RESUMEN
Purpose: To identify molecular signatures specific for ocular graft-versus-host disease (GVHD) by proteomic analysis of corneas from mice with GVHD. Methods: We identified differentially expressed proteins (DEPs) in corneal samples from GVHD model mice and syngeneic control mice 4 weeks after bone marrow transplantation. Data-independent acquisition analysis was performed on individual samples, and the roles of DEPs in biological pathways related to GVHD were evaluated via bioinformatics and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Results: Three important signaling pathways were upregulated in the cornea in mice with GVHD: (1) the necroptosis pathway, (2) the mitogen-activated protein kinase (MAPK) pathway, and (3) as previously reported, the neutrophil extracellular trap (NET) pathway. In those signaling pathways, we identified new upregulated molecules, including (1) receptor-interacting protein kinase 1 (RIPK1), RIPK3, interferon regulatory factor 9, the interferon-induced double-stranded RNA-activated protein kinase lipoxygenase, and high mobility group box1 (HMGB1) which are damage-associated molecular patterns (DAMPs) in the necroptosis pathway; (2) the sequentially upregulated interleukin 1 (IL-1) receptor-associated kinase (IRAK), an evolutionarily conserved signaling intermediate in the Toll pathway (ECSIT), and p38, which is downstream of the IL-1 receptor and increased CDC42/Rac (Rac2), a Rho family GTPase in the MAPK pathway; and (3) the integrin components CR3 and macrophage-1 antigen (MAC-1), which are DAMPs, and the pyroptosis-related protein gasdermin D (GSDMD) in the NET pathway. Conclusions: These novel molecules may help researchers elucidate the pathogenesis of GVHD and identify new therapeutic targets for corneal changes in patients with ocular GVHD.
Asunto(s)
Córnea , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped , Ratones Endogámicos C57BL , Necroptosis , Proteómica , Transducción de Señal , Regulación hacia Arriba , Animales , Ratones , Necroptosis/fisiología , Enfermedad Injerto contra Huésped/metabolismo , Córnea/metabolismo , Córnea/patología , Transducción de Señal/fisiología , Femenino , Trasplante de Médula ÓseaRESUMEN
Although dietary potassium restriction is an acceptable approach to hyperkalemia prevention, it may be insufficient for outpatients with chronic kidney disease (CKD). Most outpatients with CKD use community pharmacies owing to the free access scheme in Japan. The MieYaku-CKD project included a community pharmacist-led nutritional intervention for dietary potassium restriction, with the goal of determining its efficacy for patients' awareness of potassium restriction and serum potassium levels in outpatients with CKD. This was a five-community pharmacy multicenter prospective cohort study with an open-label, before-and-after comparison design. Eligible patients (n = 25) with an estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73 m2 received nutritional guidance from community pharmacists. The primary outcome was a change in serum potassium levels at 12 weeks post-intervention. The eligible patients' knowledge, awareness, and implementation of potassium restriction were evaluated using a questionnaire. The median value of serum potassium was significantly reduced from 4.7 mEq/L before to 4.4 mEq/L after the intervention [p < 0.001, 95% confidence interval (CI): 0.156-0.500], with no changes in eGFR (p = 0.563, 95% CI: -2.427-2.555) and blood urine nitrogen/serum creatinine ratio (p = 0.904, 95% CI: -1.793-1.214). The value of serum potassium had a tendency of attenuation from 5.3 to 4.6 mEq/L (p = 0.046, 95% CI: 0.272-1.114) in the eGFR < 30 mL/min/1.73 m2 group. A questionnaire revealed that after the intervention, knowledge and attitudes regarding dietary potassium restriction were much greater than before, suggesting that the decrease in serum potassium levels may be related to this nutritional guidance. Our findings indicate that implementing a dietary potassium restriction guidance program in community pharmacies is feasible and may result in lower serum potassium levels in outpatients with CKD.
