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In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and ß-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.
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OBJECTIVE: To determine senescence-associated changes in the gingival tissues of aged mice and gingival fibroblast cultures. MATERIALS AND METHODS: The production of senescence-associated ß-galactosidase (SA-ß-gal) and mRNA expression of p16, p21, interleukin (IL)-1ß, and tumor necrosis factor α (TNF-α) were evaluated in gingival tissues, gingival fibroblasts of 10- and 20-month-old C57BL/6NCrl mice, and multiple-passaged and hydrogen peroxide-stimulated human gingival fibroblasts (HGFs). Changes in molecular expression in HGF cultures due to senescent cell elimination by the senolytic drug ABT-263 (Navitoclax) were analyzed. RESULTS: Compared to 10-week-old mice, the 20-month-old mice had higher numbers of M1 macrophages. The proportion of cells expressing SA-ß-gal were also higher in 20- month-old mice than in 10-week-old-mice. Gingival fibroblasts in 20-month-old mice expressed less collagen 1a1, collagen 4a1, and collagen 4a2 mRNA than those in 10-week-old mice. Compared to control cells, H2O2 treated HGF cells expressed higher levels of SA-ß-gal and p16, p21, IL-1ß, and TNF-α. Furthermore, ABT-263 suppressed HGF cell expression of cytokines after senescence induction. CONCLUSIONS: Senescence-associated changes were observed in the gingival tissues of aged mice and HGF cultures. In addition, the potential of senolytic drugs to modify aging-related changes in the gingiva was shown.
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Gengiva , Fator de Necrose Tumoral alfa , Animais , Fibroblastos , Humanos , Peróxido de Hidrogênio , Lactente , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/análise , RNA Mensageiro/metabolismo , Senoterapia , Fator de Necrose Tumoral alfa/metabolismo , Fator de Necrose Tumoral alfa/farmacologiaRESUMO
Gene therapy is currently in the public spotlight. Several gene therapy products, including oncolytic virus (OV), which predominantly replicates in and kills cancer cells, and COVID-19 vaccines have recently been commercialized. Recombinant adenoviruses, including replication-defective adenoviral vector and conditionally replicating adenovirus (CRA; oncolytic adenovirus), have been extensively studied and used in clinical trials for cancer and vaccines. Here, we review the biology of wild-type adenoviruses, the methodological principle for constructing recombinant adenoviruses, therapeutic applications of recombinant adenoviruses, and new technologies in pluripotent stem cell (PSC)-based regenerative medicine. Moreover, this article describes the technology platform for efficient construction of diverse "CRAs that can specifically target tumors with multiple factors" (m-CRAs). This technology allows for modification of four parts in the adenoviral E1 region and the subsequent insertion of a therapeutic gene and promoter to enhance cancer-specific viral replication (i.e., safety) as well as therapeutic effects. The screening study using the m-CRA technology successfully identified survivin-responsive m-CRA (Surv.m-CRA) as among the best m-CRAs, and clinical trials of Surv.m-CRA are underway for patients with cancer. This article also describes new recombinant adenovirus-based technologies for solving issues in PSC-based regenerative medicine.
