigo em Inglês | MEDLINE | ID: mdl-29869881

RESUMO

The obstructive renal radioactivity after injection of antibody fragments/constructs labeled with metallic radionuclides would be improved by liberating a radiometal chelate of urinary excretion from the antibody molecules by enzymes on the renal brush border membrane (BBM). A tripeptide GFK sequence was newly evaluated as an enzyme-cleavable linkage and conjugated to a 99mTc chelate of an isonicotinic acid derivative of 2-picolylglycine (99mTc-IPG). 99mTc-IPG-glycine was liberated from 99mTc-IPG-GFK by the enzymes, while 99mTc-IPG-GK (where the tripeptide GFK was substituted with a dipeptide GK) did not. When injected into mice, 99mTc-IPG-GFK-conjugated Fab exhibited lower renal radioactivity levels than directly radioiodinated Fab shortly after injection without reducing the tumor radioactivity levels, due to a release and excretion of 99mTc-IPG-glycine by enzymes present on the renal BBM. These findings would provide insights to develop antibody fragments/constructs labeled with metallic radionuclides of the clinical relevance for improved renal radioactivity levels.


Assuntos
Rim/enzimologia , Microvilosidades/metabolismo , Peptídeos/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/farmacocinética , Animais , Humanos , Imunoconjugados/química , Imunoconjugados/farmacocinética , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/metabolismo , Fragmentos de Imunoglobulinas/química , Fragmentos de Imunoglobulinas/metabolismo , Rim/efeitos dos fármacos , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos , Microvilosidades/efeitos dos fármacos , Neoplasias Experimentais/diagnóstico por imagem , Peptídeos/química , Tecnécio/química , Tecnécio/metabolismo , Distribuição Tecidual , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Artigo em Inglês | MEDLINE | ID: mdl-25609941

RESUMO

BACKGROUND: Tiotropium (Spiriva) is an inhaled muscarinic antagonist for patients with chronic obstructive pulmonary disease (COPD), and is available in two forms: the HandiHaler and the Respimat inhaler. The aim of this study was to investigate the handling of and preference for each device immediately after switching from the HandiHaler to the Respimat and 2-3 years after the switch. MATERIALS AND METHODS: The study comprised two surveys. A questionnaire was first administered to 57 patients with COPD (male:female 52:5, mean age 73.6±7.1 years) 8 weeks after switching from the HandiHaler (18 µg) to the Respimat (5 µg). A second similar but simplified questionnaire was administered to 39 of these patients who continued to use the Respimat and were available for follow-up after more than 2 years. Pulmonary function was also measured during each period. RESULTS: In the first survey, 17.5% of patients preferred the HandiHaler, and 45.6% preferred the Respimat. There were no significant changes in pulmonary function or in the incidence of adverse events after the switch. In the second survey, performed 2-3 years later, the self-assessed handling of the Respimat had significantly improved, and the number of patients who preferred the Respimat had increased to 79.5%. CONCLUSION: The efficacy of the Respimat was similar to that of the HandiHaler. This was clear immediately after the switch, even in elderly patients with COPD who were long-term users of the HandiHaler. The preference for the Respimat increased with continued use.


Assuntos
Broncodilatadores/administração & dosagem , Pulmão/efeitos dos fármacos , Antagonistas Muscarínicos/administração & dosagem , Nebulizadores e Vaporizadores , Preferência do Paciente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Derivados da Escopolamina/administração & dosagem , Inquéritos e Questionários , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Broncodilatadores/efeitos adversos , Desenho de Equipamento , Feminino , Volume Expiratório Forçado , Pesquisas sobre Atenção à Saúde , Humanos , Pulmão/fisiopatologia , Masculino , Pessoa de Meia-Idade , Antagonistas Muscarínicos/efeitos adversos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Derivados da Escopolamina/efeitos adversos , Espirometria , Fatores de Tempo , Brometo de Tiotrópio , Resultado do Tratamento , Capacidade Vital
6.
J Cell Biol ; 205(6): 781-90, 2014 Jun 23.
Artigo em Inglês | MEDLINE | ID: mdl-24934155

RESUMO

During mitosis, genomic DNA is condensed into chromosomes to promote its equal segregation into daughter cells. Chromosome condensation occurs during cell cycle progression from G2 phase to mitosis. Failure of chromosome compaction at prophase leads to subsequent misregulation of chromosomes. However, the molecular mechanism that controls the early phase of mitotic chromosome condensation is largely unknown. Here, we show that Mps1 regulates initial chromosome condensation during mitosis. We identify condensin II as a novel Mps1-associated protein. Mps1 phosphorylates one of the condensin II subunits, CAP-H2, at Ser492 during mitosis, and this phosphorylation event is required for the proper loading of condensin II on chromatin. Depletion of Mps1 inhibits chromosomal targeting of condensin II and accurate chromosome condensation during prophase. These findings demonstrate that Mps1 governs chromosomal organization during the early stage of mitosis to facilitate proper chromosome segregation.