Asunto(s)
Tasa de Filtración Glomerular , Pacientes Ambulatorios , Farmacéuticos , Potasio , Insuficiencia Renal Crónica , Humanos , Femenino , Masculino , Insuficiencia Renal Crónica/dietoterapia , Insuficiencia Renal Crónica/sangre , Insuficiencia Renal Crónica/terapia , Estudios Prospectivos , Anciano , Potasio/sangre , Persona de Mediana Edad , Japón , Hiperpotasemia/prevención & control , Hiperpotasemia/sangre , Hiperpotasemia/dietoterapia , Potasio en la Dieta/administración & dosificación , Anciano de 80 o más AñosRESUMEN
PURPOSE: Aging is a well-established risk factor for meibomian gland dysfunction (MGD). We previously reported an accelerated cellular senescence phenomenon in the lacrimal glands of a murine model of chronic graft-versus-host disease (cGVHD). Herein, we aimed to elucidate the relationship between cellular senescence and MGD in cGVHD mice, utilizing the senolytic agent ABT-263. METHODS: A cGVHD mouse model was established through allogeneic bone marrow transplantation (BMT) from B10.D2 to BALB/c mice. Subsequently, cGVHD mice were treated with either ABT-263 or vehicle. The eyelids of recipients were analyzed at 4-week intervals post-BMT in both groups. RESULTS: Meibomian gland (MG) area was significantly smaller in cGVHD mice than in syngeneic control mice. ABT-263-treated mice retained a significantly larger MG area than their vehicle-treated counterparts. Pathological and immunohistochemical examinations revealed significant reductions in eyelid tissue inflammation and pathological fibrosis in the ABT-263 group compared to that in the vehicle-treated group. Additionally, expression of DNA damage markers, senescent cell markers, and senescence-associated secretory phenotype (SASP) factors was elevated in the eyelids of cGVHD mice compared with that in syngeneic mice. The expression of these cellular senescence-associated molecules was considerably suppressed in ABT-263-treated eyelids compared to that in vehicle-treated ones. CONCLUSIONS: Cellular senescence, along with expression of SASP factors, exhibited increased activity in the eyelids, particularly in the MGs of cGVHD mice. ABT-263 mitigated the severity of MGD. These findings highlight the potential of targeting cellular senescence as an effective approach for MGD treatment in cGVHD.
Asunto(s)
Senescencia Celular , Enfermedad Injerto contra Huésped , Disfunción de la Glándula de Meibomio , Glándulas Tarsales , Animales , Femenino , Masculino , Ratones , Compuestos de Anilina/farmacología , Trasplante de Médula Ósea/métodos , Senescencia Celular/fisiología , Enfermedad Crónica , Modelos Animales de Enfermedad , Enfermedad Injerto contra Huésped/patología , Inmunohistoquímica , Disfunción de la Glándula de Meibomio/metabolismo , Glándulas Tarsales/patología , Glándulas Tarsales/metabolismo , Ratones Endogámicos BALB C , Sulfonamidas/farmacologíaRESUMEN
OBJECTIVES: We aimed to identify associations between patterns of large-vessel lesions of large-vessel giant cell arteritis (LV-GCA) and treatment outcomes. METHODS: We extracted data on 68 newly diagnosed patients with LV-GCA from a retrospective, multi-centric, nationwide registry of GCA patients treated with glucocorticoids between 2007 and 2014. Patients with aortic lesions were identified based on the findings from contrast-enhanced computed tomography, magnetic resonance imaging, or positron emission tomography-computed tomography (Group 2, n = 49). Patients without aortic lesions were subdivided into LV-GCA with or without subclavian lesions defined as Group 1 (n = 9) or Group 3 (n = 10), respectively. The primary outcome evaluation was failure to achieve clinical remission by Week 24 and/or relapse within 104 weeks. RESULTS: The mean age and proportion of patients with cranial lesions and polymyalgia rheumatica in Group 2 were numerically lower than in the other two groups. Large-vessel lesions in Group 3 included carotid, pulmonary, renal, hepatic, or mesenteric lesions. The cumulative rate of poor treatment outcomes >2 years was 11.1%, 55.3%, and 88.0% in Groups 1, 2, and 3, respectively (by Kaplan-Meier analysis). The mean time to poor outcome was significantly different between the groups. CONCLUSIONS: Classification by subclavian and aortic lesions may be useful to determine treatment strategy.
