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1.
Cancer Sci ; 2020 Jul 03.
Artigo em Inglês | MEDLINE | ID: mdl-32619063

RESUMO

Cancer treatment with a fluoropyrimidine (FP) is often accompanied by severe toxicity that may be dependent on the activity of catalytic enzymes encoded by the DPYD, DPYS and UPB1 genes. Genotype-guided dose individualization of FP therapy has been proposed in Western countries, but our knowledge of the relevant genetic variants in East Asian populations is presently limited. To investigate the association between these genetic variations and FP-related high toxicity in a Japanese population, we obtained blood samples from 301 patients who received this chemotherapy and sequenced the coding exons and flanking intronic regions of their DPYD, DPYS and UPB1 genes. In total, 24 single nucleotide variants (15 in DPYD, 7 in DPYS and 2 in UPB1) were identified including 3 novel variants in DPYD and 1 novel variant in DPYS. We did not find a significant association between FP-related high toxicity and each of these individual variants, although a certain trend toward significance was observed for p.Arg181Trp and p.Gln334Arg in DPYS (p=0.0813 and 0.087). When we focused on 7 DPYD rare variants (p.Ser199Asn, p.IIe245Phe, p.Thr305Lys, p.Glu386Ter, p.Ser556Arg, p.Ala571Asp, p.Trp621Cys) which have an allele frequency of less than 0.01% in the Japanese population and are predicted to be loss-of-function mutations by in silico analysis, the group of patients who were heterozygous carriers of at least one these rare variants showed a strong association with FP-related high toxicity (p= 0.003). Although the availability of screening of these rare loss-of-function variants is still unknown, our data provide useful information that may help to alleviate FP-related toxicity in Japanese cancer patients.

2.
J Sex Med ; 17(7): 1280-1287, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32624131

RESUMO

BACKGROUND: High salt intake is a risk factor for hypertension, which can potentially lead to erectile dysfunction (ED); however, the underlying pathological mechanisms remain unclear. AIM: To investigate whether erectile function is directly impaired by high salt intake and whether selective inhibition of mineralocorticoid receptor (MR) could provide protection from ED. METHODS: 6-week-old male Dahl salt-sensitive rats were randomly divided into 3 groups: normal diet (0.3% NaCl; control, n = 8), high-salt diet (8% NaCl; HS, n = 8), and high-salt diet plus eplerenone (HS + EPL, n = 11). HS + EPL rats were orally administered daily doses of EPL (75 mg/kg) for 6 weeks; control and HS rats received purified water on the same schedule. OUTCOMES: At the end of the study period, erectile function was evaluated by measuring intracavernosal pressure and mean arterial pressure after cavernous nerve stimulation. Serum levels of asymmetric dimethylarginine and L-arginine were determined using ultraperformance liquid chromatography-tandem mass spectrometry. Quantitative PCR was used to assess the expression of MR, inflammation, and oxidative stress markers (nicotinamide adenine dinucleotide phosphate oxidase-1/4, p22phox, interleukin-6, and superoxide dismutase-1), and protein arginine N-methyltransferase-1. RESULTS: The intracavernosal pressure/mean arterial pressure ratio was significantly lower, whereas systolic blood pressure, MR expression, serum asymmetric dimethylarginine levels, oxidative stress, and levels of inflammatory biomarkers were significantly higher in HS rats than in control rats (P < .05). EPL administration significantly improved each of these parameters except systolic blood pressure and MR expression. No significant intergroup differences were observed for L-arginine and superoxide dismutase-1 levels. CLINICAL TRANSLATION: Our results provide a rationale for the need of salt restriction and the use of selective MR inhibitors in prophylaxis or treatment of ED in men consuming a high-salt diet. STRENGTHS & LIMITATIONS: We are the first to report that the adverse impact of high salt intake on erectile function is mediated via MR activation, independent of its effect on blood pressure. A major limitation of this study is that responses of salt-resistant rats were not studied. CONCLUSIONS: High salt intake directly impaired erectile function in Dahl salt-sensitive rats, whereas selective MR inhibition ameliorated this effect. Kishimoto T, Kataoka T, Yamamoto Y, et al. High Salt Intake Impairs Erectile Function in Salt-Sensitive Rats Through Mineralocorticoid Receptor Pathway Beyond Its Effect on Blood Pressure. J Sex Med 2020;17:1280-1287.

