RESUMO
Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.
Assuntos
Anticorpos Amplamente Neutralizantes/imunologia , Reações Cruzadas/imunologia , SARS-CoV-2/imunologia , Animais , Betacoronavirus/imunologia , Sítios de Ligação de Anticorpos , Anticorpos Amplamente Neutralizantes/química , Anticorpos Amplamente Neutralizantes/uso terapêutico , COVID-19/prevenção & controle , COVID-19/terapia , COVID-19/virologia , Cricetinae , Humanos , Switching de Imunoglobulina , Fragmentos Fab das Imunoglobulinas/química , Fragmentos Fab das Imunoglobulinas/metabolismo , Imunoglobulina G/química , Imunoglobulina G/imunologia , Camundongos , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/química , Glicoproteína da Espícula de Coronavírus/imunologia , Glicoproteína da Espícula de Coronavírus/metabolismoRESUMO
BACKGROUND: Arginine vasopressin deficiency (AVP-D) can occur due to various conditions, so clarifying its cause is important for deciding treatment strategy. Although several cases of AVP-D following coronavirus disease 2019(COVID-19) infection or COVID-19 vaccination have been reported, the diagnosis of the underlying disease has not been reported in most cases. CASE PRESENTATION: A 75-year-old woman who presented with polydipsia and polyuria 9 weeks after contracting COVID-19 and 5 weeks after receiving the SARS-CoV-2 vaccination, leading to the final diagnosis of AVP-D 8 months after the first appearance of symptoms. Interestingly, pituitary magnetic resonance imaging (MRI) still revealed stalk enlargement frequently observed in patients with SARS-CoV-2 vaccination-induced AVP-D. Although this finding could not rule out any malignancies, we additionally measured anti-rabphilin-3A antibodies, a known marker for lymphocytic infundibulo-neurohypophysitis (LINH), and found that the results were positive, strongly suggesting LINH as the cause of this disease. Thus, we avoided pituitary biopsy. At the follow-up MRI conducted 12 months after the initial consultation, enlargement of the pituitary stalk was still observed. CONCLUSION: We experienced a case with LINH probably induced by SARS-CoV-2 vaccination. In SARS-CoV-2 vaccination-related LINH, unlike typical LINH, there is a possibility of persistent pituitary stalk enlargement on MRI images for an extended period, posing challenges in differential diagnosis from other conditions. Pituitary stalk enlargement and positive anti-rabphilin-3A antibodies may help in the diagnosis of AVP-D induced by SARS-CoV-2 vaccination.
Assuntos
Vacinas contra COVID-19 , COVID-19 , Humanos , Feminino , Idoso , COVID-19/prevenção & controle , COVID-19/imunologia , COVID-19/complicações , Vacinas contra COVID-19/efeitos adversos , Proteínas Adaptadoras de Transdução de Sinal/imunologia , Arginina Vasopressina , SARS-CoV-2/imunologia , Vacinação/efeitos adversos , Autoanticorpos/sangue , Autoanticorpos/imunologia , Imageamento por Ressonância MagnéticaRESUMO
Lymphocytic hypophysitis (LYH) is a rare chronic inflammatory disease characterized by lymphocytic infiltration of the anterior or posterior pituitary gland and hypothalamus. LYH is subdivided into lymphocytic adenohypophysitis (LAH), lymphocytic infundibulo-neurohypophysitis (LINH), and lymphocytic panhypophysitis (LPH) depending on the primary site. Most cases occur in adults, with few cases reported in children, and it is especially important to distinguish LYH from suprasellar malignancies, such as germ cell tumors and other neoplastic diseases. Although a biopsy is necessary for definitive diagnosis, it is desirable to be able to diagnose the disease without biopsy if possible, especially in children, because of the surgical invasiveness of the procedure. Recently, serum anti-rabphilin-3A antibodies have attracted attention as diagnostic markers for LYH, especially in LINH, but there are only a few reports on pediatric patients. In the present study, we experienced two children with LPH and LAH, respectively, who tested positive for anti-rabphilin-3A antibodies. This is the first report of children with LYH other than LINH positive for anti-rabphilin-3A antibodies, and anti-rabphilin-3A antibodies may be a useful non-invasive diagnostic marker not only for LINH but also for LYH in general. We also discuss the sensitivity and specificity of anti-rabphilin-3A antibody testing in cases where histological diagnosis has been made.