Asunto(s)
Arteritis de Células Gigantes , Polimialgia Reumática , Humanos , Arteritis de Células Gigantes/tratamiento farmacológico , Estudios Retrospectivos , Resultado del Tratamiento , Tomografía Computarizada por Tomografía de Emisión de PositronesRESUMEN
In this study, we investigated the mechanistic features and kinetics of the thermal decomposition of solids accompanied by liquefaction as exemplified by the thermal dehydration reactions of monosodium L-glutamate monohydrate (MSG-MH). The thermal dehydration of MSG-MH occurs via two mass-loss processes comprising the elimination of crystalline water and intramolecular dehydration. Multistep kinetic behaviors and the liquefaction during both thermal dehydration processes were evidenced by systematic thermoanalytical measurements and in situ microscopic observations. During the thermal dehydration of crystalline water, the liquefaction of the surface product layer occurred midway through the reaction, and the subsequent reaction proceeded with a geometrical constraint, where the solid reactant was covered by a liquid surface layer, affording a solid anhydride. The intramolecular dehydration of the solid anhydride yielded a liquid product on the surface of the reacting particles, and the internal solid reactant dissolved in the liquid product. Subsequently, the intramolecular dehydration proceeded in the liquid phase to afford liquid sodium pyroglutamate. The net kinetic behavior of the physico-geometrical reaction steps in each thermal dehydration process was revealed using kinetic approaches based on cumulative and conjunct kinetic equations. The advanced kinetic approaches employed to reveal the specific kinetic features of the heterogeneous reaction processes in solid-liquid-gas systems are described in this article.
RESUMEN
Among organic-inorganic hybrid molecules consisting of organic structure(s) and metal(s), only few studies are available on the cytotoxicity of nucleophilic molecules. In the present study, we investigated the cytotoxicity of a nucleophilic organotellurium compound, diphenyl ditelluride (DPDTe), using a cell culture system. DPDTe exhibited strong cytotoxicity against vascular endothelial cells and fibroblasts along with high intracellular accumulation but showed no cytotoxicity and had less accumulation in vascular smooth muscle cells and renal epithelial cells. The cytotoxicity of DPDTe decreased when intramolecular tellurium atoms were replaced with selenium or sulfur atoms. Electronic state analysis revealed that the electron density between tellurium atoms in DPDTe was much lower than those between selenium atoms of diphenyl diselenide and sulfur atoms of diphenyl disulfide. Moreover, diphenyl telluride did not accumulate and exhibit cytotoxicity. The cytotoxicity of DPDTe was also affected by substitution. p-Dimethoxy-DPDTe showed higher cytotoxicity, but p-dichloro-DPDTe and p-methyl-DPDTe showed lower cytotoxicity than that of DPDTe. The subcellular distribution of the compounds revealed that the compounds with stronger cytotoxicity showed higher accumulation rates in the mitochondria. Our findings suggest that the electronic state of tellurium atoms in DPDTe play an important role in accumulation and distribution of DPDTe in cultured cells. The present study supports the hypothesis that nucleophilic organometallic compounds, as well as electrophilic organometallic compounds, exhibit cytotoxicity by particular mechanisms.