3.
Rinsho Shinkeigaku ; 60(5): 351-357, 2020 May 26.
Artigo em Japonês | MEDLINE | ID: mdl-32307398

RESUMO

The patient was a 40-year-old woman who was previously diagnosed with systemic lupus erythematosus and myasthenia gravis and had received prednisolone and tacrolimus for more than 7 years. In February 2017, she noticed pain in her lower back and weakness of the lower limbs, and was referred to our hospital on day 5. She had shingles in the right lower thoracic dermatomes and Brown-Séquard syndrome with right-sided dominant weakness in her lower limbs and left-sided superficial sensory disturbance below the L1 level. Varicella zoster virus (VZV)-associated myelopathy was suspected because of her symptoms and clinical findings. Despite the immediate administration of intravenous acyclovir after hospitalization, she lost consciousness and experienced a seizure related to cerebral hemorrhage in the left temporal lobe on the night of day 5. MRI showed enhanced lesions along the spinal cord and leptomeninges of the brainstem and temporal lobe. VZV-IgG and VZV-DNA were positive in the cerebrospinal fluid. Based on these clinical features and laboratory findings, she was diagnosed as VZV-associated vasculopathy and myelopathy. She subsequently had multiple cerebral infractions and hemorrhage, and developed sudden cardiopulmonary arrest on day 6, culminating in death on day 17. Autopsy showed that inflammatory mononuclear cells had infiltrated the vascular walls of the spinal cord. Immunohistochemistry revealed that some neurons and macrophages in the white matter of the spinal cord were positive for VZV. In addition, atrophic neurons, satellite cells surrounding these neurons, and infiltrating macrophages were immune-positive for VZV at the L2 dorsal root ganglia. These findings were consistent with VZV-associated vasculopathy and myelitis. Under immunosuppressive conditions, VZV can cause shingles and neuronal complications such as vasculopathy and myelitis, which are sometimes fatal despite the immediate administration of intravenous acyclovir. New treatment drugs or drugs to prevent VZV activation are desired.

4.
CEN Case Rep ; 9(3): 210-214, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32128695

RESUMO

Unlike complete deficiency of hypoxanthine phosphoribosyltransferase (HPRT) (i.e., Lesch-Nyhan syndrome), partial HPRT deficiency causes HPRT-related hyperuricemia without neurological symptoms. Herein, we describe a 22-year-old man without neurological symptoms that presented gout, hyperuricemia (serum urate level, 12.2 mg/dL), multiple renal microcalculi, and a family history of juvenile gout that was exhibited by his brother and grandfather. Genetic testing revealed a novel missense mutation, c.103G>A (p.V35M), in the HPRT1 gene, and biochemical testing (conducted using the patient's erythrocytes) showed that the patient retained only 12.4% HPRT enzymatic activity compared to that exhibited by a healthy control subject. We thus diagnosed the patient with HPRT-related hyperuricemia caused by partial HPRT deficiency. After his serum urate level was controlled via treatment with febuxostat, his gout did not recur. Thus, this study emphasizes that HPRT deficiency should be considered as a potential cause of familial juvenile gout, even in the absence of neurological symptoms.

5.
Arthritis Res Ther ; 22(1): 32, 2020 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-32085768

RESUMO

BACKGROUND: Patients with systemic sclerosis (SSc) complicated by gastrointestinal dysmotility are difficult to treat and have high mortality. To clarify the pathogenesis of gastrointestinal manifestations, we aimed to demonstrate the association among the clinical features of SSc, the serological markers, the autoantibodies against nicotinic acetylcholine receptor at autonomic ganglia (gAChR). METHODS: Fifty patients were enrolled and divided into two groups according to the presence or absence of gastrointestinal manifestations, and the characteristics were analyzed between these two groups. We measured biomarkers and the autoantibodies against two gAChRα3 and ß4 subunits to test sera samples. Furthermore, patients were classified based on the presence or absence of anti-gAChR autoantibodies, and their clinical features were compared. RESULTS: In patients with SSc and gastrointestinal manifestations, digital ulcers were more frequent (p = 0.050) and VEGF expression was significantly higher (p = 0.038). Seven subjects with SSc were seropositive for α3 subunit, whereas one patient was seropositive for ß4 subunit. The mean level of anti-gAChRα3 autoantibodies in SSc patients with gastrointestinal manifestations was significantly higher than that in SSc patients without gastrointestinal manifestations (p = 0.001). The group of patients with SSc and gAChR autoantibodies had significantly higher endostatin levels (p = 0.046). CONCLUSIONS: This study is the first to demonstrate that clinical characteristics of SSc patients with seropositivity for gAChR autoantibodies. Patients with SSc have circulating autoantibodies against gAChR, which may contribute to gastrointestinal manifestations associated with this disease, suggesting that gAChR-mediated autonomic neurotransmission may provide a pathomechanism for gastrointestinal dysmotility in SSc.

