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BACKGROUND: Evidence on the efficacy of mamushi antivenom serum is limited. OBJECTIVE: To investigate the effectiveness of mamushi (Gloydius blomhoffii) antivenom serum. METHODS: The Observational Research Of the Clinical course after mamusHI bite (OROCHI) study was a prospective multicenter study conducted at 24 hospitals in Japan. Patients hospitalized due to mamushi bite were registered. The primary endpoint was the length of hospital stay. Secondary endpoints were adverse effects, pain (numerical rating scale), and grade of swelling. We performed a cohort analysis to compare outcomes between patients treated with mamushi antivenom serum (antivenom group) and those who were not treated with the serum (no-antivenom group). RESULTS: Overall, 106 patients were registered across 18 hospitals between April 22, 2020, and October 31, 2022. Of these, 92 were eligible for the analyses, with 53 and 39 in the antivenom and no-antivenom groups. The median (interquartile) length of hospital stay was not significantly different between the antivenom and no-antivenom groups (5 (3-6) days vs. 3 (1-8) days, P = 0.369). In multivariable analysis, the adjusted odds ratio for a hospital stay of >4 days was 1.331 in patients treated with mamushi antivenom serum (95% confidence interval (CI) = 0.744â2.015, P = 0.574) and 6.154 in patients treated with cepharanthine (95% CI = 1.442-26.258, P = 0.014). Pain and the grade of swelling were worse in the antivenom group than in the no-antivenom group up to 24 h after arrival, but there were no differences in these outcomes after 48 h. CONCLUSION: Although the effectiveness of mamushi antivenom serum in reducing the length of hospitalization was not demonstrated, beneficial effects on pain and swelling were observed.
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[This corrects the article DOI: 10.1371/journal.pone.0296006.].
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The Cre-loxP strategy for tissue-specific gene inactivation has become a widely employed tool in several research studies. Conversely, inadequate breeding and genotyping without considering the potential for non-specific Cre-recombinase expression may lead to misinterpretations of results. Nestin-Cre transgenic mice, widely used for the selective deletion of genes in neurons, have been observed to have an incidence of Cre-line germline recombination. In this study, we attempted to generate neuron-specific Glucagon-like peptide 1 receptor (Glp1r) knock-out mice by crossing mice harboring the Nestin-Cre transgene with mice harboring the Glp1r gene modified with loxP insertion, in order to elucidate the role of Glp1r signaling in the nervous system. Surprisingly, during this breeding process, we discovered that the null allele emerged in the offspring irrespective of the presence or absence of the Nestin-Cre transgene, with a high probability of occurrence (93.6%). To elucidate the cause of this null allele, we conducted breeding experiments between mice carrying the heterozygous Glp1r null allele but lacking the Nestin-Cre transgene. We confirmed that the null allele was inherited by the offspring independently of the Nestin-Cre transgene. Furthermore, we assessed the gene expression, protein expression, and phenotype of mice carrying the homozygous Glp1r null allele generated from the aforementioned breeding, thereby confirming that the null allele indeed caused a global knock-out of Glp1r. These findings suggest that the null allele in the NestinCre-Glp1r floxed breeding arose due to germline recombination. Moreover, we demonstrated the possibility that germline recombination may occur not only during the spermatogenesis at testis but also during epididymal sperm maturation. The striking frequency of germline recombination in the Nestin-Cre driver underscores the necessity for caution when implementing precise breeding strategies and employing suitable genotyping methods.