Assuntos
Hipofisite Autoimune , Hipopituitarismo , Doenças da Hipófise , Neuro-Hipófise , Adulto , Humanos , Criança , Hipofisite Autoimune/complicações , Hipopituitarismo/complicações , Doenças da Hipófise/diagnósticoRESUMO
BACKGROUND: Follow-up care for adolescent childhood cancer survivors (ACCS) after they return to school requires an understanding of their psychosocial issues. Therefore, this study developed the adolescent childhood cancer survivors' psychosocial issues scale (ACCSPIS) and evaluated its reliability and validity. METHODS: In the development phase, pediatric oncology clinical professionals created the 24 item questionnaire of ACCS's psychosocial issues. In the feasibility phase, a survey was administered to 165 ACCS aged 12-18 years after discharge from hospital in Japan, and 57 completed questionnaires were analyzed. The survey items were psychosocial issues, attributes, K6 scale, and impact of event scale-revised (IES-R) scale. Factor analysis was conducted for psychosocial issues. Regarding reliability, Cronbach's α coefficients and item-total correlation coefficients were calculated. Regarding validity, Spearman's rank correlation coefficients between ACCSPIS and K6 and IES-R were calculated, and confirmatory factor analysis was conducted. RESULTS: Four factors comprising 15 items were extracted: "appearance changes due to treatment effects," "anxiety about marriage and the future," "change in appearance due to treatment", and "psychological distress due to interpersonal relationships and information about the disease." The model fit was good, with a total ACCSPIS α coefficient of 0.901 and α coefficients for the subscales ranging from 0.651 to 0.914. The K6 and IES-R were significantly associated with the total ACCSPIS, and item-total correlations were satisfactory. CONCLUSIONS: The reliability and validity of ACCSPIS were generally confirmed. This scale could be useful to measure psychosocial issues in ACCS aged 12-18 years after their return to school.
Assuntos
Sobreviventes de Câncer , Neoplasias , Humanos , Adolescente , Criança , Reprodutibilidade dos Testes , Neoplasias/terapia , Neoplasias/psicologia , Inquéritos e Questionários , Ansiedade , PsicometriaRESUMO
BACKGROUND: The appropriate timing of introducing the home-based nursing service to patients with advanced cancer has not been clarified. This study conducted a retrospective cohort study to investigate the associations of the early utilization of the home-based nursing service during chemotherapy with the place of care immediately after the last chemotherapy treatment in patients with advanced cancer. METHODS: Among the patients referred to the palliative care team of the University of Tsukuba Hospital between January 2018 and December 2019, patients with advanced cancer undergoing chemotherapy or before the start of chemotherapy at referral were included. The study patients who utilized the home-based nursing service during chemotherapy were classified into the early utilization group. The primary endpoint was the place of care immediately after the last chemotherapy treatment. RESULTS: Of the 1154 patients referred to the palliative care team during the study period, 261 were eligible for this study. Of these patients, 15.3% of patients (n = 40) received the home-based nursing service during chemotherapy. The proportion of patients transferred to home care after the last chemotherapy treatment was 17.5% in the early utilization group and 7.2% in the control group. The multivariate analysis revealed that the early utilization of the home-based nursing service during chemotherapy was significantly associated with the transfer to home care (odds ratio = 3.077; 95% confidence interval, 1.113-8.502). CONCLUSION: The early utilization of the home-based nursing service during chemotherapy might be associated with the transfer to home care immediately after the last chemotherapy treatment.
Assuntos
Serviços de Assistência Domiciliar , Neoplasias , Assistência Terminal , Humanos , Neoplasias/tratamento farmacológico , Cuidados Paliativos , Estudos RetrospectivosRESUMO
PURPOSE: To explore the clinical significance of anti-rabphillin-3A antibody for the differential diagnosis of lymphocytic panhypophysitis. METHODS AND RESULTS: A 58-year-old Japanese man developed uveitis of unknown cause in 2017. In 2019, he became aware of polyuria. In August 2020, he noticed transient diplopia and was diagnosed with right abducens nerve palsy. At the same time, he complained of fatigue and loss of appetite. Head magnetic resonance imaging demonstrated enlargement of the pituitary stalk and pituitary gland, corresponding to hypophysitis. Hormone stimulation tests showed blunted responses with respect to all anterior pituitary hormones. Central diabetes insipidus was diagnosed on the basis of a hypertonic saline loading test. Taking these findings together, a diagnosis of panhypopituitarism was made. Computed tomography showed enlargement of hilar lymph nodes. Biopsies of the hilar lymph nodes revealed non-caseating epithelioid cell granulomas that were consistent with sarcoidosis. Biopsy of the anterior pituitary revealed mild lymphocyte infiltration in the absence of IgG4-positive cells, non-caseating granulomas, or neoplasia. Western blotting revealed the presence of anti-rabphilin-3A antibody, supporting a diagnosis of lymphocytic panhypophysitis. Because the patient had no visual impairment or severe uveitis, we continued physiological hormone replacement therapy and topical steroid therapy for the uveitis. CONCLUSION: To the best of our knowledge, this is the first case of anti-rabphilin 3A antibody positive lymphocytic panhypophysitis comorbid with sarcoidosis, diagnosed by both pituitary and hilar lymph node biopsy. The utility of anti-rabphilin-3A antibody for the differential diagnosis of hypophysitis like this case should be clarified with further case studies.