6.
PLoS One ; 14(12): e0226154, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31805144

RESUMO

Amiselimod (MT-1303) is a novel sphingosine 1-phosphate receptor-1 (S1P1 receptor) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. MT-1303 phosphate (MT-1303-P), an active metabolite of MT-1303, exhibits S1P1 receptor agonism at a lower EC50 value than other S1P1 receptor modulators currently being developed. We aimed to evaluate the efficacy of MT-1303 and its mode of action in chronic colitis using an inflammatory bowel disease (IBD) model. Oral administration of MT-1303 (0.3 mg/kg) once daily for 3 days to mice almost completely abolished S1P1 receptor expression on CD4+ T cells from mesenteric lymph nodes, which corresponded to a marked decrease in CD4+ T cell count in peripheral blood, indicating that MT-1303-P acts as a functional antagonist of the S1P1 receptor. The potential benefit of MT-1303 for IBD was assessed using immunodeficient SCID mice with chronic colitis induced by adoptive transfer of CD4+CD45RBhigh T cells from BALB/c mice. An oral dose of 0.1 and 0.3 mg/kg MT-1303 administered daily one week after the cell transfer inhibited the development of chronic colitis with an efficacy comparable to that of an anti-mTNF-α mAb (250 µg/mouse). In addition, MT-1303 administration significantly reduced the number of infiltrating Th1 and Th17 cells into the lamina propria of the colon in colitis mice. Our results suggest that MT-1303 acts as a functional antagonist of the S1P1 receptor on lymphocytes, regulates lymphocyte trafficking, and inhibits infiltration of colitogenic Th1 and Th17 cells into the colon to inhibit the development of chronic colitis.


Assuntos
Linfócitos T CD4-Positivos/transplante , Colite/tratamento farmacológico , Antígenos Comuns de Leucócito/metabolismo , Propanolaminas/administração & dosagem , Administração Oral , Transferência Adotiva , Animais , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/metabolismo , Colite/imunologia , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos SCID , Propanolaminas/farmacologia , Receptores de Esfingosina-1-Fosfato/antagonistas & inibidores
7.
Neurology ; 92(16): e1868-e1877, 2019 04 16.
Artigo em Inglês | MEDLINE | ID: mdl-30867270

RESUMO

OBJECTIVE: To investigate whether arginine methylation is altered in patients with amyotrophic lateral sclerosis (ALS) and how it affects disease severity, progression, and prognosis. METHODS: We compared the immunoreactivity of protein arginine methyltransferase 1 (PRMT1) and its products, asymmetric dimethylated proteins (ASYM), in postmortem spinal cord. We also measured the concentrations of total l-arginine and methylated arginine residues, including asymmetric dimethyl l-arginine (ADMA), symmetric dimethyl arginine, and monomethyl arginine, in CSF samples from 52 patients with ALS using liquid chromatography-tandem mass spectrometry, and we examined their relationship with the progression and prognosis of ALS. RESULTS: The immunoreactivity of both PRMT1 (p < 0.0001) and ASYM (p = 0.005) was increased in patients with ALS. The concentration of ADMA in CSF was substantially higher in patients with ALS than in disease controls. The ADMA/l-arginine ratio was correlated with the change of decline in the ALS Functional Rating Scale at 12 months after the time of measurement (r = 0.406, p = 0.010). A Cox proportional hazards model showed that the ADMA/l-arginine ratio was an independent predictor for overall survival. Moreover, a high ADMA/l-arginine ratio predicted poor prognosis, even in a group with normal percentage forced vital capacity. CONCLUSION: There was an enhancement of arginine dimethylation in patients with ALS, and the ADMA/l-arginine ratio predicted disease progression and prognosis in such patients.