Asunto(s)
Derivados del Benceno/farmacología , Células Endoteliales/efectos de los fármacos , Compuestos Organometálicos/farmacología , Compuestos de Organoselenio/farmacología , Telurio/farmacología , Animales , Derivados del Benceno/química , Derivados del Benceno/metabolismo , Bovinos , Línea Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Células Endoteliales/citología , Células Endoteliales/metabolismo , Células Epiteliales/citología , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Fibroblastos/citología , Fibroblastos/efectos de los fármacos , Fibroblastos/metabolismo , Humanos , Células LLC-PK1 , Modelos Químicos , Estructura Molecular , Miocitos del Músculo Liso/citología , Miocitos del Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/metabolismo , Compuestos Organometálicos/química , Compuestos Organometálicos/metabolismo , Compuestos de Organoselenio/química , Compuestos de Organoselenio/metabolismo , Porcinos , Telurio/químicaRESUMEN
Factor V deficiency is an extremely rare hematologic disorder with an incidence of one in one million. However, the risks related to cardiac surgery employing cardiopulmonary bypass in patients with factor V deficiency are not well established. Herein, we report the case of a 71-year-old male who was incidentally diagnosed with acquired factor V deficiency underwent mitral valve repair for severe mitral regurgitation. The patient was treated preoperatively with an adrenocorticosteroid immunosuppressant therapy; the procedure was performed safely with a positive outcome.
Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Deficiencia del Factor V , Implantación de Prótesis de Válvulas Cardíacas , Insuficiencia de la Válvula Mitral , Anciano , Puente Cardiopulmonar , Deficiencia del Factor V/diagnóstico , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Humanos , Masculino , Válvula Mitral/diagnóstico por imagen , Válvula Mitral/cirugía , Insuficiencia de la Válvula Mitral/diagnóstico por imagen , Insuficiencia de la Válvula Mitral/etiología , Insuficiencia de la Válvula Mitral/cirugía , Resultado del TratamientoRESUMEN
BACKGROUND: Relapses frequently occur in giant cell arteritis (GCA), and long-term glucocorticoid therapy is required. The identification of associated factors with poor treatment outcomes is important to decide the treatment algorithm of GCA. METHODS: We enrolled 139 newly diagnosed GCA patients treated with glucocorticoids between 2007 and 2014 in a retrospective, multi-center registry. Patients were diagnosed with temporal artery biopsy, 1990 American College of Rheumatology classification criteria, or large vessel lesions (LVLs) detected by imaging based on the modified classification criteria. Poor treatment outcomes (non-achievement of clinical remission by week 24 or relapse during 52 weeks) were evaluated. Clinical remission was defined as the absence of clinical signs and symptoms in cranial and large vessel areas, polymyalgia rheumatica (PMR), and elevation of C-reactive protein (CRP) levels. A patient was determined to have a relapse if he/she had either one of the signs and symptoms that newly appeared or worsened after achieving clinical remission. Re-elevation of CRP without clinical manifestations was considered as a relapse if other causes such as infection were excluded and the treatment was intensified. Associated factors with poor treatment outcomes were analyzed by using the Cox proportional hazard model. RESULTS: Cranial lesions, PMR, and LVLs were detected in 77.7%, 41.7%, and 52.5% of the enrolled patients, respectively. Treatment outcomes were evaluated in 119 newly diagnosed patients who were observed for 24 weeks or longer. The mean initial dose of prednisolone was 0.76 mg/kg/day, and 29.4% received any concomitant immunosuppressive drugs at baseline. Overall, 41 (34.5%) of the 119 patients had poor treatment outcomes; 13 did not achieve clinical remission by week 24, and 28 had a relapse after achieving clinical remission. Cumulative rates of the events of poor treatment outcomes in patients with and without LVLs were 47.5% and 17.7%, respectively. A multivariable model showed the presence of LVLs at baseline was significantly associated with poor treatment outcomes (adjusted hazard ratio [HR] 3.54, 95% CI 1.52-8.24, p = 0.003). Cranial lesions and PMR did not increase the risk of poor treatment outcomes. CONCLUSION: The initial treatment intensity in the treatment algorithm of GCA could be determined based upon the presence or absence of LVLs detected by imaging at baseline.