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Integrases , Sêmen , Animais , Masculino , Camundongos , Células Germinativas/metabolismo , Peptídeo 1 Semelhante ao Glucagon , Integrases/genética , Integrases/metabolismo , Camundongos Knockout , Camundongos Transgênicos , Nestina/genética , Recombinação Genética , Sêmen/metabolismoRESUMO
Aim: To determine whether dispatcher-provided cardiopulmonary resuscitation (CPR) instructions improve the outcomes of out-of-hospital cardiac arrest (OHCA). Methods: Cases registered in the Japanese Association for Acute Medicine Out-of-Hospital Cardiac Arrest (JAAM-OHCA) Registry between June 2014 and December 2019 were included. Cases in which the dispatcher provided CPR instructions to the bystander were included in the "Instructions" group", and cases without CPR instructions were included in the "No Instructions" group. The primary outcome was the proportion of patients with a favorable neurological outcome, defined as a Glasgow-Pittsburgh cerebral performance category scale of 1 to 2 at 1 month after OHCA. Results: Overall, 51,199 patients with OHCA were registered in the JAAM-OHCA Registry during the study period. Of these, 33,745 were eligible for the study, with 16,509 in the Instructions group and 17,236 in the No Instructions group. The proportion of patients with a favorable neurological outcome at 1 month after OHCA was inferior in the Instructions group than in the No Instructions group (2.3% versus 3.0%, p < 0.001). After adjustment for patient background characteristics, no association was found between CPR instructions provided by a dispatcher and favorable neurological outcomes at 1 month after OHCA (adjusted odds ratio, 1.000; 95% confidence interval, 0.869-1.151, p = 0.996). Conclusion: The present study found no clear clinical benefit of dispatcher-provided CPR instructions on the neurological outcomes of cases with OHCA.
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We previously reported that the IL-2 Luc LTT can detect immunosuppressive effects of drugs that are attributed to their antimitotic activity. Here, we report an official validation study of the IL-2 Luc LTT. In the Phase I study that evaluated five coded chemicals, the within-laboratory reproducibility of three independent laboratories was 100.0%. In the combined results of the Phase I and II studies that evaluated 20 coded chemicals, the between-laboratory reproducibility was 92.0%. When compared with the reference data based on the previously-reported immunotoxicological information, the predictivity of the combined Phase I and II studies was 76.0% for Lab A and 72.0% for Labs B and C. In contrast, in the study in which the lead laboratory examined 37 non-pharmaceutical chemicals, the predictivity of the IL-2 Luc LTT and the IL-2 Luc assay was 48.6% and 64.9%, respectively, whereas that of the combined assays was 74.3%. It is clear that an integrated approach combining multiple assays is necessary for the development of in vitro immunosuppression testing. These data suggest that the IL-2 Luc LTT alone is not sufficient as a component of the integrated approach, but the combination of the IL-2 Luc assay and IL-2 Luc LTT is promising.
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Imunossupressores , Interleucina-2 , Reprodutibilidade dos Testes , Imunossupressores/toxicidade , Luciferases , Testes de Toxicidade/métodosRESUMO
AIMS/INTRODUCTION: Diabetes mellitus is a major risk factor for the development of cardiovascular diseases. Heart failure with preserved ejection fraction is characterized by left ventricular diastolic dysfunction (LVDD). It has been reported that excess cortisol found in patients with Cushing's syndrome was associated with the development of LVDD. However, the relationship between cortisol concentration and LVDD in patients with diabetes mellitus has not been addressed. MATERIALS AND METHODS: We enrolled 109 patients with diabetes mellitus and 104 patients without diabetes mellitus who had undergone echocardiographic examination at Kyushu University Hospital, Fukuoka, Japan, between November 2016 and March 2019. Left ventricular function was evaluated and the ratio of early diastolic velocity from transmitral inflow to early diastolic velocity (E/e') was used as an index of diastolic function. Plasma cortisol concentrations, glycemic control, lipid profiles, treatment with antidiabetic drugs and other clinical characteristics were evaluated, and their associations with E/e' were determined using univariate and multivariate analyses. RESULTS: Multivariate linear regression analysis showed that log E/e' was positively correlated with age (P = 0.017), log systolic blood pressure (P = 0.004) and cortisol (P = 0.037), and negatively correlated with estimated glomerular filtration rate (P = 0.016) and the use of sodium-glucose cotransporter 2 inhibitors (P = 0.042) in patients with diabetes mellitus. Multivariate analysis showed that cortisol was positively correlated with age (P = 0.016) and glycated hemoglobin (P = 0.011). There was no association between E/e' and cortisol in patients without diabetes mellitus. CONCLUSIONS: Increased cortisol levels might increase the risk of developing LVDD in diabetes mellitus patients.