Assuntos
Esclerose Amiotrófica Lateral/diagnóstico , Esclerose Amiotrófica Lateral/metabolismo , Arginina/análogos & derivados , Arginina/metabolismo , Proteína-Arginina N-Metiltransferases/metabolismo , Proteínas Repressoras/metabolismo , Idoso , Esclerose Amiotrófica Lateral/epidemiologia , Esclerose Amiotrófica Lateral/patologia , Biomarcadores/metabolismo , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Metilação , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Índice de Gravidade de Doença , Medula Espinal/metabolismo , Medula Espinal/patologia , Análise de Sobrevida
8.
Mult Scler Relat Disord ; 31: 22-31, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30901701

RESUMO

BACKGROUND: Hereditary diffuse leukoencephalopathy with axonal spheroids (HDLS) is a rare autosomal-dominant white matter disease, typically characterized by juvenile cognitive decline and frontoparietal white matter lesions. A portion of HDLS patients exhibit preferential motor dysfunctions as their initial symptoms, mimicking multiple sclerosis (MS). However, there is no study comparing this phenotype of HDLS and primary progressive multiple sclerosis (PPMS), which greatly resemble each other. This is the first preliminary study to clarify the clinical and neuroimaging features of motor-predominant HDLS, and compare it with PPMS, using cases whose colony stimulating factor 1 receptor (CSF1R) were sequenced. METHODS: Clinical and radiological data from Japanese patients at the Department of Neurology, Kyushu University Hospital, Fukuoka, Japan, were evaluated retrospectively and cross-sectionally. Twenty-nine brain and 18 spinal cord magnetic resonance imaging (MRI) scans from four motor-predominant HDLS patients with CSF1R mutations and 15 PPMS patients without CSF1R mutations, were evaluated using an HDLS MRI scoring system. RESULTS: Two patients with HDLS were initially diagnosed with MS and received immunotherapy. Clinically, motor-predominant HDLS and PPMS patients resembled each other in onset age and disability. However, motor-predominant HDLS patients had a significantly higher frequency of frontal release signs, lower positivity rates of oligoclonal IgG bands (OCB), and lower IgG index values. Total HDLS MRI scores, total white matter lesions (WMLs), and brain atrophy were similar between the diseases. However, motor-predominant HDLS patients had more marked atrophy of the corpus callosum (CC) body, more WMLs in the deep and subcortical regions of the frontoparietal lobes, fewer WMLs in the occipitotemporal periventricular regions, and more restricted diffusivity lesions on MRI than PPMS patients. There was a stronger association between disease duration and CC index in HDLS, suggesting more rapid progression compared with PPMS. CONCLUSIONS: Motor-predominant HDLS has characteristic frequent frontal release signs, normal findings for OCB and the IgG index, severe CC body atrophy, abundant deep and subcortical WMLs in the frontoparietal lobes, subtle occipitotemporal lobe periventricular WMLs, and more restricted diffusivity lesions on MRI. Although the present study was limited by the small number of HDLS cases, we propose that immunotherapy should be avoided in such cases.


Assuntos
Encéfalo/patologia , Leucoencefalopatias/diagnóstico , Leucoencefalopatias/patologia , Esclerose Múltipla Crônica Progressiva/diagnóstico , Esclerose Múltipla Crônica Progressiva/patologia , Adulto , Atrofia , Encéfalo/diagnóstico por imagem , Corpo Caloso/diagnóstico por imagem , Corpo Caloso/patologia , Estudos Transversais , Feminino , Humanos , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Medula Espinal/patologia , Substância Branca/diagnóstico por imagem , Substância Branca/patologia
9.
Rinsho Shinkeigaku ; 59(3): 149-152, 2019 Mar 28.
Artigo em Japonês | MEDLINE | ID: mdl-30814449