Asunto(s)
Arteritis de Células Gigantes/tratamiento farmacológico , Glucocorticoides/uso terapéutico , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , Adulto , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/análisis , Femenino , Arteritis de Células Gigantes/diagnóstico , Humanos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Evaluación de Resultado en la Atención de Salud/métodos , Modelos de Riesgos Proporcionales , Recurrencia , Inducción de Remisión , Estudios Retrospectivos , Factores de RiesgoAsunto(s)
Cardiología/normas , Vasculitis/terapia , Consenso , Técnicas de Diagnóstico Cardiovascular/normas , Medicina Basada en la Evidencia/normas , Humanos , Valor Predictivo de las Pruebas , Factores de Riesgo , Síndrome , Resultado del Tratamiento , Vasculitis/diagnóstico , Vasculitis/epidemiología , Vasculitis/fisiopatologíaRESUMEN
Objectives: To identify the prognostic predictive factor of complete renal response (CR) at week 12 by focusing on the plasma mycophenolic acid (MPA) concentration in induction therapy in lupus nephritis.Methods: We prospectively enrolled patients with biopsy-proven LN class III/IV who were hospitalized between 2016 and 2017. As an induction therapy, mycophenolate mofetil was continuously introduced at 2000 mg/day. We measured the MPA plasma concentration at two time points depending on the induction therapy phase, early (week 4) or middle (week 12). The association between these concentrations and CR rate at week 12 was evaluated.Results: Ten patients were enrolled. A significantly higher AUC0-12 between 0 and 12 h of MPA at the early phase was observed in the patients with CR at week 12 than in those without (p = .03). All the patients with high MPA-AUC0-12 (> 40 mg h/L) at the early phase achieved CR at week 12, but no such association was found at the middle phase. The multivariate analysis revealed that MPA-AUC0-12 was selected as an independent predictive factor of CR at week 12 (odds ratio: 1.12; 95% confidence interval: 1.01-1.45, p = .02).Conclusion: The high AUC0-12 of MPA at the early phase of induction therapy may predict good renal response.
Asunto(s)
Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Ácido Micofenólico/sangre , Inducción de Remisión/métodos , Adulto , Biomarcadores/sangre , Femenino , Humanos , Nefritis Lúpica/sangre , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Hereditary transthyretin amyloidosis (ATTRv amyloidosis) is caused by a variant transthyretin (TTR), which is a serum protein secreted by the liver. Mass spectrometry (MS) is a useful tool that can detect variant TTRs in serum samples from patients with ATTRv amyloidosis. We previously reported several mass spectrometric methods to detect variant TTRs in serum samples. Those methods require cumbersome immunoprecipitation with anti-TTR antibodies and significant time to analyze the variant TTRs. In our study here, we developed a new simple and quick method to detect variant TTRs in serum samples by means of matrix-assisted laser desorption-ionization time-of-flight (MALDI-TOF) MS without immunoprecipitation (direct MALDI). METHODS: By using direct MALDI, we analyzed 288 serum samples obtained from patients who were clinically suspected having amyloidosis to investigate the usefulness of this direct MALDI method to detect variant TTRs in serum samples. RESULTS: The method completed the process within 30 min. We successfully identified variant TTRs in serum samples from patients, except for a few patients with TTR Glu61Lys and Glu89Gln mutations because of the small mass shift of those variant TTRs from wild-type TTR. We also found that the mass shifts of variant TTRs measured by direct MALDI corresponded to theoretical mass changes. CONCLUSION: Our results suggest that the direct MALDI method is useful for the screening of ATTRv amyloidosis.