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Diabetes Mellitus , Disfunção Ventricular Esquerda , Diástole , Humanos , Hidrocortisona , Volume Sistólico , Disfunção Ventricular Esquerda/complicações , Função Ventricular EsquerdaRESUMO
AIMS/INTRODUCTION: Diagnosis of diabetic peripheral neuropathy (DPN) depends on subjective findings, certain investigations for DPN risks have not been performed enough. Bilirubin protects against vascular complications by reducing oxidative stress in diabetes, but is not fully tested for DPN. This study aimed to evaluate sural nerve conduction impairments (SNCI) as an objective DPN marker and the contribution of bilirubin to SNCI. MATERIALS AND METHODS: Using DPN-Check® , SNCI was defined as a decline of amplitude potential or conduction velocity below the normal limit in 150 inpatients with diabetes. The correlations between SNCI and conventional DPN diagnosis criteria, the incidence of diabetic retinopathy/nephropathy, biomarkers for atherosclerosis, cardiac function by ultrasonic cardiogram, and bilirubin were statistically tested, followed by the comparison of logistic regression models for SNCI to find confounders with bilirubin. RESULTS: The incidence of SNCI was 72.0%. The sensitivity and specificity of SNCI for DPN prediagnosis by simplified criteria were 54.6 and 90.5%, respectively, and similarly corresponded with diabetic retinopathy and nephropathy (sensitivity 57.4 and 50.0%, respectively). SNCI significantly related to diabetes duration, declined estimated glomerular filtration rate, albuminuria and total bilirubin. SNCI incidence was attenuated in the higher bilirubin tertiles (89.8/65.3/54.8%, P < 0.001). Bilirubin was an independent inverse risk factor for SNCI, even after adjustment by known risk factors for DPN and markers for microvascular complications. CONCLUSIONS: SNCI is a comprehensive marker for diabetic complications. We first showed the independent inverse relationship between bilirubin and SNCI through the independent pathway with other complications, provably reducing oxidative stress, as previously reported.
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Bilirrubina/sangue , Diabetes Mellitus/sangue , Neuropatias Diabéticas/diagnóstico , Doenças do Sistema Nervoso Periférico/diagnóstico , Nervo Sural/fisiopatologia , Idoso , Albuminúria/diagnóstico , Biomarcadores/sangue , Estudos Transversais , Diabetes Mellitus/fisiopatologia , Neuropatias Diabéticas/epidemiologia , Retinopatia Diabética/diagnóstico , Retinopatia Diabética/epidemiologia , Feminino , Taxa de Filtração Glomerular , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Condução Nervosa , Valor Preditivo dos Testes , Fatores de Risco , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Previous reports have indicated that serum bilirubin levels may be associated with diabetic retinopathy. However, the detailed mechanism is not fully understood. In this study, we evaluated the relationship between the severity of diabetic retinopathy and various factors including bilirubin levels and factors influencing bilirubin metabolism. METHODS: The study participants consisted of 94 consecutive patients with diabetes mellitus admitted to Kyushu University Hospital from April 2011 to July 2012. The patients were classified into three groups: no retinopathy (NDR), simple retinopathy (SDR), and pre-proliferative or proliferative retinopathy (PDR). The relationship between the severity of retinopathy and various factors was evaluated using univariate and logistic regression analyses. In addition, multivariate regression analysis was performed to evaluate the significant determinants for bilirubin levels. RESULTS: In univariate analysis, a significant difference was found among NDR, SDR and PDR in bilirubin levels, duration of diabetes, systolic blood pressure, and macroalbuminuria. Logistic regression analysis showed that PDR was significantly associated with bilirubin levels, duration of diabetes, and systolic blood pressure (OR 0.737, 95% CI 0.570-0.952, P = 0.012; OR 1.085, 95% CI 1.024-1.149, P = 0.006; OR 1.036, 95% CI 1.011-1.062, P = 0.005, respectively). In turn, multivariate regression analysis showed that bilirubin levels were negatively associated with high-sensitivity C-reactive protein levels and PDR, but positively correlated with urinary biopyrrin levels, oxidized metabolites of bilirubin. CONCLUSION: PDR was negatively associated with bilirubin levels. This negative association may be due to a decreased production of bilirubin rather than its increased consumption considering the positive association between bilirubin and biopyrrin levels.