RESUMO

A 73-year-old woman with Parkinson disease (PD) was admitted to our hospital because of aspiration pneumonia. She presented with recurrent episodes of loss of consciousness with bradycardia while swallowing solid foods or fluids. Upper endoscopy revealed a normal esophagus without hiatus hernia, cancer, diverticulum, stenosis, or achalasia. Balloon inflation at the cervical esophagus induced sinus arrest and bradycardia followed by a loss of consciousness. The diagnosis of swallow syncope (SS) was confirmed. Esophageal dilatation and an increase in the esophageal pressure induced by esophageal peristaltic disturbance associated with PD can cause SS by stimulating the vagal reflex. In addition, the head-up tilt test showed that she had orthostatic hypotension, and the coefficients of variations of the R-R intervals on electrocardiograms and the total number of beat-to-beat differences greater than 50 mseconds in the RR interval during a 24 hour ambulatory electrocardiogram were normal. The cardiovascular autonomic dysfunction characterized by the presence of sympathetic inhibition and a preserved parasympathetic function might be involved in the onset of SS. Permanent pacemaker implantation improved her clinical symptoms. The recognition of SS on the examination of a PD patient with loss of consciousness while eating is important, as PD patients might develop SS due to peristaltic disturbance and autonomic dysfunction caused by PD.


Assuntos
Transtornos de Deglutição/etiologia , Doença de Parkinson/complicações , Síncope/etiologia , Idoso , Doenças do Sistema Nervoso Autônomo/etiologia , Bradicardia/etiologia , Sistema Cardiovascular/inervação , Transtornos de Deglutição/diagnóstico , Eletrocardiografia , Feminino , Humanos , Marca-Passo Artificial , Pneumonia Aspirativa/etiologia , Recidiva , Reflexo , Síncope/diagnóstico , Síncope/terapia , Teste da Mesa Inclinada , Nervo Vago/fisiologia
10.
Int J Clin Oncol ; 24(4): 445-453, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30421023

RESUMO

BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.


Assuntos
Antineoplásicos/uso terapêutico , Mesilato de Imatinib/uso terapêutico , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Dasatinibe/uso terapêutico , Feminino , Humanos , Japão , Leucemia Mielogênica Crônica BCR-ABL Positiva/mortalidade , Leucemia Mielogênica Crônica BCR-ABL Positiva/patologia , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Tempo , Resultado do Tratamento , Suspensão de Tratamento
11.
Brain Dev ; 41(3): 280-284, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30384990

RESUMO

Dihydropyrimidinase deficiency is a rare autosomal recessive disease affecting the second step of pyrimidine degradation. It is caused by mutations in the DPYS gene. Only approximately 30 cases have been reported to date, with a phenotypical variability ranging from asymptomatic to severe neurological illness. We report a case of dihydropyrimidinase deficiency incidentally detected by urine metabolome analysis. Gas chromatography-mass spectrometry-based urine metabolomics demonstrated significant elevations of dihydrouracil and dihydrothymine, which were subsequently confirmed by a quantitative analysis using liquid chromatography-tandem mass spectrometry. Genetic testing of the DPYS gene revealed two mutations: a novel mutation (c.175G > T) and a previously reported mutation (c.1469G > A). Dihydropyrimidinase deficiency is probably underdiagnosed, considering its wide phenotypical variability, nonspecific neurological presentations, and an estimated prevalence of 2/20,000. As severe 5-fluorouracil-associated toxicity has been reported in patients and carriers of congenital pyrimidine metabolic disorders, urinary pyrimidine analysis should be considered for those who will undergo 5-fluorouracil treatment.


Assuntos
Erros Inatos do Metabolismo/complicações , Erros Inatos do Metabolismo/urina , Metaboloma , Erros Inatos do Metabolismo da Purina-Pirimidina/complicações , Adolescente , Cromatografia Líquida , Humanos , Espectrometria de Massas , Erros Inatos do Metabolismo/diagnóstico por imagem , Cãibra Muscular/etiologia , Condução Nervosa , Erros Inatos do Metabolismo da Purina-Pirimidina/diagnóstico por imagem , Erros Inatos do Metabolismo da Purina-Pirimidina/urina , Pirimidinas/urina
12.
J Immunol Res ; 2019: 5821589, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31930150