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Infecções por Adenoviridae/virologia , Adenoviridae/genética , Adenoviridae/fisiologia , COVID-19/prevenção & controle , Terapia Genética , Animais , Vacinas contra COVID-19 , Linhagem Celular Tumoral , Expressão Gênica , Vetores Genéticos , Humanos , Imunoterapia , Vírus Oncolíticos/genética , Células-Tronco Pluripotentes , Regiões Promotoras Genéticas , SARS-CoV-2 , Survivina , Replicação ViralAssuntos
Mordeduras e Picadas , Vírus da Raiva , Raiva , Humanos , Japão , Raiva/prevenção & controleRESUMO
ObjectiveãThis study aimed to develop an event scale for perceiving well-being in high school students (hereinafter called "the scale"). The scale includes ten items for one factor and measures the frequency with which students perceive experience-based well-being.MethodãThis study comprised two surveys. Survey I was conducted for constructive concept validity based on the factor structural model, reliability for internal consistency, and clarifying each item's performance. The survey contents comprised the event frequency of perceived well-being. The constructive concept validity of the scale was examined with confirmatory factor analysis by structural equation modeling using data of 1,095 students. The reliability was tested using McDonald ω reliability coefficients for internal consistency. Each item's performance was examined using the item response theory.ãSurvey II was conducted to examine constructive concept validity using hypotheses testing. The survey contents were as follows: event frequency of perceived well-being, satisfaction in life, and mood. For the measurement, the scale was used for event frequency of well-being, the life satisfaction scale was used for satisfaction, and the abridged version of mood scale was used for moods. For the statistical analysis, we constructed a model in which the event frequency of perceived well-being influences the level of life satisfaction, and a model where the event frequency of perceived well-being influences mood. We examined the fit of the models using data of 2,003 students following structural equation modeling.ResultãThe results of Survey I showed that the model fit for data assumed for the scale was as follows: CFI=0.932, RMSEA=0.098, and ω reliability coefficients were 0.828. Discernment of each item was 0.65~1.06, and the difficulty level was -1.99~2.27, thus all values were acceptable.ãThe results of Survey II showed that the mode fit for the data where event frequency of perceived well-being influences the level of life satisfaction was CFI=0.978, RMSEA=0.060; thus, the values were acceptable. Model fit for data where event frequency of perceived well-being influences mood was CFI=0.952, RMSEA=0.057; thus, values were acceptable.ConclusionãThe scale developed in this study supported the following: constructive concept validity based on the factor structural model, reliability with each item performance tested for internal consistency, and constructive concept validity using hypotheses testing. We believe that the scale will be helpful in developing support methods that enhance high school students' subjective sense of well-being.
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Saúde do Adolescente , Afeto , Formação de Conceito/fisiologia , Felicidade , Satisfação Pessoal , Psicometria/métodos , Instituições Acadêmicas , Estudantes/psicologia , Inquéritos e Questionários , Adolescente , Estudos Transversais , Feminino , Humanos , Masculino , Reprodutibilidade dos TestesRESUMO
Mowat-Wilson syndrome (MWS) is a rare genetic disorder characterized by intellectual disability, distinctive facial features, epilepsy, and multiple anomalies caused by heterozygous loss-of-function mutations in the zinc finger E-box-binding homeobox-2 gene (ZEB2). Treatment choice is very important as patients with MWS because patients sometimes develop drug-resistant epilepsy. Here, we report the case of a 45-year-old male patient with MWS who developed drug-resistant status epilepticus after a 26-years seizure-free period while taking multiple anti-seizure medications. He showed a characteristic magnetic resonance imaging finding with a focal lesion in his left thalamic pulvinar nucleus, a finding not previously reported in status epilepticus with MWS. We succeeded in controlling seizures in the patient after trying multiple new antiseizure drug combinations. These findings indicate that patients with MWS may develop drug-resistant status epilepticus with age, even after a long-term seizure-free period, which can be managed with anti-seizure medication. Therefore, careful monitoring of seizures is important for the treatment of people with MWS, even in patients who have not experienced seizures for a long time.
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Meningitis has not been described to the same extent as other neurological complications of infective endocarditis(IE). The appropriate selection and dosing of antibiotics for patients with IE and meningitis do not exist. Herein, we described an instructive surgical case of mitral valve endocarditis and meningitis caused in a patient with atopic dermatitis, that was successfully treated using a multi-disciplinary approach.
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Dermatite Atópica , Endocardite Bacteriana , Endocardite , Meningite , Humanos , Valva MitralRESUMO
OBJECTIVE: Painful ophthalmoplegia includes nonspecific magnetic resonance imaging (MRI) manifestations and various clinical features including orbital pain and cranial nerve palsies. Treatment for painful ophthalmoplegia remains controversial. The aim of this report was to describe detailed clinical features, MRI findings, treatments, and prognosis of patients with painful ophthalmoplegia. Patients and Methods. We retrospectively investigated four cases of patients with painful ophthalmoplegia diagnosed using the International Classification of Headache Disorders, 3rd edition. RESULTS: All patients experienced unilateral orbital pain and oculomotor nerve palsy with diplopia but no vision loss. One of the four patients was diagnosed with Tolosa-Hunt syndrome based on the appearance of a granulomatous inflammation of the cavernous sinus on MRI. No specific lesions were detected on brain MRI for the other three patients; therefore, their headaches were attributed to ischaemic ocular motor nerve palsy. In all patients, a high-intensity ring appearance around the ipsilateral optic nerve was observed on MRI. Steroid therapy was administered to these patients, and good prognoses were anticipated. CONCLUSION: These results indicate that prednisolone is a useful treatment for painful ophthalmoplegia that displays ipsilateral hyperintense ring lesions around the optic nerve on MRI, regardless of the presence of granulomatous inflammation of the cavernous sinus.