Assuntos
Hipofisite Autoimune , Diabetes Insípido Neurogênico , Hipopituitarismo , Sarcoidose Pulmonar , Sarcoidose , Hipofisite Autoimune/diagnóstico , Hipofisite Autoimune/tratamento farmacológico , Diabetes Insípido Neurogênico/diagnóstico , Humanos , Hipopituitarismo/diagnóstico , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Sarcoidose/complicações , Sarcoidose/tratamento farmacológico , Sarcoidose/patologia , Sarcoidose Pulmonar/complicações , Sarcoidose Pulmonar/patologiaRESUMO
BACKGROUND: It is imperative that a team consisting of a physician, pharmacist, and nursing professional provides pharmacotherapy support to achieve the optimal effect of pharmacotherapy for older adults with dementia. This study reviewed Japanese publications on the process of pharmacotherapy support practised by various professionals for home-based older adults with dementia and investigated healthcare professionals' perceived importance and practice of pharmacotherapy support. METHODS: This study aimed to shed light on basic pharmacotherapy support for behavioural and psychological symptoms among home-based older adults with dementia using multidisciplinary collaboration, through a literature review of Japanese publications. Based on the literature review, 13 items pertaining to basic pharmacotherapy support for home-based older adults with dementia were extracted. A mail-based, self-administered, anonymous questionnaire survey was conducted with professionals including physicians, pharmacists, and nursing professionals who provide pharmacotherapy support to home-based older adults with dementia. Participants rated 13 items on their perceived importance and practice of basic pharmacotherapy support using a four-point Likert scale. RESULTS: The results indicated that participants recognised the importance of all 13 items. At least 80% of all professionals indicated that they practised seven out of 13 items. Less than 80% of all professionals indicated they practised the other six items that should be provided after the commencement of pharmacotherapy. A relatively high proportion of nursing professionals (70%) indicated they practised the remaining six items. The 13 items were indeed deemed important for characterising pharmacotherapy support. However, in Japan, suboptimal support is provided following the commencement of medication. This may be because appropriate modifications to dementia care are not made as the patient's condition progresses. CONCLUSIONS: It is suggested that multidisciplinary collaboration focusing on the progression of dementia and the process of pharmacotherapy, especially after the commencement of pharmacotherapy, may help provide effective, continuous pharmacotherapy.
Assuntos
Demência , Médicos , Idoso , Demência/tratamento farmacológico , Humanos , Japão , Farmacêuticos , Inquéritos e QuestionáriosRESUMO
Autoimmune hypophysitis (AH) is thought to be an autoimmune disease characterized by lymphocytic infiltration of the pituitary gland. Among AH pathologies, lymphocytic infundibulo-neurohypophysitis (LINH) involves infiltration of the neurohypophysis and/or the hypothalamic infundibulum, causing central diabetes insipidus resulting from insufficiency of arginine vasopressin secretion. The pathophysiological and pathogenetic mechanisms underlying LINH are largely unknown. Clinically, differentiating LINH from other pituitary diseases accompanied by mass lesions, including tumours, has often been difficult, because of similar clinical manifestations. We recently reported that rabphilin-3A is an autoantigen and that anti-rabphilin-3A antibodies constitute a possible diagnostic marker for LINH. However, the involvement of rabphilin-3A in the pathogenesis of LINH remains to be elucidated. This study was undertaken to explore the role of rabphilin-3A in lymphocytic neurohypophysitis and to investigate the mechanism. We found that immunization of mice with rabphilin-3A led to neurohypophysitis. Lymphocytic infiltration was observed in the neurohypophysis and supraoptic nucleus 1 month after the first immunization. Mice immunized with rabphilin-3A showed an increase in the volume of urine that was hypotonic as compared with control mice. Administration of a cocktail of monoclonal anti-rabphilin-3A antibodies did not induce neurohypophysitis. However, abatacept, which is a chimeric protein that suppresses T-cell activation, decreased the number of T cells specific for rabphilin-3A in peripheral blood mononuclear cells (PBMCs). It ameliorated lymphocytic infiltration of CD3+ T cells in the neurohypophysis of mice that had been immunized with rabphilin-3A. Additionally, there was a linear association between the number of T cells specific for rabphilin-3A in PBMCs and the number of CD3+ T cells infiltrating the neurohypophysis. In conclusion, we suggest that rabphilin-3A is a pathogenic antigen, and that T cells specific for rabphilin-3A are involved in the pathogenesis of neurohypophysitis in mice. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Hipofisite Autoimune/induzido quimicamente , Autoimunidade , Proteínas do Tecido Nervoso , Neuro-Hipófise/metabolismo , Proteínas de Transporte Vesicular , Abatacepte/administração & dosagem , Animais , Anticorpos Monoclonais/administração & dosagem , Hipofisite Autoimune/imunologia , Hipofisite Autoimune/metabolismo , Hipofisite Autoimune/prevenção & controle , Autoimunidade/efeitos dos fármacos , Modelos Animais de Doenças , Feminino , Imunossupressores/administração & dosagem , Camundongos , Neuro-Hipófise/efeitos dos fármacos , Neuro-Hipófise/imunologia , Neuro-Hipófise/patologia , Núcleo Supraóptico/imunologia , Núcleo Supraóptico/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Micção , Rabfilina-3ARESUMO
The molecular mechanism involved in the exocytosis of arginine vasopressin (AVP) is not fully known. Rabphilin-3A has been suggested as a novel autoantigen in infundibulo-neurohypophysitis (LINH), which leads to central diabetes insipidus through insufficient secretion of AVP. However, the role of rabphilin-3A in the pathogenesis of LINH remains unclear. Thus, the aim of the present study was to identify proteins binding rabphilin-3A in the posterior pituitary. Using glutathione S-transferase (GST)-pulldown assays and proteomic analyses, cullin-associated NEDD8-dissociated protein 1 (CAND1) was identified as a rabphilin-3A-binding protein in the posterior pituitary. Co-immunoprecipitation assays indicated that CAND1 interacted endogenously with rabphilin-3A. In addition, immunohistochemistry experiments showed that CAND1 immunoreactivity was detected mainly in the posterior pituitary, intermediate lobe, and the supraoptic nucleus in the hypothalamus, and less in the anterior lobe, partially co-localizing with rabphilin-3A. Overexpression of CAND1 resulted in deubiquitylation of rabphilin-3A in PC12 cells. Moreover, overexpression of CAND1 in PC12 cells co-transfected with AVP enhanced both basal and KCl-stimulated AVP secretion. The findings indicate that CAND1 inhibits the ubiquitylation of rabphilin-3A and positively regulates AVP secretion. These data shed light on a novel potential mechanism involving rabphilin-3A in AVP secretion, and suggest a new role of CAND1 as a regulator of hormone or neurotransmitter secretion.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Arginina Vasopressina/metabolismo , Enzimas Desubiquitinantes/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Neuro-Hipófise/metabolismo , Fatores de Transcrição/metabolismo , Proteínas de Transporte Vesicular/metabolismo , Animais , Enzimas Desubiquitinantes/genética , Células PC12 , Ratos , Ratos Sprague-Dawley , Fatores de Transcrição/genética , Rabfilina-3ARESUMO
PURPOSE: IgG4-related disease is a systemic inflammatory disease characterized by infiltration of IgG4-positive plasma cells into multiple organs, including the pituitary gland. Autoimmunity is thought to be involved in the pathogenesis of IgG4-related disease. The diagnosis of IgG4-related hypophysitis (IgG4-RH) is difficult because its clinical features, such as pituitary swelling and hypopituitarism, are similar to those of other pituitary diseases, including lymphocytic hypophysitis and sellar/suprasellar tumors. The presence and significance of anti-pituitary antibodies (APA) in IgG4-RH is unclear. METHODS: In this case-control study, we used single indirect immunofluorescence on human pituitary substrates to assess the prevalence of serum APA in 17 patients with IgG4-RH, 8 control patients with other pituitary diseases (lymphocytic infundibulo-neurohypophysitis, 3; craniopharyngioma, 2; germinoma, 3), and 9 healthy subjects. We further analyzed the endocrine cells targeted by the antibodies using double indirect immunofluorescence. RESULTS: APA were found in 5 of 17 patients with IgG4-RH (29%), and in none of the pituitary controls or healthy subjects. The endocrine cells targeted by the antibodies in the 5 IgG4-RH cases were exclusively corticotrophs. Antibodies were of the IgG1 subclass, rather than IgG4, in all 5 cases, suggesting that IgG4 is not directly involved in the pathogenesis. Finally, antibodies recognized pro-opiomelanocortin in 2 of the cases. CONCLUSIONS: Our study suggests that autoimmunity is involved in the pathogenesis of IgG4-RH and that corticotrophs are the main antigenic target, highlighting a possible new diagnostic marker for this condition.