RESUMO

Amiselimod (MT-1303) is a novel and selective sphingosine 1-phosphate receptor-1 (S1P1) modulator with a more favorable cardiac safety profile than other S1P1 receptor modulators. In this study, we evaluated the effects of MT-1303 on the progression of lupus nephritis in two well-known murine systemic lupus erythematosus (SLE) models, MRL/lpr and NZBWF1 mice, compared with those of FK506. Daily oral doses of 0.1 and 0.3 mg/kg MT-1303 not only inhibited the development of lupus nephritis when administered before onset in MRL/lpr and NZBWF1 mice but also improved symptoms of lupus nephritis when administered after onset in MRL/lpr mice. Its efficacy in these models was more potent or comparable to that of FK506 (1 and 3 mg/kg). In histological analysis, treatment with MT-1303 inhibited infiltration of T cells into the kidneys, mesangial expansion, and glomerular sclerosis. MT-1303 treatment resulted in a marked reduction in T cells and B cells in the peripheral blood and significantly inhibited increases in the number of plasma cells in the spleen and T cells in the kidneys. In addition, administration of MT-1303 suppressed elevations in serum anti-dsDNA antibody levels in MRL/lpr mice, but not in NZBWF1 mice. Our findings show that MT-1303 exhibits marked therapeutic effects on lupus nephritis in two SLE models, likely by reducing the infiltration of autoreactive T cells into the kidneys. These results suggest that MT-1303 has the potential to be used as a therapeutic agent for patients suffering from SLE, including lupus nephritis.


Assuntos
Rim/efeitos dos fármacos , Nefrite Lúpica/tratamento farmacológico , Propanolaminas/uso terapêutico , Receptores de Esfingosina-1-Fosfato/efeitos dos fármacos , Animais , Anticorpos Antinucleares/sangue , Anticorpos Antinucleares/efeitos dos fármacos , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Modelos Animais de Doenças , Progressão da Doença , Feminino , Rim/citologia , Rim/imunologia , Rim/patologia , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Linfonodos/citologia , Linfonodos/efeitos dos fármacos , Masculino , Células Mesangiais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos MRL lpr , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Receptores de Esfingosina-1-Fosfato/metabolismo , Baço/citologia , Baço/efeitos dos fármacos , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia
13.
BJR Case Rep ; 4(1): 20170049, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30363166

RESUMO

Calcium pyrophosphate dihydrate (CPPD) crystal deposition disease is characterized by the accumulation of CPPD crystal in articular and periarticular tissues, but CPPD crystal deposition along the spinal dura mater has not been previously reported. We report a 54-year-old male presenting with progressive neck pain and numbness of the extremities. CT showed diffuse dorsal epidural calcification from C3-T6 which resulted in spinal canal stenosis. On MR imaging, the lesion was hypointense on both T 1 and T 2 weighted images. From these findings, CPPD crystal deposition in the ligamentum flavum was suspected preoperatively. Biopsy at the level of C5-6 were performed to confirm the diagnosis. Perioperative and histopathological findings revealed that CPPD crystals were deposited along the dorsal dura mater, not in the ligamentum flavum. We firstly report the CT and MR imaging features of a possible new concept in the differential diagnosis of CPPD crystal deposition disease.

14.
Expert Rev Neurother ; 18(12): 953-965, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30352532

RESUMO

INTRODUCTION: Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to autonomic failure. The disorder is associated with autoantibodies to the ganglionic nicotinic acetylcholine receptor (gAChR). We subsequently reported that AAG is associated with an overrepresentation of psychiatric symptoms, sensory disturbance, autoimmune diseases, and endocrine disorders. Area covered: The aim of this review was to describe AAG and highlight its pivotal pathophysiological aspects, clinical features, laboratory examinations, and therapeutic options. Expert commentary: AAG is a complex neuroimmunological disease, these days considered as an autonomic failure with extra-autonomic manifestations (and various limited forms). Further comprehension of the pathophysiology of this disease is required, especially the mechanisms of the extra-autonomic manifestations should be elucidated. There is the possibility that the co-presence of antibodies that were directed against the other subunits in both the central and peripheral nAChRs in the serum of the AAG patients. Some patients improve with immunotherapies such as IVIg and/or corticosteroid and/or plasma exchange. 123I-MIBG myocardial scintigraphy may be a useful tool to monitor the therapeutic effects of immunotherapies.


