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OBJECTIVE: To evaluate the risk of end-stage kidney disease (ESKD) in lupus nephritis (LN) patients using tubulointerstitial lesion scores. METHODS: Clinical profiles and histopathological presentations of 151 biopsy-proven LN patients were retrospectively examined. Risk factors of ESKD based on characteristics and scoring of their tubulointerstitial lesions (e.g. interstitial inflammation [II], tubular atrophy [TA], and interstitial fibrosis [IF]) were analyzed. RESULTS: The mean age of 151 LN patients was 36 years old, and 136 (90.1%) were female. The LN cases examined included: class I/II (n = 3, 2%), class III/IV (n = 119, 78.8%), class V (n = 23, 15.2%), and class VI (n = 6, 4.0%). The mean serum creatinine level was 1.4 mg/dl. Tubulointerstitial lesions were recorded in 120 (79.5%) patients. Prior to receiving renal biopsy, 9 (6.0%) patients developed ESKD. During the follow-up period (mean, 58 months), an additional 47 patients (31.1%) progressed to ESKD. Multivariate analyses identified serum creatinine (hazard ratio [HR]: 1.7, 95% confidence interval [CI]: 1.42-2.03, p < 0.001) and IF (HR: 3.2, 95% CI: 1.58-6.49, p = 0.001) as independent risk factors of ESKD. Kaplan-Meier analysis further confirmed a heightened risk of ESKD associated with IF. CONCLUSION: Tubulointerstitial involvement is commonly observed in histopathological presentation of LN. However, IF, rather than II, or TA, was found to increase the risk of ESKD in our cohort. Therefore, to predict renal outcome in LN patients prior to adjusting immunosuppressive treatment, degree of IF should be reviewed.
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BACKGROUND: Immune-mediated diseases (IMDs) after nucleic acid-based vaccines have been sporadically reported since their introduction during the worldwide COVID-19 crisis. Confirming their cause-effect association remains challenging. We analysed the effects of AZD1222 (ChAdOx1 nCoV-19), BNT-162b2, and/or mRNA-1273 on the development &/or deterioration of IMDs in terms of the time of clinical onsets of IMDs after exposure to these vaccines. METHODS: We retrospectively reviewed 78 in-patients in Taipei Veterans General Hospital, who presented with IMDs within 120 days after receiving AZD1222, BNT-162b2, &/or mRNA-1273 vaccinations in Taiwan from May 2021 to April 2022. The duration from inoculation to development of IMD was analysed by two-tailed Kolmogorov-Smirnov (K-S) test for goodness of fit. RESULTS: The average time to new IMDs or flare-up of the diseases following vaccinations was 36 ± 26 days for all 91 events in these 78 patients. The onset time of IMDs after vaccinations was not haphazard as analysed by two-tailed K-S test for overall 91 events (40 new and 51 deteriorating episodes, p < 0.001). The IMDs presenting as non-connective tissue diseases (non-CTDs) have a shorter duration of incubation after vaccinations than those of CTDs (<14.7 days, 95 % confidence interval [CI], 3.0 to 26.4, p = 0.014). Furthermore, systemic vasculitis and type 2 inflammatory diseases were observed exclusively in those receiving AZD1222. CONCLUSION: AZD1222, BNT-162b2, or mRNA-1273 influence the activities of IMDs in ways yet to be explored. High index of suspicion to IMDs after nucleic acid-based vaccine inoculation against COVID-19 may be important for primary care physicians.
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COVID-19 , Enfermedades del Sistema Inmune , Humanos , ChAdOx1 nCoV-19 , Vacuna BNT162 , Vacuna nCoV-2019 mRNA-1273 , Estudios Retrospectivos , Vacunación/efectos adversos , COVID-19/prevención & control , Vacunación Basada en Ácidos NucleicosRESUMEN
ABSTRACT: With documented high specificity, 99m Tc-pyrophosphate (PYP) scan enables the diagnosis of transthyretin cardiomyopathy to be made reliably without endomyocardial biopsy in patients who do not have monoclonal gammopathy. We report a case with extensive myocardial uptake of Perugini 3 score in the 3-hour 99m Tc-PYP myocardial SPECT that suggested transthyretin cardiac amyloidosis. However, a followed endomyocardial biopsy revealed no amyloid deposition. In this case, hyperphosphatemia was the most likely and presumptive cause of the false-positive 99m Tc-PYP scan. With this case, our experiences of the potential causes of false-positive results of 99m Tc-PYP are further expanded.