Assuntos
Anticorpos/uso terapêutico , Hipofisite Autoimune/tratamento farmacológico , Hipofisite Autoimune/imunologia , Corticotrofos/imunologia , Imunoglobulina G/metabolismo , Doenças da Hipófise/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Casos e Controles , Hormônio Liberador da Corticotropina/sangue , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Hormônio Liberador de Hormônio do Crescimento/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Doenças da Hipófise/tratamento farmacológico , Hipófise/efeitos dos fármacos , Hipófise/imunologia , Hormônio Liberador de Tireotropina/sangue , Adulto JovemRESUMO
Isolated adrenocorticotropin deficiency (IAD) is characterized by low or absent adrenocorticotropic hormone (ACTH) production. IAD is presumed to be caused in part by an autoimmune mechanism, and several lines of evidence have suggested the presence of anti-pituitary antibodies in IAD. However, the exact autoantigens remain unknown. The present study was designed to identify the autoantigen(s) in IAD using chromatography-tandem mass spectrometry (LC-MS/MS) analysis. Rat anterior pituitary lysate was subjected to SDS-PAGE, and immunoblotting was performed using the sera from two patients with IAD and from a healthy subject. The bands detected by the patient serum samples, but not by the healthy subject sample, were excised, in-gel digested using trypsin, and subjected to LC-MS/MS analysis. On immunoblots, a 51-kDa band in the insoluble pellet was detected by the sera from the IAD patients but not from the healthy subject. Mass spectrometric analysis revealed the 51-kDa band contained Rab guanine nucleotide dissociation inhibitor (GDI) alpha. Consistent with the mass spectrometric analysis, a recombinant full-length human Rab GDI alpha was recognized by the two IAD patient samples but not by the healthy subject sample using immunoblotting. In total, anti-Rab GDI alpha antibodies were detected in serum samples from three of five patients with IAD (60%) but were absent in 5 healthy subjects. In addition, Rab GDI alpha was expressed in the anterior pituitary. In conclusion, it appears that Rab GDI alpha is a candidate autoantigen involved in IAD, and that anti-Rab GDI alpha antibodies are present predominantly in patients with IAD.
Assuntos
Hormônio Adrenocorticotrópico/deficiência , Autoanticorpos/análise , Autoantígenos/metabolismo , Doenças Autoimunes/metabolismo , Autoimunidade , Doenças do Sistema Endócrino/metabolismo , Doenças Genéticas Inatas/metabolismo , Inibidores de Dissociação do Nucleotídeo Guanina/metabolismo , Hipoglicemia/metabolismo , Adeno-Hipófise/metabolismo , Hormônio Adrenocorticotrópico/sangue , Hormônio Adrenocorticotrópico/imunologia , Hormônio Adrenocorticotrópico/metabolismo , Adulto , Idoso , Animais , Especificidade de Anticorpos , Autoantígenos/química , Autoantígenos/genética , Doenças Autoimunes/sangue , Doenças Autoimunes/imunologia , Doenças do Sistema Endócrino/sangue , Doenças do Sistema Endócrino/imunologia , Feminino , Doenças Genéticas Inatas/sangue , Doenças Genéticas Inatas/imunologia , Inibidores de Dissociação do Nucleotídeo Guanina/química , Inibidores de Dissociação do Nucleotídeo Guanina/genética , Humanos , Hipoglicemia/sangue , Hipoglicemia/imunologia , Japão , Masculino , Pessoa de Meia-Idade , Peso Molecular , Mapeamento de Peptídeos , Adeno-Hipófise/imunologia , Ratos Sprague-Dawley , Proteínas Recombinantes/química , Proteínas Recombinantes/metabolismo , Homologia de Sequência de Aminoácidos , Organismos Livres de Patógenos EspecíficosRESUMO
Signs and symptoms of hypernatremia largely indicate central nervous system dysfunction. Acute hypernatremia can cause demyelinating lesions similar to that observed in osmotic demyelination syndrome (ODS). We have previously demonstrated that microglia accumulate in ODS lesions and minocycline protects against ODS by inhibiting microglial activation. However, the direct effect of rapid rise in the sodium concentrations on microglia is largely unknown. In addition, the effect of chronic hypernatremia on microglia also remains elusive. Here, we investigated the effects of acute (6 or 24â¯h) and chronic (the extracellular sodium concentration was increased gradually for at least 7 days) high sodium concentrations on microglia using the microglial cell line, BV-2. We found that both acute and chronic high sodium concentrations increase NOS2 expression and nitric oxide (NO) production. We also demonstrated that the expression of nuclear factor of activated T-cells-5 (NFAT5) is increased by high sodium concentrations. Furthermore, NFAT5 knockdown suppressed NOS2 expression and NO production. We also demonstrated that high sodium concentrations decreased intracellular Ca2+ concentration and an inhibitor of Na+/Ca2+ exchanger, NCX, suppressed a decrease in intracellular Ca2+ concentrations and NOS2 expression and NO production induced by high sodium concentrations. Furthermore, minocycline inhibited NOS2 expression and NO production induced by high sodium concentrations. These in vitro data suggest that microglial activity in response to high sodium concentrations is regulated by NFAT5 and Ca2+ efflux through NCX and is suppressed by minocycline.