Assuntos
Doenças Autoimunes do Sistema Nervoso/diagnóstico , Doenças Autoimunes do Sistema Nervoso/terapia , Gânglios Autônomos/imunologia , 3-Iodobenzilguanidina , Corticosteroides/uso terapêutico , Autoanticorpos/sangue , Doenças Autoimunes do Sistema Nervoso/imunologia , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imagem de Perfusão do Miocárdio , Troca Plasmática , Compostos Radiofarmacêuticos , Receptores Nicotínicos/imunologia
15.
Cancer Sci ; 109(10): 3209-3215, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30007103

RESUMO

Although azacitidine is the first-line drug for higher-risk myelodysplastic syndrome (MDS) patients, its efficacy for lower-risk MDS remains unestablished. Therefore, we conducted a prospective study to examine the efficacy and safety of a 5-day regimen of azacitidine (AZA-5) for lower-risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower-risk MDS based on the French-American-British (FAB) classification (44 patients with refractory anemia [RA] and 7 patients with refractory anemia with ringed sideroblasts [RARS]) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51-88). These patients received AZA-5 (75 mg/m2 ; once daily for 5 sequential days). The median number of AZA-5 courses was 8 (range: 1-57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA-5 is feasible and effective for lower-risk MDS patients as well as for higher-risk MDS patients.


Assuntos
Anemia Refratária/tratamento farmacológico , Anemia Sideroblástica/tratamento farmacológico , Antimetabólitos Antineoplásicos/uso terapêutico , Azacitidina/uso terapêutico , Idoso , Idoso de 80 Anos ou mais , Anemia Refratária/sangue , Anemia Sideroblástica/sangue , Transfusão de Componentes Sanguíneos/estatística & dados numéricos , Esquema de Medicação , Estudos de Viabilidade , Neutropenia Febril/induzido quimicamente , Neutropenia Febril/epidemiologia , Feminino , Humanos , Japão/epidemiologia , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Trombocitopenia/induzido quimicamente , Trombocitopenia/epidemiologia , Resultado do Tratamento
16.
J Gastroenterol ; 53(12): 1227-1240, 2018 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29766276

RESUMO

BACKGROUND: The existence of several autoantibodies suggests an autoimmune basis for gastrointestinal (GI) dysmotility. Whether GI motility disorders are features of autoimmune autonomic ganglionopathy (AAG) or are related to circulating anti-ganglionic acetylcholine receptor (gAChR) antibodies (Abs) is not known. The aim of this study was to determine the associations between autonomic dysfunction, anti-gAChR Abs, and clinical features in patients with GI motility disorders including achalasia and chronic intestinal pseudo-obstruction (CIPO). METHODS: First study: retrospective cohort study and laboratory investigation. Samples from 123 patients with seropositive AAG were obtained between 2012 and 2017. Second study: prospective study. Samples from 28 patients with achalasia and 14 patients with CIPO were obtained between 2014 and 2016, and 2013 and 2017, respectively. In the first study, we analyzed clinical profiles of seropositive AAG patients. In the second study, we compared clinical profiles, autonomic symptoms, and results of antibody screening between seropositive, seronegative achalasia, and CIPO groups. RESULTS: In the first study, we identified 10 patients (8.1%) who presented with achalasia, or gastroparesis, or paralytic ileus. In the second study, we detected anti-gAChR Abs in 21.4% of the achalasia patients, and in 50.0% of the CIPO patients. Although patients with achalasia and CIPO demonstrated widespread autonomic dysfunction, bladder dysfunction was observed in the seropositive patients with CIPO as a prominent clinical characteristic of dysautonomia. CONCLUSIONS: These results demonstrate a significant prevalence of anti-gAChR antibodies in patients with achalasia and CIPO. Anti-gAChR Abs might mediate autonomic dysfunction, contributing to autoimmune mechanisms underlying these GI motility disorders.


Assuntos
Doenças Autoimunes/imunologia , Doenças do Sistema Nervoso Autônomo/imunologia , Gastroenteropatias/imunologia , Motilidade Gastrointestinal/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Doenças Autoimunes/fisiopatologia , Doenças do Sistema Nervoso Autônomo/fisiopatologia , Criança , Doença Crônica , Estudos de Coortes , Acalasia Esofágica/imunologia , Acalasia Esofágica/fisiopatologia , Feminino , Gânglios Autônomos/imunologia , Gastroenteropatias/fisiopatologia , Humanos , Pseudo-Obstrução Intestinal/imunologia , Pseudo-Obstrução Intestinal/fisiopatologia , Japão , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Receptores Colinérgicos/imunologia , Estudos Retrospectivos
17.
Ann Clin Transl Neurol ; 5(4): 486-492, 2018 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29687025