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Glucose/metabolismo , Proteínas S100/genética , Fator de Transcrição AP-1/metabolismo , Administração Cutânea , Células Cultivadas , Colforsina/farmacologia , Meios de Cultura/metabolismo , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/patologia , Proteínas Filagrinas , Glucose/administração & dosagem , Transportador de Glucose Tipo 1/antagonistas & inibidores , Transportador de Glucose Tipo 1/metabolismo , Humanos , Queratinócitos/metabolismo , Cultura Primária de Células , Regulação para Cima/efeitos dos fármacosRESUMO
BACKGROUND AND AIMS: To date, the correlation between sarcopenia, which exists before a stroke, and acute stroke outcome remains partially understood. This study aims to evaluate the skeletal muscle mass deficit using the bioelectrical impedance analysis in patients with acute ischemic stroke. METHODS: We enrolled 164 geriatric patients with acute ischemic stroke (108 males and 56 females) who underwent the bioelectrical impedance analysis. We evaluated clinical outcomes and their impact on patients with the skeletal muscle mass deficit determined using the skeletal muscle mass index. RESULTS: The skeletal muscle mass deficit was obtained using the bioelectrical impedance analysis in 101 patients. Patients with the skeletal muscle mass deficit determined by the skeletal muscle mass index exhibited severe neurological impairment and functional status on admission; moreover, they tended to display poor functional outcome and prolonged hospital stay. Logistic regression analysis revealed that the skeletal muscle mass deficit remained an independent poor outcome predictor. CONCLUSIONS: This study establishes the presence of the skeletal muscle mass deficit in over half patients with acute ischemic stroke. Furthermore, the skeletal muscle mass deficit correlates with neurological impairment owing to stroke with poorer functional prognosis.
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Composição Corporal , Isquemia Encefálica/fisiopatologia , Músculo Esquelético/fisiopatologia , Sarcopenia/fisiopatologia , Acidente Vascular Cerebral/fisiopatologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Isquemia Encefálica/complicações , Isquemia Encefálica/diagnóstico , Isquemia Encefálica/terapia , Impedância Elétrica , Feminino , Avaliação Geriátrica , Humanos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Força Muscular , Prognóstico , Recuperação de Função Fisiológica , Fatores de Risco , Sarcopenia/complicações , Sarcopenia/diagnóstico , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/diagnóstico , Acidente Vascular Cerebral/terapia , Reabilitação do Acidente Vascular Cerebral , Fatores de TempoRESUMO
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the central nervous system caused by reactivation of the JC virus under an immunosuppressed state. This condition carries a high risk of cryptococcal meningitis. We herein report a 65-year-old woman who simultaneously developed PML and cryptococcal meningitis and presented with bilateral sixth nerve palsy. She had been treated with methotrexate and infliximab for rheumatoid arthritis. Her symptoms improved with antifungal drug treatment and discontinuation of immunosuppression therapy. Although concurrent PML and cryptococcal meningitis is rare, it should be considered in immunosuppressed patients.
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Antifúngicos/uso terapêutico , Antirreumáticos/efeitos adversos , Artrite Reumatoide/tratamento farmacológico , Terapia de Imunossupressão/efeitos adversos , Infliximab/efeitos adversos , Leucoencefalopatia Multifocal Progressiva/tratamento farmacológico , Meningite Criptocócica/tratamento farmacológico , Metotrexato/efeitos adversos , Idoso , Antirreumáticos/uso terapêutico , Feminino , Humanos , Infliximab/uso terapêutico , Vírus JC/isolamento & purificação , Leucoencefalopatia Multifocal Progressiva/etiologia , Meningite Criptocócica/etiologia , Metotrexato/uso terapêutico , Resultado do TratamentoRESUMO
Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in aceruloplasminemia patients with other gene mutations.