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Cardiomiopatías , Hiperfosfatemia , Humanos , Difosfatos , Prealbúmina , Pirofosfato de Tecnecio Tc 99m , Hiperfosfatemia/diagnóstico por imagen , Tecnecio , Cardiomiopatías/diagnóstico por imagen , BiopsiaRESUMEN
AIMS: A subset of IgA nephropathy (IgAN) patients exhibiting minimal change disease (MCD) like features present with nephrotic-range proteinuria and warrants immunosuppressive therapy (IST). However, the diagnosis of MCD-like IgAN varied by reports. We aimed to identify the key pathological features of MCD-like IgAN. METHODS: In this cohort, 228 patients had biopsy-proven IgAN from 2009 to 2021, of which 44 without segmental sclerosis were enrolled. Patients were classified into segmental (< 50% glomerular capillary loop involvement) or global (> 50%) foot process effacement (FPE) groups. We further stratified them according to the usage of immunosuppressant therapy after biopsy. Clinical manifestations, treatment response, and renal outcome were compared. RESULTS: 26 cases (59.1%) were classified as segmental FPE group and 18 cases (40.9%) as global FPE group. The global FPE group had more severe proteinuria (11.48 [2.60, 15.29] vs. 0.97 [0.14, 1.67] g/g, p = 0.001) and had a higher proportion of complete remission (81.8% vs. 20%, p = 0.018). In the global FPE group, patients without IST experienced more rapid downward eGFR change than the IST-treated population (-0.38 [-1.24, 0.06] vs. 1.26 [-0.17, 3.20]mL/min/1.73 m2/month, p = 0.004). CONCLUSIONS: The absence of segmental sclerosis and the presence of global FPE are valuable pathological features that assist in identifying MCD-like IgAN.
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Glomerulonefritis por IGA , Nefrosis Lipoidea , Humanos , Glomerulonefritis por IGA/patología , Nefrosis Lipoidea/patología , Esclerosis , Estudios Retrospectivos , Proteinuria/tratamiento farmacológicoRESUMEN
BACKGROUND: Neuronal intranuclear inclusion disease (NIID), caused by GGC (guanine-guanine-cytosine) repeat expansion in NOTCH2NLC, has several clinical and radiological features akin to cerebral small vessel disease (cSVD). The present study tested the hypothesis that NOTCH2NLC GGC expansion may contribute to cSVD. METHODS: One hundred and ninety-seven unrelated patients with genetically unsolved vascular leukoencephalopathy without NOTCH3, HTRA1, and mitochondrial m.3243A>G mutations and 730 healthy individuals were screened for NOTCH2NLC GGC repeat expansion using repeat-primed polymerase chain reaction, fragment analysis, Southern blot analysis, or nanopore sequencing with Cas9 (CRISPR associated protein 9)-mediated enrichment. The clinical and neuroimaging features of the patients were compared between individuals with and without NOTCH2NLC GGC repeat expansion. RESULTS: Six of the 197 (3.0%) patients with unsolved vascular leukoencephalopathy and none of the controls carried the GGC repeat expansion (P=0.00009). Skin biopsy of 1 patient revealed eosinophilic, ubiquitin-positive, and p62-positive intranuclear inclusions in the cells of sweat gland and capillary, providing pathologic evidence for the involvement of small vessels in NIID. For the 6 patients, gait disturbance and cognitive decline were common manifestations with a median onset age of 65 (59-69) years. They all had multiple neuroimaging features suggestive of cSVD, including diffuse white matter hyperintensities, lacunes, and enlarged perivascular space in all 6 patients, cerebral microbleeds in 5, and old intracerebral hemorrhage in 4. Four patients had linear hyperintensity in the corticomedullary junction on diffusion-weighted imaging-the characteristic neuroimaging feature of NIID. There was no difference in the severity of cSVD imaging features between the patients with and without the GGC expansion but more pronounced brain atrophy in the patients with the GGC expansion. CONCLUSIONS: NOTCH2NLC GGC repeat expansion accounted for 3% of genetically unsolved Taiwanese vascular leukoencephalopathy cases after excluding participants with cerebral autosomal dominant arteriopathy with subcortical infarct and leukoencephalopathy (CADASIL), cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes (MELAS). NIID should be considered in patients manifesting cSVD, especially in those with characteristic neuroimaging feature of NIID.