RESUMO

The aim of this study was to evaluate the association between postural orthostatic tachycardia syndrome (POTS) and circulating antiganglionic acetylcholine receptor (gAChR) antibodies. We reviewed clinical assessments of Japanese patients with POTS, and determined the presence of gAChR antibodies in serum samples from those patients. Luciferase immunoprecipitation systems detected anti-gAChR α3 and ß4 antibodies in the sera from POTS (29%). Antecedent infections were frequently reported in patients in POTS patients. Moreover, autoimmune markers and comorbid autoimmune diseases were also frequent in seropositive POTS patients. Anti-gAChR antibodies were detectable in significant number of patients with POTS, and POTS entailed the element of autoimmune basis.

18.
Mol Ther Methods Clin Dev ; 8: 131-140, 2018 Mar 16.
Artigo em Inglês | MEDLINE | ID: mdl-29687032

RESUMO

Adoptive T cell therapy using chimeric antigen receptor (CAR)-modified T cells is a promising cancer immunotherapy. We previously developed a non-viral method of gene transfer into T cells using a piggyBac transposon system to improve the cost-effectiveness of CAR-T cell therapy. Here, we have further improved our technology by a novel culture strategy to increase the transfection efficiency and to reduce the time of T cell manufacturing. Using a CH2CH3-free CD19-specific CAR transposon vector and combining irradiated activated T cells (ATCs) as feeder cells and virus-specific T cell receptor (TCR) stimulation, we achieved 51.4% ± 14% CAR+ T cells and 2.8-fold expansion after 14 culture days. Expanded CD19.CAR-T cells maintained a significant fraction of CD45RA+CCR7+ T cells and demonstrated potent antitumor activity against CD19+ leukemic cells both in vitro and in vivo. Therefore, piggyBac-based gene transfer may provide an alternative to viral gene transfer for CAR-T cell therapy.

19.
Cancer Med ; 7(6): 2269-2279, 2018 06.
Artigo em Inglês | MEDLINE | ID: mdl-29663729

RESUMO

We conducted data mining using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) database on spontaneously reported adverse events to evaluate the association between anticancer drug therapy and hepatitis B infection. Reports of hepatitis B infection were retrieved from the FAERS database. The reporting odds ratio (ROR) was used to estimate the association between hepatitis B infection and various anticancer agents and drug combinations. We detected statistically significant risk signals of hepatitis B for 33 of 64 anticancer agents by ROR (26 cytotoxicity drugs and seven molecular-targeted drugs). We focused on molecular-targeted drugs and assessed the risk of hepatitis B from specific anticancer drug combinations. The frequency of hepatitis B infection was significantly high for drugs such as rituximab, bortezomib, imatinib, and everolimus. The addition of cyclophosphamide, doxorubicin, and fludarabine to drug combinations additively enhanced the frequency of hepatitis B infection. There were no reports on hepatitis B infection associated with trastuzumab or azacitidine monotherapy. However, trastuzumab-containing regimens (e.g., combinations with docetaxel or paclitaxel) were correlated with the incidence of hepatitis B infection, similar to azacitidine monotherapy. Our findings suggest that the concomitant use of anticancer drugs, such as trastuzumab, taxane, and azacitidine, may contribute to the risk of hepatitis B infection. The unique signals detected from the public database might provide clues to eliminate the threat of HBV in oncology.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Hepatite B/etiologia , Neoplasias/complicações , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Hepatite B/patologia , Humanos , Estados Unidos , United States Food and Drug Administration
20.
Clin Lymphoma Myeloma Leuk ; 18(5): 353-360.e1, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29610029

RESUMO

INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.


Assuntos
Antineoplásicos/uso terapêutico , Dasatinibe/uso terapêutico , Desprescrições , Leucemia Mielogênica Crônica BCR-ABL Positiva/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Feminino , Seguimentos , Proteínas de Fusão bcr-abl/genética , Humanos , Leucemia Mielogênica Crônica BCR-ABL Positiva/sangue , Leucemia Mielogênica Crônica BCR-ABL Positiva/genética , Masculino , Pessoa de Meia-Idade , Recidiva , Indução de Remissão , Fatores de Risco , Resultado do Tratamento
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