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Bilirrubina/sangue , Retinopatia Diabética/sangue , Retinopatia Diabética/urina , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Pressão Sanguínea , Retinopatia Diabética/fisiopatologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
To evaluate the immunotoxic effects of xenobiotics, we have established the Multi-ImmunoTox assay, in which three stable reporter cell lines are used to evaluate the effects of chemicals on the IL-2, IFN-γ, IL-1ß and IL-8 promoters. Here, we report the official validation study of the IL-2 luciferase assay (IL-2 Luc assay). In the Phase I study that evaluated five coded chemicals in three sets of experiments, the average within-laboratory reproducibility was 86.7%. In the Phase II study, 20 coded chemicals were evaluated at multiple laboratories. In the combined results of the Phase I and II studies, the between-laboratory reproducibility was 80.0%. These results suggested that the IL-2 Luc assay was reproducible both between and within laboratories. To determine the predictivity, we collected immunotoxicological information and constructed the reference data by classifying the chemical into immunotoxic compounds targeting T cells or others according to previously reported criteria. When compared with the reference data, the average predictivity of the Phase I and II studies was 75.0%, while that of additional 60 chemicals examined by the lead laboratory was 82.5%. Although the IL-2 Luc assay alone is not sufficient to predict immunotoxicity, it will be a useful tool when combined with other immune tests.
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Bioensaio , Fatores Imunológicos/toxicidade , Interleucina-2/imunologia , Linfócitos T/efeitos dos fármacos , Testes de Toxicidade/métodos , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-2/genética , Luciferases/metabolismo , Reprodutibilidade dos Testes , Linfócitos T/imunologiaRESUMO
OBJECTIVE: Accumulating epidemiological studies have demonstrated that diabetes is an important risk factor for dementia. However, the underlying pathological and molecular mechanisms, and effective treatment, have not been fully elucidated. Herein, we investigated the effect of the dipeptidyl peptidase-4 (DPP-4) inhibitor, linagliptin, on diabetes-related cognitive impairment. METHOD: Streptozotocin (STZ)-induced diabetic mice were treated with linagliptin (3 mg/kg/24 h) for 17 weeks. The radial arm water maze test was performed, followed by evaluation of oxidative stress using DNP-MRI and the expression of NAD(P)H oxidase components and proinflammatory cytokines and of microglial activity. RESULTS: Administration of linagliptin did not affect the plasma glucose and body weight of diabetic mice; however, it improved cognitive impairment. Additionally, linagliptin reduced oxidative stress and the mRNA expression of NAD(P)H oxidase component and TNF-α, and the number and body area of microglia, all of which were significantly increased in diabetic mice. CONCLUSIONS: Linagliptin may have a beneficial effect on diabetes-related dementia by inhibiting oxidative stress and microglial activation, independently of glucose-lowering.
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Diabetes Mellitus Experimental/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Linagliptina/farmacologia , Microglia/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Animais , Glicemia/análise , Peso Corporal/efeitos dos fármacos , Encéfalo/metabolismo , Diabetes Mellitus Experimental/induzido quimicamente , Inibidores da Dipeptidil Peptidase IV/farmacologia , Linagliptina/uso terapêutico , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Microglia/citologia , Microglia/efeitos dos fármacos , NADPH Oxidases/genética , NADPH Oxidases/metabolismo , Estreptozocina/toxicidade , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Human hepatocytes are essential cell types for pharmacokinetics and the safety evaluation of pharmaceuticals. However, widely used primary hepatocytes with individual variations in liver function lose those functions rapidly in culture. Hepatic cell lines are convenient to use but have low liver functions. Human-Induced Pluripotent Stem (hiPS) cells can be expanded and potentially differentiated into any cell or tissue, including the liver. HiPS cell-derived Hepatocyte-Like Cells (hiPSHeps) are expected to be extensively used as consistent functional human hepatocytes. Many laboratories are investigating methods of using hiPS cells to differentiate hepatocytes, but the derived cells still have immature liver functions. In this paper, we describe the current uses and limitations of conventional hepatic cells, evaluating the suitability of hiPS-Heps to pharmacokinetics and the safety evaluation of pharmaceuticals, and discuss the potential future use of non-conventional non-monolayer culture methods to derive fully functional hiPS-Heps.