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CADASIL , Leucoencefalopatías , Enfermedades Neurodegenerativas , Anciano , Humanos , CADASIL/patología , Serina Peptidasa A1 que Requiere Temperaturas Altas , Cuerpos de Inclusión Intranucleares/genética , Cuerpos de Inclusión Intranucleares/patología , Leucoencefalopatías/genética , Enfermedades Neurodegenerativas/patología , Persona de Mediana EdadRESUMEN
CONTEXT.: Galectin-9 reduces tissue damage in certain immune-mediated glomerular diseases. However, its role in structural and functional renal changes in patients with varying types of chronic kidney disease (CKD) is less clear. OBJECTIVE.: To investigate the association between plasma galectin-9 levels, proteinuria, tubulointerstitial lesions, and renal function in different CKD stages. DESIGN.: We measured plasma galectin-9 levels in 243 patients undergoing renal biopsy for determining the CKD etiology. mRNA and protein expression levels of intrarenal galectin-9 were assessed by quantitative real-time polymerase chain reaction and immunostaining. Relationships between plasma galectin-9, clinical characteristics, and tubulointerstitial damage were analyzed with logistic regression. We investigated galectin-9 expression patterns in vitro in murine J774 macrophages treated with differing stimuli. RESULTS.: To analyze the relationship between galectin-9 and clinical features, we divided the patients into 2 groups according to median plasma galectin-9 levels. The high galectin-9 group tended to be older and to have decreased renal function, higher proteinuria, and greater interstitial fibrosis. After multivariable adjustment, elevated plasma galectin-9 levels were independently associated with stage 3b or higher CKD. An analysis of gene expression in the tubulointerstitial compartment in the biopsy samples showed a significant positive correlation between intrarenal galectin-9 mRNA expression and plasma galectin-9 levels. Immunohistochemistry confirmed increased galectin-9 expression in the renal interstitium of patients with advanced CKD, and most galectin-9-positive cells were macrophages, as determined by double-immunofluorescence staining. In vitro experiments showed that galectin-9 expression in macrophages was significantly increased after interferon-γ stimulation. CONCLUSIONS.: Our findings suggest that plasma galectin-9 is a good biomarker for diagnosing advanced CKD.
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Riñón , Insuficiencia Renal Crónica , Humanos , Ratones , Animales , Riñón/patología , Insuficiencia Renal Crónica/diagnóstico , Galectinas/metabolismo , Biomarcadores , Proteinuria/metabolismo , Proteinuria/patología , Biopsia , ARN MensajeroRESUMEN
Background: While cardiovascular complications are the most common cause of mortality in Fabry disease, the relationship between globotriaosylceramide (GL-3) accumulation, the hallmark of Fabry cardiomyopathy, and cardiac hypertrophy has not been fully elucidated. Methods: We developed unbiased stereology protocols to quantify the ultrastrcture of Fabry cardiomyopathy. Endomyocardial biopsies from 10 adult male enzyme replacement therapy naïve Fabry patients with IVS4 + 919G>A GLA mutation were studied. The findings were correlated with cardiac MRI and clinical data. Results: Ultrastructural parameters showed significant relationships with key imaging and clinical and functional variables. Average cardiomyocyte volume and GL-3 volume per cardiomyocyte were progressively increased with age. Eighty-four percent of left ventricular mass index (LVMI) variability was explained by cardiomyocyte nuclear volume, age and plasma globotriaosylsphingosine with cardiomyocyte nuclear volume being the only independent predictor of LVMI. Septal thickness was directly and left ventricular ejection fraction (LVEF) was inversely correlated with cardiomyocyte GL-3 accumulation. Sixty-five percent of left ventricular ejection fraction (LVEF) variability was explained by cardiomyocyte GL3 volume, serum α-galactosidase-A activity and age with cardiomyocyte GL3 volume being the only independent predictor of LVEF. Residual α-galactosidase-A activity was directly correlated with myocardial microvasculature density. Conclusions: The unbiased stereological methods introduced in this study unraveled novel relationships between cardiomyocyte structure and important imaging and clinical parameters. These novel tools can help better understand Fabry cardiomyopathy pathophysiology.
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Amyloidosis cardiomyopathy is a rare and underdiagnosed disease characterized by amyloid fibril deposition in the myocardium. The diagnosis of cardiac amyloidosis is often delayed due to a lack of awareness and the necessity of biopsy to confirm the diagnosis. Recent advances in cardiovascular imaging modalities have enhanced earlier recognition of this disease. A 66-year-old man experiences progressive shortness of breath for two weeks. Laboratory testing was significant for an elevation of cardiac biomarkers (creatine kinase: 522 U/L, troponin I: 0.10 ng/mL) and NT-pro-BNP (5074 pg/mL). He was diagnosed with acute coronary syndrome and received stent deployment. Nonetheless, progressive shortness of breath recurred in 2 months. Transthoracic echocardiography (TTE) demonstrated an increased left ventricular (LV) wall thickness with apical sparing. Cardiac magnetic resonance (CMR) imaging demonstrated high native T1 value, increased extracellular volume fraction as well as diffused subendocardial late gadolinium enhancement. Technetium-99m pyrophosphate (99mTc-PYP) scintigraphy, endomyocardial biopsy (EMB), and the genetic study confirmed the diagnosis of wild-type transthyretin amyloidosis (ATTRwt). The nonspecific clinical manifestations, lack of diagnostic biomarkers, and the rarity of systemic amyloidosis usually lead to delayed diagnosis and treatment. Our objective is to emphasize the role of multimodalities imaging in reducing delays to the diagnosis of cardiac amyloidosis.