Asunto(s)
Neuropatías Amiloides Familiares/sangre , Neuropatías Amiloides Familiares/diagnóstico , Prealbúmina/análisis , Espectrometría de Masa por Láser de Matriz Asistida de Ionización Desorción/métodos , Humanos , Sensibilidad y EspecificidadRESUMEN
AIM: This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients. METHODS: We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using 99m thallium (99m Tl) and 123 I-ß-methyl-P-iodophenyl-pentadecanoic acid (123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of 123 I-BMIPP from that of 99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing 99m Tl and 123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis. RESULTS: Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases. CONCLUSIONS: Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients.
Asunto(s)
Circulación Coronaria , Ácidos Grasos/administración & dosificación , Cardiopatías/diagnóstico por imagen , Radioisótopos de Yodo/administración & dosificación , Yodobencenos/administración & dosificación , Imagen de Perfusión Miocárdica/métodos , Radiofármacos/administración & dosificación , Esclerodermia Sistémica/complicaciones , Talio/administración & dosificación , Anciano , Enfermedades Asintomáticas , Causas de Muerte , Progresión de la Enfermedad , Ecocardiografía , Femenino , Fibrosis , Cardiopatías/etiología , Cardiopatías/mortalidad , Cardiopatías/fisiopatología , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Miocardio/patología , Valor Predictivo de las Pruebas , Pronóstico , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/mortalidadRESUMEN
OBJECTIVE: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). METHODS: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. RESULTS: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. CONCLUSION: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV.
Asunto(s)
Anticuerpos Anticardiolipina/metabolismo , Riñón/efectos de los fármacos , Riñón/fisiopatología , Inhibidor de Coagulación del Lupus/metabolismo , Nefritis Lúpica/tratamiento farmacológico , Nefritis Lúpica/inmunología , Inhibidores de Agregación Plaquetaria/farmacología , Adulto , Síndrome Antifosfolípido/complicaciones , Citoprotección/efectos de los fármacos , Interacciones Farmacológicas , Femenino , Tasa de Filtración Glomerular/efectos de los fármacos , Humanos , Terapia de Inmunosupresión , Riñón/patología , Nefritis Lúpica/complicaciones , Nefritis Lúpica/fisiopatología , Masculino , Inhibidores de Agregación Plaquetaria/uso terapéutico , Estudios RetrospectivosRESUMEN
To clarify whether patients with connective tissue disease (CTD)-associated borderline mean pulmonary artery pressure (mPAP) have distinctive hemodynamic characteristics from those with normal mPAP and whether pathogenesis is as heterogeneous as manifest pulmonary hypertension (PH). Seventy-five CTD patients who underwent right heart catheterization (RHC) from 2008 through 2016 were retrospectively analyzed. We compared between-group differences in clinical and hemodynamic findings: normal mPAP (n = 35), borderline mPAP (n = 15), and PH (n = 25). A therapeutic intervention trial based on RHC results was performed in nine patients. The values of tricuspid regurgitation pressure gradient (TRPG) in patients with borderline mPAP were comparable at rest but became higher after exercise compared to those with a normal mPAP (P = 0.01). Pulmonary artery wedge pressure in patients with borderline mPAP was higher than in those with normal mPAP (P < 0.0001) and comparable to those with PH. Each of the three patients was treated for pre-capillary and post-capillary disease and two for interstitial lung disease (ILD). During the mean follow-up period of 40 months, mPAP or TRPG normalized in all patients treated for pre-capillary and post-capillary disease. One patient with severe ILD developed to PH and died from it. CTD patients with borderline mPAP, the underlining pathogenesis of which is heterogeneous as PH, have distinctive hemodynamic characteristics from those with normal mPAP. Whether a specific treatment targeting the inflammatory process or local hemodynamics may alter the clinical course to PH is a topic for future research.