Assuntos
Hipernatremia , Microglia , Minociclina , Óxido Nítrico Sintase Tipo II , Óxido Nítrico , Microglia/metabolismo , Microglia/efeitos dos fármacos , Animais , Óxido Nítrico/metabolismo , Hipernatremia/metabolismo , Hipernatremia/patologia , Hipernatremia/genética , Minociclina/farmacologia , Camundongos , Óxido Nítrico Sintase Tipo II/metabolismo , Óxido Nítrico Sintase Tipo II/genética , Sódio/metabolismo , Linhagem Celular , Cálcio/metabolismo , Trocador de Sódio e Cálcio/metabolismo , Trocador de Sódio e Cálcio/genética , Fatores de Transcrição NFATC/metabolismo , Fatores de Transcrição NFATC/genéticaRESUMO
Background: Gestational diabetes insipidus (DI) is a very rare complication of pregnancy. We present a case of gestational DI combining two different types of DI. Case Presentation. A 39-year-old pregnant woman suddenly presented with thirst, polydipsia, and polyuria after 31 gestation weeks (GWs). Based on laboratory findings of hypotonic urine (78 mOsm/kgH2O) with higher plasma osmolality (298 mOsm/kgH2O) and higher serum sodium levels (149 mEq/L), gestational DI was suspected, and the clinical course was monitored without therapy until the results of a measurement of plasma arginine vasopressin (AVP) levels were available. However, she subsequently developed acute prerenal failure and underwent an emergency cesarean section at 34 GWs. Her resected placenta weighed 920 g, nearly twice the normal weight. Immediately following delivery, intranasal 1-desamino-8-D-arginine vasopressin was administered, and her symptoms promptly disappeared. Afterward, her predelivery plasma AVP level was found to have been inappropriately low (0.7 pg/mL) given her serum sodium level. The patient's serum vasopressinase level just before delivery was 2,855 ng/mL, more than 1,000 times the upper limit of the normal range, suggesting excess vasopressinase-induced DI. The presence of anti-rabphilin-3A antibodies in the patient's blood, a hypertonic saline infusion test result, and loss of the high-intensity signal of the posterior pituitary on fat-suppressed T1-weighted magnetic resonance images without thickening of the stalk and enlargement of the neurohypophysis suggested concurrent central DI-like lymphocytic infundibulo-neurohypophysitis (LINH). Conclusion: In addition to the degradation of AVP by excess placental vasopressinase due to the enlarged placenta, an insufficient compensatory increase in AVP secretion from the posterior pituitary gland due to LINH-like pathogenesis might have led to DI symptoms.
RESUMO
Hyponatremia is the most common clinical electrolyte disorder. Chronic hyponatremia has been recently reported to be associated with falls, fracture, osteoporosis, neurocognitive impairment, and mental manifestations. In the treatment of chronic hyponatremia, overly rapid correction of hyponatremia can cause osmotic demyelination syndrome (ODS), a central demyelinating disease that is also associated with neurological morbidity and mortality. Using a rat model, we have previously shown that microglia play a critical role in the pathogenesis of ODS. However, the direct effect of rapid correction of hyponatremia on microglia is unknown. Furthermore, the effect of chronic hyponatremia on microglia remains elusive. Using microglial cell lines BV-2 and 6-3, we show here that low extracellular sodium concentrations (36 mmol/L decrease; LS) suppress Nos2 mRNA expression and nitric oxide (NO) production of microglia. On rapid correction of low sodium concentrations, NO production was significantly increased in both cells, suggesting that acute correction of hyponatremia partly directly contributes to increased Nos2 mRNA expression and NO release in ODS pathophysiology. LS also suppressed expression and nuclear translocation of nuclear factor of activated T cells-5 (NFAT5), a transcription factor that regulates the expression of genes involved in osmotic stress. Furthermore, overexpression of NFAT5 significantly increased Nos2 mRNA expression and NO production in BV-2 cells. Expressions of Nos2 and Nfat5 mRNA were also modulated in microglia isolated from cerebral cortex in chronic hyponatremia model mice. These data indicate that LS modulates microglial NO production dependent on NFAT5 and suggest that microglia contribute to hyponatremia-induced neuronal dysfunctions.