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Técnicas de Cultura de Células/métodos , Desenvolvimento de Medicamentos , Drogas em Investigação , Hepatócitos/citologia , Hepatócitos/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/citologia , Diferenciação Celular/fisiologia , Linhagem Celular , Drogas em Investigação/efeitos adversos , Drogas em Investigação/farmacocinética , Hepatócitos/metabolismo , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Fígado/efeitos dos fármacos , Fígado/fisiologiaRESUMO
Mast cells are key players in the inflammatory response with an important role in allergic reactions and are therefore useful for assessing the risk of anaphylaxis. However, they are difficult to isolate due to their low abundance and wide distribution. To overcome this, we generated and characterized mast cell-like cells derived from human induced pluripotent stem (hiPS) cells. These hiPS cell-derived mast cells (hiPS-MCs) were generated using recombinant human bone morphogenetic protein 4 (BMP4), vascular endothelial growth factor 165 (VEGF), stem cell factor (SCF), interleukin-4 (IL-4), interleukin-6 (IL-6), and interleukin-9 (IL-9) in a StemPro-34 medium. The hiPS-MCs exhibited the morphological characteristics of human mast cells, expressing high affinity-IgE receptor (FcεRI) and mast cell markers such as tryptase, chymase, and CD117. In addition, FcεRI stimulation with agonistic anti-IgE functionally increased the expression of activation markers CD63 and CD203c, as well as the amount of released histamine. We think the hiPS-MCs generated in this study will be useful for assessing the pharmacology and toxicity of anti-allergy medicines.
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Células-Tronco Pluripotentes Induzidas/citologia , Mastócitos/metabolismo , Diferenciação Celular , Linhagem Celular , Quimases/metabolismo , Liberação de Histamina , Humanos , Hipersensibilidade , Subunidade alfa de Receptor de Interleucina-3/metabolismo , Fenótipo , Proteínas Proto-Oncogênicas c-kit/metabolismo , Receptores de IgE/metabolismo , Triptases/metabolismoRESUMO
OBJECTIVE: Although previous studies have reported a negative relationship between serum bilirubin concentration and the development of diabetes mellitus (DM), the relationship between bilirubin and insulin resistance has not been thoroughly assessed. This study was designed to determine the relationships between bilirubin, body fat distribution, and adipose tissue inflammation in patients with type 2 DM and the effect of bilirubin in an obese animal model. METHOD: Body fat distribution was measured using an abdominal dual bioelectrical impedance analyzer in patients with type 2 DM. We also measured glycemic control, lipid profile, serum bilirubin concentration and other clinical characteristics, and determined their relationships with body fat distribution. In the animal study, biliverdin (20 mg/kg daily) was orally administered to high-fat diet (HFD)-induced obese (DIO) mice for 2 weeks, after which intraperitoneal insulin tolerance testing was performed. Then, adipocyte area, adipocytokine expression, and macrophage polarization were evaluated in epididymal adipose tissues. RESULTS: In the clinical study, univariate analysis showed that a lower bilirubin concentration was significantly correlated with higher body mass index, waist circumference, triglyceride, uric acid, creatinine, visceral fat area and lower HDL-C. In multivariate analyses, bilirubin concentration significantly correlated with diastolic blood pressure, creatinine, and visceral fat area. However, there was no association between bilirubin concentration and subcutaneous fat area. In the animal study, DIO mice treated with biliverdin had smaller adipocytes than untreated DIO mice and biliverdin improved HFD-induced insulin resistance. Biliverdin treatment reversed the higher gene expression of Cd11c, encoding an M1 macrophage marker, and Tnfa, encoding the proinflammatory cytokine tumor necrosis factor-α, in the adipose tissues of DIO mice. These data suggest biliverdin administration alleviates insulin resistance by ameliorating inflammation and the dysregulation of adipocytokine expression in adipose tissues of DIO mice. CONCLUSIONS: Bilirubin may protect against insulin resistance by ameliorating visceral obesity and adipose tissue inflammation.