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Ceruloplasmina/deficiência , Hemossiderose/complicações , Hemossiderose/terapia , Distúrbios do Metabolismo do Ferro/complicações , Doenças Neurodegenerativas/complicações , Flebotomia/efeitos adversos , Idoso , Diabetes Mellitus Tipo 1/complicações , Diabetes Mellitus Tipo 1/tratamento farmacológico , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Mutação INDEL , Insulina/uso terapêuticoRESUMO
Patients with thrombotic microangiopathies (TMAs), which include thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), and Shiga toxin-producing Escherichia coli hemolytic uremic syndrome (STEC-HUS), exhibit multiple symptoms. These include thrombocytopenia (platelet count <15×104/µl), microangiopathic hemolytic anemia (hemoglobin <10 g/dl), and organ damage, such as renal dysfunction or neurological abnormalities. Guidelines for the management of TTP, aHUS, and STEC-HUS have been published. Diagnosis of TTP, STEC-HUS, or aHUS requires ADAMTS13 activity <10%, the detection of STEC or Shiga toxins, or a genetic analysis to investigate the complement regulatory system, respectively. In the established management of TMAs, fresh frozen plasma is used for congenital TTP to supplement ADAMTS13. Plasma exchange (PE) is used in acquired TTP (ATTP) to remove inhibitors and replace ADAMTS13. Steroid therapy is administered in ATTP to suppress inhibitor production, and rituximab is administered in ATTP without response to PE or with high titers of ADAMTS13 inhibitors. Eculizumab, a monoclonal antibody for complement protein 5, is used for the treatment of aHUS. Supportive therapy is required for some TMAs, particularly STEC-HUS, but platelet transfusion is generally contraindicated for other TMAs, such as TTP. Treatments should be administered in accordance with these guidelines to improve the outcome of TMAs.
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Microangiopatias Trombóticas/terapia , Síndrome Hemolítico-Urêmica/diagnóstico , Síndrome Hemolítico-Urêmica/terapia , Humanos , Japão , Guias de Prática Clínica como Assunto , Microangiopatias Trombóticas/diagnósticoRESUMO
Disseminated intravascular coagulation (DIC) was considered to be a fatal disease. However, it has recently been suggested that very early DIC protects the host against microthrombosis and infection localization. Therefore, early treatment of DIC may be contraindicated in patients with sepsis. These factors suggest that the diagnosis and treatment of DIC will gain further importance. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2016 (J-SSCG2016), which include details regarding the management of DIC, have been recently published. Differences in recommendations for DIC treatment, such as antithrombin and recombinant human thrombomodulin, between J-SSCG2016 and other guidelines, including the Japanese Society on Thrombosis and Hemostasis (JSTH), British Committee for Standards in Haematology (BCST), Italian Society for Thrombosis and Haemostasis (SISET), and International Society on Thrombosis and Haemostasis (ISTH) have been discussed. Furthermore, differences in the diagnostic criteria for DIC between the Japanese Ministry of Health, Labor and Welfare, ISTH overt, ISTH non-overt, Japanese Association for Acute Medicine, and JSTH have been discussed.
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Coagulação Intravascular Disseminada , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/terapia , Hemostasia , Humanos , Guias de Prática Clínica como Assunto , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Cerebrospinal fluid (CSF) shunting can improve symptoms of elderly patients' idiopathic normal pressure hydrocephalus (iNPH). However, adjunctive means for confirming the diagnosis remain unavailable. We have previously reported the specific increase of leucine-rich alpha-2-glycoprotein (LRG) in iNPH CSF, and the present study investigates its potential clinical applications. METHODS: We performed CSF tap test (TT) on 90 patients (mean age 73.4 years) and shunting in 52 patients (mean age 73.5 years), evaluating symptom improvement and higher cerebral functions-mini-mental state examination (MMSE) and Frontal Assessment Battery (FAB) before and 12 months after shunting. LRG and tau protein concentrations in TT CSF were simultaneously measured using enzyme-linked immunosorbent assay. We then compared the predictive value of these concentrations with TT results regarding successful shunting outcomes. RESULTS: Positive combinations of TT and LRG concentrations of 67 ng/ml or higher, gave 81.6% sensitivity and 78.6% specificity. Therefore we used LRG (67 ng/ml) and tau (200 pg/ml) cut-off values, dividing patients into four groups. In group A (LRG ≥ 67 ng/ml and tau < 200 pg/ml) 31 of 34 patients (91.2%) had a positive TT and all operated 22 patients were shunt responders. Dementia MMSE and FAB scores in them increased from a baseline of 22.05(SE ± 0.96) to 25.65 (±0.85) and 11.38 (±0.68) to 13.08 (±0.57) respectively. In group B, (LRG ≥ 67 ng/ml and tau ≥ 200 pg/ml), the mean MMSE score increased from 17.62 (±2.03) to 21.62 (±1.96), and the FAB decreased slightly from 9.25 (±1.15) to 10.5 (±1.59), without improvement beyond the range of dementia. In group C, (LRG < 67 ng/ml, tau < 200 pg/ml), the mean MMSE score improved from 22.06 (±1.25) to 24.29 (±1.23) and the FAB score improved slightly from 12.0 (±0.72) to 12.87 (±0.72). Finally, in group D, (LRG < 67 ng/ml, tau ≥ 200 pg/ml), there was almost no improvement in MMSE score CONCLUSIONS: A combination of positive TT and biomarkers quantification such as LRG and tau protein, can reliably predict shunting outcome in iNPH patients.