Asunto(s)
Presión Arterial , Enfermedades del Tejido Conjuntivo/fisiopatología , Hemodinámica , Hipertensión Pulmonar/fisiopatología , Arteria Pulmonar/fisiopatología , Adulto , Anciano , Cateterismo Cardíaco , Progresión de la Enfermedad , Ecocardiografía , Femenino , Humanos , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
A 49-year-old woman with primary Sjögren syndrome initially developed pulmonary venous hypertension (PVH) due to heart failure with preserved ejection fraction. Endomyocardial biopsy specimens showed mild myocardial fibrosis. Pulmonary arterial hypertension (PAH) was revealed after the treatment with diuretics. During the treatment for PAH using upfront combination with pulmonary vasodilators and immunosuppressants, the patient developed combined disease with PAH and PVH. A careful hemodynamic assessment is necessary in such cases.
Asunto(s)
Insuficiencia Cardíaca/complicaciones , Hipertensión Pulmonar/complicaciones , Síndrome de Sjögren/complicaciones , Volumen Sistólico/fisiología , Cateterismo Cardíaco , Femenino , Insuficiencia Cardíaca/fisiopatología , Humanos , Hipertensión Pulmonar/fisiopatología , Persona de Mediana Edad , Síndrome de Sjögren/fisiopatologíaRESUMEN
Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.
Asunto(s)
Ciclofosfamida/uso terapéutico , Debilidad Muscular/tratamiento farmacológico , Poliarteritis Nudosa/complicaciones , Poliarteritis Nudosa/tratamiento farmacológico , Prednisolona/uso terapéutico , Rabdomiólisis/tratamiento farmacológico , Rabdomiólisis/etiología , Anciano , Antiinflamatorios/uso terapéutico , Anticuerpos Anticitoplasma de Neutrófilos/sangre , Antirreumáticos/uso terapéutico , Humanos , Masculino , Debilidad Muscular/diagnóstico , Poliarteritis Nudosa/diagnóstico , Resultado del TratamientoRESUMEN
In patients with connective tissue disease, vascular injury induced by primary or secondary vasculitis syndromes can lead to organ dysfunction due to the loss of nutrient supply from the blood. Such vasculitis syndromes can be refractory to treatment and fatal. The nomenclature and the definition of vasculitis syndromes have recently been revised, and clinical practice guidelines for diseases associated with vasculitis syndrome are evolving. The present review provides an overview of vasculitis syndromes from the viewpoint of diagnosis and treatment.
RESUMEN
Endothelin 1 (ET-1), mainly produced from vascular endothelial cells, induces vasoconstriction in physiological conditions. The endothelin receptor antagonist is among the most effective agents for pulmonary hypertension. However, little is known about the production source of ET-1 in inflammation and immunity. Here, we studied whether T cell-mediated ET-1 production system exists and operates independent of the production system in vascular endothelial cells. ET-1 production was readily detectable in the culture supernatant of human PBMCs and murine spleen cells stimulated with anti-CD3 antibody. Immunocytostaining showed that ET-1-producing cells emerged only in PBMCs stimulated with anti-CD3 antibody. Using the Transwell system, both murine and human monocytes sorted with magnetic beads in the inner chamber produced ET-1 when T cells were activated with antigen or anti-CD3 antibody in the outer chamber. This ET-1 production was inhibited by anti-IFN-γ and/or TNF-α antibody. Furthermore, monocytes purified from ETflox/flox;Tie2-Cre( + ) mice, which conditionally lack ET-1 in hematopoietic stem cells and vascular endothelial cells, did not produce ET-1 even when stimulated by antigen-specific T cell activation. This study demonstrates the existence of an immune-mediated ET-1 production induced by T cells upon activation through IFN-γ and TNF-α.
Asunto(s)
Endotelina-1/metabolismo , Interferón gamma/metabolismo , Monocitos/inmunología , Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/metabolismo , Inmunidad Adaptativa , Animales , Células de la Médula Ósea/inmunología , Complejo CD3/metabolismo , Células Cultivadas , Endotelina-1/genética , Humanos , Interferón gamma/antagonistas & inhibidores , Ratones , Ratones Transgénicos , Monocitos/citología , Bazo/citología , Bazo/inmunología , Linfocitos T/citología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresRESUMEN
The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.