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Bilirrubina/metabolismo , Citocinas/metabolismo , Mediadores da Inflamação/metabolismo , Resistência à Insulina , Obesidade Abdominal/metabolismo , Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Idoso , Animais , Biomarcadores , Feminino , Humanos , Insulina/metabolismo , Gordura Intra-Abdominal/metabolismo , Masculino , Camundongos , Pessoa de Meia-Idade , NADPH Oxidases/metabolismoRESUMO
Differentiation of stem cells to hepatocytes provides an unlimited supply of human hepatocytes and therefore has been vigorously studied. However, to date, the stem cell-derived hepatocytes were suggested to be of immature features. To obtain matured hepatocytes from stem cells, we tested the effect of culturing human-induced pluripotent stem (hiPS) cell-derived endoderm cells on collagen vitrigel membrane and compared with our previous reported nanofiber matrix. We cultured hiPS cell-derived endoderm cells on a collagen vitrigel membrane and examined the expression profiles, and tested the activity of metabolic enzymes. Gene expression profile analysis of hepatocytic differentiation markers revealed that upon culture on collagen vitrigel membrane, immature markers of AFP decreased, with a concomitant increase in the expression of mature hepatocyte transcription factors and mature hepatocyte markers such as ALB, ASGR1 Mature markers involved in liver functions, such as transporters, cytochrome P450 enzymes and phase II metabolic enzymes were also upregulated. We observed the upregulation of the liver markers for at least 2â weeks. Gene array profiling analysis revealed that hiPS cell-derived hepatocyte-like cells (hiPS-hep) resemble those of the primary hepatocytes. Functions of the CYP enzyme activities were tested in multi-institution and all revealed high CYP1A, CYP2C19, CYP2D6, CYP3A activity, which could be maintained for at least 2â weeks in culture. Taken together, the present approach identified that collagen vitrigel membrane provides a suitable environment for the generation of hepatocytes from hiPS cells that resemble many characteristics of primary human hepatocytes.
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To detect potential risk of severe cytokine release syndrome, in vitro assay formats with human cells have been developed. The two major testing platforms are a combination of whole blood with aqueous-phase test articles (whole blood cytokine assay, WBCA) and peripheral blood mononuclear cells with solid-phase articles (PBMC assay). Significant induction of cytokines was seen in both assays after treatment with a widely used control agent, TGN1412 or its analog CD28SA, but the WBCA cytokine profile differed from what was expected from clinical experience. In the WBCA, potential risk of CD28SA was detected by elevation of IL-8 whereas IL-2, a key cytokine after stimulation of CD28, was not induced in approximately 40% of donor samples. Therefore, further mechanistic understanding of the different responses in the in vitro assay was needed. In this study of donor samples treated with CD28SA, we compared the induction of cytokines and identified the cytokine-producing cells in the two assays. IL-2 was markedly elevated in all the donors in the PBMC assay but only in 1 of 3 donors in the WBCA. IL-8, the most sensitive biomarker in the WBCA, was produced by monocytes and granulocytes. T cells, the most relevant player in the PBMC assay with CD28SA, did not contribute to the positive response seen in two donors in the WBCA, which suggests that different players caused the positive cytokine responses to CD28SA in the two assays.