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Glicoproteínas/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Entrevista Psiquiátrica Padronizada , Pessoa de Meia-Idade , Exame Neurológico , Testes Neuropsicológicos , Valor Preditivo dos Testes , Derivação Ventriculoperitoneal , Proteínas tau/líquido cefalorraquidianoRESUMO
INTRODUCTION: Since the invention of the pulse oximeter, physicians often or even routinely perform venous blood gas analysis (VBGA). However, it has not been generally agreed that the application of VBGA is practically meaningful in routine clinical situations such as in an ED. METHODS: We measured venous-arterial Pco(2) difference ((v-a)Pco(2)) and arterial-venous pH difference ((a-v)pH), and analyzed the physiological factors that affect these differences in healthy volunteers and hyperventilation patients. RESULTS: In healthy volunteers, both (v-a)Pco(2) and (a-v)pH increased during finger exercise or hyperventilation in an intensity-dependent manner. Doppler echography indicated that increases in (v-a)Pco(2) and (a-v)pH during hyperventilation are induced by reduction of peripheral blood flow. Approximately 40% of patients with untreated respiratory alkalosis were found to be incorrectly diagnosed if based only on VBGA. CONCLUSIONS: It must be noted that VBGA may lead to overestimation of acidosis and to underestimation of respiratory alkalosis when extremities muscles are active or patients are hyperventilating. Physicians should keep these limitations in mind when conducting VBGA.
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Alcalose Respiratória/diagnóstico , Gasometria/métodos , Hiperventilação/sangue , Acidose/sangue , Acidose/diagnóstico , Adolescente , Adulto , Idoso , Alcalose Respiratória/sangue , Erros de Diagnóstico , Exercício Físico/fisiologia , Feminino , Humanos , Concentração de Íons de Hidrogênio , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Macrophage-derived chemokine (MDC) CCL22 is a potent chemoattractant for Th2 cells and has been implicated in Th2-predominant allergic inflammation. In the present study, we demonstrated that basophils produce MDC in response to monomeric IgE. In trinitrophenyl (TNP)-IgE transgenic mice, serum levels of MDC were persistently higher than in wild-type mice. The i.v. administration of TNP-specific IgE to wild-type mice transiently induced an elevation in serum MDC, which appeared to be mediated by Fc epsilonRI, as no increase in serum MDC was observed after IgE administration in FcRgamma (-/-) mice. However, the IgE-mediated increase in MDC was observed in mast cell-deficient mice. Freshly isolated bone marrow cells and bone marrow-derived basophils secreted MDC in response to TNP-IgE without Ag stimulation. Furthermore, MDC production was not observed in bone marrow-derived basophils isolated from FcRgamma (-/-) mice. IgE activated Lyn and ERK 1/2 in bone marrow-derived basophils. Treatment of TNP-IgE transgenic mice with a basophil-depletion Ab (Ba103) resulted in decreased serum MDC levels. Thus, IgE appears to be capable of stimulating basophils to produce MDC in the absence of a specific Ag, which may contribute to IgE-mediated and/or Th2-predominant allergic inflammation.