RESUMO
Maintenance of an appropriate magnesium ion (Mg(2+)) concentration is essential for plant growth. In Arabidopsis thaliana, the CorA-MRS2-ALR-type proteins, named MRS2/MGT family proteins, are reportedly localized in various membranes and they function in Mg transport. However, knowledge of this family in other plant species is extremely limited. Furthermore, differential diversification among dicot and monocot plants suggested by phylogenetic analysis indicates that the role of the Arabidopsis MRS2/MGT family proteins is not the same in monocot plants. For a further understanding of this family in higher plants, functional analysis and gene expression profiling of rice MRS2/MGT family members were performed. A phylogenetic tree based on the isolated mRNA sequences of nine members of the OsMRS2 family confirmed that the MRS2/MGT family consists of five clades (A-E). A complementation assay in the yeast CM66 strain showed that four of the nine members possessed the Mg(2+) transport ability. Transient green fluorescent protein (GFP) expression in the isolated rice protoplast indicated that OsMRS2-5 and OsMRS2-6, belonging to clades D and A, respectively, localized in the chloroplast. Expression levels of these genes were low in the unexpanded yellow-green leaf, but increased considerably with leaf maturation. In addition, diurnal oscillation of expression was observed, particularly in OsMRS2-6 expression in the expanded leaf blade. We conclude that OsMRS2 family members function as Mg transporters and suggest that the genes belonging to clade A encode the chloroplast-localized Mg(2+) transporter in plants.
Assuntos
Proteínas de Transporte de Cátions/genética , Regulação da Expressão Gênica de Plantas , Magnésio/metabolismo , Oryza/genética , Proteínas de Plantas/genética , Sequência de Aminoácidos , Sequência de Bases , Proteínas de Transporte de Cátions/classificação , Proteínas de Transporte de Cátions/metabolismo , Cloroplastos/metabolismo , Teste de Complementação Genética , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Microscopia Confocal , Dados de Sequência Molecular , Família Multigênica , Mutação , Oryza/metabolismo , Filogenia , Proteínas de Plantas/classificação , Proteínas de Plantas/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Protoplastos/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , Fatores de TempoAssuntos
Relógios Biológicos , Digestão , Motilidade Gastrointestinal , Células Intersticiais de Cajal/fisiologia , Intestino Delgado/fisiologia , Potenciais da Membrana , Músculo Liso/fisiologia , Animais , Comunicação Celular , Eletrofisiologia/instrumentação , Intestino Delgado/citologia , Camundongos , Microeletrodos , Modelos Animais , Músculo Liso/citologia , Fatores de TempoRESUMO
Magnesium (Mg) is an essential macronutrient supporting various functions, including photosynthesis. However, the specific physiological responses to Mg deficiency remain elusive. In this study, 2-week-old rice seedlings (Oryza sativa. cv. Nipponbare) with three expanded leaves (L2-L4) were transferred to Mg-free nutrient solution for 8 days. In the absence of Mg, on day 8, L5 and L6 were completely developed, while L7 just emerged. We also studied several mineral deficiencies to identify specific responses to Mg deficiency. Each leaf was analyzed in terms of chlorophyll, starch, anthocyanin and carbohydrate metabolites, and only absence of Mg was found to cause irreversible senescence of L5. Resupply of Mg at various time points confirmed that the borderline of L5 death was between days 6 and 7 of Mg deficiency treatment. Decrease in chlorophyll concentration and starch accumulation occurred simultaneously in L5 and L6 blades on day 8. However, nutrient transport drastically decreased in L5 as early as day 6. These data suggest that the predominant response to Mg deficiency is a defect in transpiration flow. Furthermore, changes in myo-inositol and citrate concentrations were detected only in L5 when transpiration decreased, suggesting that they may constitute new biological markers of Mg deficiency.
Assuntos
Metabolismo dos Carboidratos , Magnésio/metabolismo , Oryza/fisiologia , Doenças das Plantas , Folhas de Planta/crescimento & desenvolvimento , Transpiração Vegetal/fisiologia , Antocianinas/metabolismo , Biomassa , Metabolismo dos Carboidratos/efeitos dos fármacos , Clorofila/metabolismo , Magnésio/farmacologia , Oryza/efeitos dos fármacos , Fósforo/metabolismo , Fotossíntese/efeitos dos fármacos , Folhas de Planta/efeitos dos fármacos , Folhas de Planta/metabolismo , Raízes de Plantas/efeitos dos fármacos , Raízes de Plantas/crescimento & desenvolvimento , Brotos de Planta/efeitos dos fármacos , Brotos de Planta/fisiologia , Transpiração Vegetal/efeitos dos fármacos , Plântula/efeitos dos fármacos , Plântula/metabolismo , Solubilidade , Amido/metabolismoRESUMO
Childhood-onset lymphocytic infundibuloneurohypophysitis (LINH) has rarely been reported. Pathological evaluation via pituitary biopsy is necessary for a definitive diagnosis of LINH. However, pituitary biopsy is a highly invasive procedure. Recently, anti-rabphilin-3A antibody (RPH3A-Ab) has been reported as a promising diagnostic marker for LINH in adults; however, there are few such reports in the pediatric population. We report the case of an 8-year-old boy with central diabetes insipidus (CDI) who was clinically diagnosed with LINH based on RPH3A-Ab positivity. He was diagnosed with CDI using a water deprivation test combined with desmopressin administration. Serum and cerebrospinal fluid tumor markers were negative, and T1-weighted magnetic resonance imaging (MRI) revealed the absence of high signal intensity in the posterior pituitary gland and an enlarged pituitary stalk. Anterior pituitary function tests revealed no abnormalities. No pituitary biopsy was performed because of its invasive nature, and desmopressin treatment was initiated. Three months after CDI onset, the patient tested positive for RPH3A-Ab. MRI performed 9 months after CDI onset revealed amelioration of the pituitary stalk enlargement, and the clinical course corroborated our diagnosis of LINH. RPH3A-Ab may be useful as an early diagnostic tool for LINH in the pediatric population.