Assuntos
Adenosina Trifosfatases/metabolismo , Proteínas de Ciclo Celular/fisiologia , Cromossomos/metabolismo , Proteínas de Ligação a DNA/metabolismo , Complexos Multiproteicos/metabolismo , Proteínas Serina-Treonina Quinases/fisiologia , Proteínas Tirosina Quinases/fisiologia , Adenosina Trifosfatases/análise , Proteínas de Ciclo Celular/análise , Proteínas de Ciclo Celular/metabolismo , Núcleo Celular/metabolismo , Proteínas Cromossômicas não Histona/química , Proteínas Cromossômicas não Histona/metabolismo , Proteínas de Ligação a DNA/análise , Pontos de Checagem da Fase G2 do Ciclo Celular , Células HEK293 , Células HeLa , Humanos , Mitose/fisiologia , Complexos Multiproteicos/análise , Fosforilação , Proteínas Serina-Treonina Quinases/análise , Proteínas Serina-Treonina Quinases/metabolismo , Proteínas Tirosina Quinases/análise , Proteínas Tirosina Quinases/metabolismo , Serina/metabolismo
7.
Artigo em Inglês | MEDLINE | ID: mdl-24489464

RESUMO

BACKGROUND: Indacaterol is a novel, once-daily, inhaled, long-acting b2-agonist for patients with chronic obstructive pulmonary disease (COPD). The study objective was to evaluate the efficacy of indacaterol on quality of life and pulmonary function in patients with COPD in a real-world setting, and also to evaluate its inhaler device (Breezhaler®), which is important for both adherence and management. METHODS: Twenty-eight outpatients with COPD were treated with indacaterol (150 µg once daily for 8 weeks), and the effects on pulmonary function were evaluated using a questionnaire survey with the modified Medical Research Council (mMRC) dyspnea scale and COPD assessment test (CAT) before and after treatment. Similar investigations were also performed separately among different baseline medications. Moreover, original questionnaire surveys for indacaterol and its device were performed. RESULTS: Overall, mMRC dyspnea scale and CAT scores significantly improved (1.96±1.04 to 1.57±1.07 and 17.39±8.23 to 12.82±8.42, respectively; P<0.05). Significant improvements in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were also observed on pulmonary function tests (2.91±0.66 L to 3.07±0.65 L and 1.46±0.60 L to 1.58±0.59 L, respectively; P<0.05). Replacement therapy from salmeterol to indacaterol significantly improved mMRC and FVC values, but did not significantly improve CAT scores or other pulmonary functions. Add-on therapy with indacaterol significantly improved mMRC score, CAT score, FVC, and FEV1, regardless of whether tiotropium was used as a baseline treatment. All subjects in a questionnaire survey found the inhaler device easy to use. There were no serious adverse events leading to treatment discontinuation. CONCLUSION: Indacaterol is thought to be effective and well tolerated as a bronchodilator for the management of COPD. Treatment with indacaterol in addition to a long-acting muscarinic antagonist was also useful.


Assuntos
Agonistas de Receptores Adrenérgicos beta 2/administração & dosagem , Broncodilatadores/administração & dosagem , Indanos/administração & dosagem , Pulmão/efeitos dos fármacos , Nebulizadores e Vaporizadores , Preferência do Paciente , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Qualidade de Vida , Quinolonas/administração & dosagem , Administração por Inalação , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Combinada , Desenho de Equipamento , Feminino , Volume Expiratório Forçado , Humanos , Pulmão/fisiopatologia , Masculino , Antagonistas Muscarínicos/administração & dosagem , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Doença Pulmonar Obstrutiva Crônica/psicologia , Recuperação de Função Fisiológica , Índice de Gravidade de Doença , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Capacidade Vital
8.
Drug Deliv ; 21(5): 321-7, 2014 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-24148015

RESUMO

BACKGROUND: The systemic administration of theophylline is useful for asthma treatment. However its narrow therapeutic range makes it difficult to use. Little is known about its potential in inhalation therapy, particularly repeated inhalation. OBJECTIVE: The purpose of this study is to investigate the therapeutic usefulness of inhaled aminophylline in an asthma model. METHODS: The effects of pretreatment with inhaled aminophylline (25 mg/mL for 30 min/dose) on airway response and inflammation after an ovalbumin (OVA) challenge and airway hypersensitivity to acetylcholine (Ach) were evaluated using guinea pigs sensitized with OVA. RESULTS: Aminophylline relaxed the ACh-induced contraction of tracheal smooth muscle in vitro in a concentration-dependent manner. Pretreatment with single-dose aminophylline inhalation suppressed OVA-induced airway constriction to the same extent as the intraperitoneal pretreatment with high-dose aminophylline (10-20 mg/kg). However, pretreatment with single-dose aminophylline inhalation did not suppress eosinophil infiltration into airways (neither bronchoalveolar lavage [BAL] fluid nor lung tissue) and did not suppress airway hyperreactivity to ACh, 24 h after OVA challenge. Repeated inhalation of aminophylline (twice daily for 7 days) suppressed the infiltration of eosinophils and suppressed airway hypersensitivity to ACh. In addition, high concentrations of aminophylline inhibited production of oxygen radicals by BAL cells. CONCLUSION: Single-dose inhalation treatment with aminophylline has transient but relatively strong bronchodilating effects due to delivery of high doses into local airways. Repeated inhalation treatment suppressed airway inflammation and hypersensitivity induced by allergens. Therefore, inhaled aminophylline may be useful for asthma treatment.


Assuntos
Aminofilina/farmacologia , Broncoconstrição/efeitos dos fármacos , Inflamação/induzido quimicamente , Inflamação/tratamento farmacológico , Ovalbumina/farmacologia , Administração por Inalação , Animais , Asma/tratamento farmacológico , Líquido da Lavagem Broncoalveolar/química , Eosinófilos/efeitos dos fármacos , Cobaias , Pulmão/efeitos dos fármacos , Masculino
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