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Basófilos/imunologia , Células da Medula Óssea/imunologia , Quimiocina CCL22/imunologia , Hipersensibilidade/imunologia , Imunoglobulina E/imunologia , Células Th2/imunologia , Animais , Basófilos/metabolismo , Células da Medula Óssea/metabolismo , Quimiocina CCL22/genética , Quimiocina CCL22/metabolismo , Hipersensibilidade/genética , Hipersensibilidade/metabolismo , Imunoglobulina E/genética , Imunoglobulina E/metabolismo , Imunoglobulina E/farmacologia , Inflamação/genética , Inflamação/imunologia , Inflamação/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Transgênicos , Proteína Quinase 1 Ativada por Mitógeno/genética , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 1 Ativada por Mitógeno/metabolismo , Proteína Quinase 3 Ativada por Mitógeno/genética , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/metabolismo , Receptores de IgE/genética , Receptores de IgE/imunologia , Receptores de IgE/metabolismo , Células Th2/metabolismo , Quinases da Família src/genética , Quinases da Família src/imunologia , Quinases da Família src/metabolismoRESUMO
Heat-capacity changes (deltaC(p)0) were determined for the complexation of 1-alkanecarboxylates with protonated hexakis(6-amino-6-deoxy)-alpha-cyclodextrin (per-NH3(+)-alpha-CD) and heptakis(6-amino-6-deoxy)-beta-cyclodextrin (per-NH3(+)-beta-CD). DeltaC(p)0 decreased with an increase in the binding constant (K) and plateaued at K = 4000 M(-1). The complexes of 1-pentanoate, 1-hexanoate, and 1-heptanoate with per-NH3(+)-alpha-CD are classified as the host-guest system in which the size of the guest fits the CD cavity well. In such a system, van der Waals interaction is the major force for complexation, leading to a negative deltaH0 value. Simultaneously, the water molecules around the hydrophobic alkyl chain of the guest and inside the CD cavity are released to the aqueous bulk phase, leading to a positive deltaS0 value. The negative deltaC(p)0 value in such complexation is ascribed to dehydration of the hydrophobic alkyl chain of the guest and extrusion of the water molecules inside the CD cavity. Meanwhile, the complexes that show positive deltaC(p)0 values are characterized by complexation in which the guest molecules are significantly smaller than the CD cavities. In such a case, the complexation is endothermic and driven by the entropy gain. When the guest is much smaller than the CD cavity, the main binding force should be Coulomb interaction. To form an ionic bond, dehydration of the charged groups must occur. This process is endothermic and leads to positive deltaH0 and deltaS0 values. As the top of the CD cavity is capped by a small but hydrophobic alkyl chain, the water molecules inside the CD cavity may form the iceberg structure. This process must be accompanied by a positive deltaC(p)0 value. Hence, the complexation of a small guest with the CD with a large cavity through Coulomb interactions shows positive and large deltaC(p)0 values. These conclusions were applied to the electrostatic binding of proteins with an anionic ligand.
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Ciclodextrinas/química , Ácidos Graxos/química , Temperatura Alta , Água/química , Entropia , Soluções , Eletricidade EstáticaRESUMO
Both the QT interval and QT dispersion in diabetic patients have been reported to increase with the progression of cardiac autonomic neuropathy and to have a prognostic value. We assessed the cardiac autonomic influences on QT indices using the measurements of baroreflex sensitivity, heart rate variability, and cardiac (123)I-metaiodobenzylguanidine scintigraphic findings in patients with type 2 diabetes mellitus. Forty-two consecutive patients with type 2 diabetes (mean+/-SD: 54+/-10 years, 22 women and 20 men) were studied. Baroreflex sensitivity negatively correlated with the maximum and minimum QTc intervals as well as QT/QTc dispersion. However, the high-frequency power and the ratio of low-frequency power to high-frequency power of heart rate variability did not correlate with any QT indices. The percent washout rate of (123)I-metaiodobenzylguanidine positively correlated with QT/QTc dispersion, but not with maximum and minimum QTc intervals. Our findings suggest that cardiac vagal dysfunction is related to QT interval prolongation while both sympathetic and vagal dysfunctions are related to increased QT dispersion in type 2 diabetic patients. Baroreflex sensitivity and percent washout rate of (123)I-metaiodobenzylguanidine may be useful parameters indicating the abnormalities of the cardiac ventricular repolarization in this population.