RESUMO
A 36-year-old female was pointed out to have liver enzyme elevation by routine health checkup. Subsequent contrast-enhanced CT scan identified gigantic uterine fibroids and retroperitoneal tumor. She was referred to the gynecologist at JA Toride Medical Center and planned to undergo a uterus enucleation and biopsy of the retroperitoneal tumor. The surgery was conducted without any troubles. After the surgery, the patient presented polyuria with urine volume 10-20 L a day and developed hypovolemic shock. Laboratory test revealed hypotonic urine and hypernatremia. Arginine vasopressin (AVP) loading test suggested shortage of endogenous vasopressin. Since the subcutaneous administration of AVP was not sufficient to control the urine volume, continuous intravenous infusion of AVP was initiated. After achieving hemodynamic stability, the treatment was switched to oral desmopressin. MRI finding indicated attenuation of high signal in posterior pituitary in T1 weighted image while neither enlargement of pituitary nor thickening of pituitary stalk was indicated by enhanced MRI. Hypertonic salt solution test indicated no responsive elevation of AVP, confirming the diagnosis of central diabetes insipidus (CDI). Her anterior pituitary function was preserved. Only anti-rabphilin-3A antibody was found positive in the serum of the patient, while other secondary causes for CDI were denied serologically and radiologically. Hence, lymphocytic infundibuloneurohypophysitisã(LINH) was suspected as the final diagnosis. Hormonal replacement therapy by nasal desmopressin was continued and the patient managed to control her urine volume. In cases of CDI considered idiopathic with conventional examinations, anti-rabphilin-3A antibody may be a clue for determining the cause as LINH.
Assuntos
Diabetes Insípido Neurogênico , Diabetes Mellitus , Neoplasias Retroperitoneais , Feminino , Humanos , Adulto , Diabetes Insípido Neurogênico/diagnóstico , Diabetes Insípido Neurogênico/tratamento farmacológico , Diabetes Insípido Neurogênico/etiologia , Desamino Arginina Vasopressina/uso terapêutico , Neoplasias Retroperitoneais/complicaçõesRESUMO
BACKGROUND: Families raising children with disabilities assume risks to their health and lives. Therefore, it is necessary to support these families to improve family empowerment, which is the ability of these families to control their own lives and to promote the collaborative raising of children with disabilities. This is the first online intervention program focusing on the empowerment of families raising children with disabilities who live at home in Japan. METHOD: The program consists of four online peer-based group sessions. Moreover, the families engage in several activities in stages wherein they discover their own issues, find measures to resolve them, and take action, while visualizing interfamily relationships, including social resources, and the status of their family life, with facilitators and other peer members. This study is a non-randomized, waitlist-controlled trial. It compares the results of the intervention group (early group) and the waitlist-controlled group (delayed group). The participants are allocated to the early or delayed group in the order of their applications. The main outcome is family empowerment. Other outcomes are the caregiver burden, self-reported capability to use social resources, self-compassion, and the quality of life (QOL) of primary caregivers. The timeline of the online outcome evaluation is as follows: the initial evaluation (Time 1 [T1]) is conducted before the start of the first early group program, and post-intervention evaluation (Time 2 [T2]) is conducted immediately (within 1 week) after the early group completes all four sessions (4 weeks) of the program. Follow-up evaluation (Time 3 [T3]) is conducted 4 weeks after the post-intervention evaluation. This timing is the same in the delayed group, but the delayed group will attend the program after a 4-week waiting period, compared to the early group. DISCUSSION: The intention is to evaluate whether the provision of the program developed in this study and the evaluation test design are feasible and to verify the efficacy of this program. TRIAL REGISTRATION: The UMIN Clinical Trials Registry (UMIN000044172), registration date: May 19, 2021.