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Anticorpos Monoclonais Humanizados/imunologia , Citocinas/imunologia , Leucócitos Mononucleares/imunologia , Células Cultivadas , Citocinas/análise , Citometria de Fluxo/métodos , Humanos , Proteínas Imobilizadas/imunologiaRESUMO
INTRODUCTION: Previous studies have shown that serum bilirubin concentration is inversely associated with the risk of cardiovascular disease. The relationship between serum bilirubin concentration and left ventricular geometry, however, has not been investigated in patients with diabetes mellitus. METHODS: In this cohort study, 158 asymptomatic patients with type 2 diabetes mellitus without overt heart disease were enrolled. Left ventricular structure and function were assessed using echocardiography. Serum bilirubin concentration, glycemic control, lipid profile, and other clinical characteristics were evaluated, and their association with left ventricular geometry was determined. Patients with New York Heart Association Functional Classification greater than I, left ventricular ejection fraction less than 50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance less than 30 ml/min, and those receiving insulin treatment, were excluded. RESULTS: Univariate analyses showed that relative wall thickness (RWT) was significantly correlated with diastolic blood pressure (P = 0.003), HbA1c (P = 0.024), total cholesterol (P = 0.043), urinary albumin (P = 0.023), and serum bilirubin concentration (P = 0.009). There was no association between left ventricular mass index and serum bilirubin concentration. Multivariate linear regression analysis showed that log RWT was positively correlated with diastolic blood pressure (P = 0.010) and that log RWT was inversely correlated with log bilirubin (P = 0.003). In addition, the patients with bilirubin less than 0.8 mg/dl had a higher prevalence of concentric left ventricular remodeling compared with those with bilirubin 0.8 mg/dl or more. CONCLUSION: Our study shows that the serum bilirubin concentration may be associated with the progression of concentric left ventricular remodeling in patients with type 2 diabetes mellitus.
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OBJECTIVE: Although diabetes mellitus is associated with an increased risk of heart failure with preserved ejection fraction, the underlying mechanisms leading to left ventricular diastolic dysfunction (LVDD) remain poorly understood. The study was designed to assess the risk factors for LVDD in patients with type 2 diabetes mellitus. RESEARCH DESIGN AND METHODS: The study cohort included 101 asymptomatic patients with type 2 diabetes mellitus without overt heart disease. Left ventricular diastolic function was estimated as the ratio of early diastolic velocity (E) from transmitral inflow to early diastolic velocity (e') of tissue Doppler at mitral annulus (E/e'). Parameters of glycemic control, plasma insulin concentration, treatment with antidiabetic drugs, lipid profile, and other clinical characteristics were evaluated, and their association with E/e' determined. Patients with New York Heart Association class >1, ejection fraction <50%, history of coronary artery disease, severe valvulopathy, chronic atrial fibrillation, or creatinine clearance <30â mL/min, as well as those receiving insulin treatment, were excluded. RESULTS: Univariate analysis showed that E/e' was significantly correlated with age (p<0.001), sex (p<0.001), duration of diabetes (p=0.002), systolic blood pressure (p=0.017), pulse pressure (p=0.010), fasting insulin concentration (p=0.025), and sulfonylurea use (p<0.001). Multivariate linear regression analysis showed that log E/e' was significantly and positively correlated with log age (p=0.034), female sex (p=0.019), log fasting insulin concentration (p=0.010), and sulfonylurea use (p=0.027). CONCLUSIONS: Hyperinsulinemia and sulfonylurea use may be important in the development of LVDD in patients with type 2 diabetes mellitus.
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After the life-threatening cytokine release syndrome (CRS) occurred in the clinical study of the anti-CD28 monoclonal antibody (mAb) TGN1412, in vitro cytokine release assays using human blood cells have been proposed for non-clinical evaluation of the potential risk of CRS. Two basic assay formats are frequently used: human peripheral blood mononuclear cells (PBMC) with immobilized mAbs, and whole blood with aqueous mAbs. However, the suitability of the whole blood cytokine assay (WBCA) has been questioned, because an unrealistically large sample size would be required to detect the potential risk of CRS induced by TGN1412, which has low sensitivity. We performed a WBCA using peripheral blood obtained from 68 healthy volunteers to compare two high risk mAbs, the TGN1412 analogue anti-CD28 superagonistic mAb (CD28SA) and the FcγR-mediated alemutuzumab, with a low risk mAb, panitumumab. Based on the cytokine measurements in this study, the sample size required to detect a statistically significant increase in cytokines with 90% power and 5% significance was determined to be n = 9 for CD28SA and n = 5 for alemtuzumab. The most sensitive marker was IL-8. The results suggest that WBCA is a practical test design that can warn of the potential risk of FcγR-mediated alemtuzumab and T-cell activating CD28SA but, because there was apparently a lower response to CD28SA, it cannot be used as a risk-ranking tool. WBCA is suggested to be a helpful tool for identifying potential FcγR-mediated hazards, but further mechanistic understanding of the response to CD28SA is necessary before applying it to T cell-stimulating mAbs.
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Anticorpos Monoclonais Humanizados/toxicidade , Anticorpos Monoclonais/toxicidade , Células Sanguíneas/efeitos dos fármacos , Citocinas/sangue , Testes de Toxicidade/métodos , Alemtuzumab , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Biomarcadores/sangue , Células Sanguíneas/imunologia , Células Sanguíneas/metabolismo , Humanos , Infusões Parenterais , Panitumumabe , Reprodutibilidade dos Testes , Medição de RiscoRESUMO
Case: A 57-year-old woman was transferred to our emergency department by ambulance with cardiopulmonary arrest caused by massive genital bleeding. Cardiopulmonary resuscitation, including massive transfusion, was carried out and the return of spontaneous circulation was achieved. A giant uterine tumor was considered the source of the bleeding. Although hysterectomy was necessary to achieve definitive hemostasis, the patient was unable to tolerate the operation because of hemodynamic instability, acidosis, and coagulopathy. Therefore, we undertook vaginal gauze packing and uterine artery embolization to attain temporary hemostasis, which resulted in hemodynamic stabilization. Abdominal hysterectomy for definitive hemostasis was carried out 10 h after the embolization. Outcome: The patient made a good post-surgical recovery without any complications. Conclusion: In treating hemorrhagic shock due to uterine leiomyoma, damage-control resuscitation may be useful as a bridge prior to definitive hemostasis through hysterectomy.
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OBJECTIVE: Accumulating evidence has implicated that GLP-1 may have a beneficial effect on cardiovascular but the mechanism is not fully understood. Here we show that GLP-1 analog, liraglutide, inhibits cardiac steatosis, oxidative stress and apoptosis in streptozotocin (STZ)-induced type 1 diabetic rats, via activation of AMPK-Sirt1 pathway. METHODS: Diabetic rats were treated with subcutaneous injections of liraglutide (0.3 mg/kg/12 h) for 4 weeks. Myocardial steatosis (detected by oil red O staining and myocardial triglyceride and diacylglycerol (DAG) contents assay), expression of protein kinase C (PKC), heart NAD(P)H oxidase activity, oxidative stress markers (8-hydroxy-2'-deoxyguanosine staining), apoptosis (TUNEL analysis) and genes that affect apoptosis and lipid metabolism were evaluated. RESULTS: Administration of liraglutide did not affect plasma glucose and insulin levels or body weights in STZ-induced diabetic rats, but normalized myocardial steatosis, expression of PKC, NAD(P)H oxidase activity, oxidative stress markers and apoptosis, all of which were significantly increased in diabetic hearts. Additionally, expression of genes mediating lipid uptake, synthesis and oxidation were increased in the diabetic hearts, and these increases were all reduced by liraglutide. In addition, liraglutide increased expression of Sirt1 and phosphorylated AMPK in the diabetic hearts. CONCLUSIONS: Liraglutide may have a beneficial effect on cardiac steatosis, DAG-PKC-NAD(P)H pathway, oxidative stress and apoptosis via activation of AMPK-Sirt1 pathway, independently of a glucose-lowering effect.