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Neuropatías Amiloides Familiares , Cardiomiopatías , Masculino , Humanos , Anciano , Prealbúmina/genética , Medios de Contraste , Gadolinio , Neuropatías Amiloides Familiares/diagnóstico por imagen , Neuropatías Amiloides Familiares/genética , Cardiomiopatías/diagnóstico por imagen , Disnea , BiomarcadoresRESUMEN
In spite of advances in medical technology, the repair of Achilles tendon ruptures remains challenging. Reconstruction with an autograft tendon provides the advantage of a higher healing rate; nevertheless, the development of donor-site morbidity cannot be ignored. We developed biodegradable, drug-eluting, nanofibrous membranes employing an electrospinning technique and evaluated their effectiveness on the healing of allograft tendons. Poly-D-L-lactide-glycolide was used as the polymeric material for the nanofibers, while doxycycline was selected as the drug for delivery. The in vitro and in vivo drug-release profiles were investigated. The biomechanical properties of allografted Achilles tendons repaired using the nanofibrous membranes were tested in euthanized rabbits at 2-, 4-, and 6-week time intervals. Histological examination was performed for the evaluation of tissue reaction and tendon healing. The level of postoperative animal activity was also monitored using an animal behavior cage. The experimental results showed that the degradable nanofibers used as a vehicle could provide sustained release of doxycycline for 42 days after surgery with very low systemic drug concentration. Allograft Achilles tendon reconstruction assisted by drug-loaded nanofibers was associated with better biomechanical properties at 6 weeks post-surgery. In addition, the animals exhibited a better level of activity after surgery. The use of drug-eluting, nanofibrous membranes could enhance healing in Achilles tendon allograft reconstruction surgery.
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Neuronal intranuclear inclusion disease (NIID), caused by an expansion of GGC repeats in the 5'-untranslated region of NOTCH2NLC, is an important but underdiagnosed cause of adult-onset leukoencephalopathies. The present study aimed to investigate the prevalence, clinical spectrum and brain MRI characteristics of NIID in adult-onset nonvascular leukoencephalopathies and assess the diagnostic performance of neuroimaging features. One hundred and sixty-one unrelated Taiwanese patients with genetically undetermined nonvascular leukoencephalopathies were screened for the NOTCH2NLC GGC repeat expansions using fragment analysis, repeat-primed PCR, Southern blot analysis and/or nanopore sequencing with Cas9-mediated enrichment. Among them, 32 (19.9%) patients had an expanded NOTCH2NLC allele and were diagnosed with NIID. We enrolled another two affected family members from one patient for further analysis. The size of the expanded NOTCH2NLC GGC repeats in the 34 patients ranged from 73 to 323 repeats. Skin biopsies from five patients all showed eosinophilic, p62-positive intranuclear inclusions in the sweat gland cells and dermal adipocytes. Among the 34 NIID patients presenting with nonvascular leukoencephalopathies, the median age at symptom onset was 61 years (range, 41-78 years) and the initial presentations included cognitive decline (44.1%; 15/34), acute encephalitis-like episodes (32.4%; 11/34), limb weakness (11.8%; 4/34) and parkinsonism (11.8%; 4/34). Cognitive decline (64.7%; 22/34) and acute encephalitis-like episodes (55.9%; 19/34) were also the most common overall manifestations. Two-thirds of the patients had either bladder dysfunction or visual disturbance. Comparing the brain MRI features between the NIID patients and individuals with other undetermined leukoencephalopathies, corticomedullary junction curvilinear lesions on diffusion weighted images were the best biomarkers for diagnosing NIID with high specificity (98.4%) and sensitivity (88.2%). However, this diffusion weighted imaging abnormality was absent in 11.8% of the NIID patients. When only fluid-attenuated inversion recovery images were available, the presence of white matter hyperintensity lesions either in the paravermis or middle cerebellar peduncles also favoured the diagnosis of NIID with a specificity of 85.3% and sensitivity of 76.5%. Among the MRI scans of 10 patients, performed within 5 days of the onset of acute encephalitis-like episodes, five showed cortical hyperintense lesions on diffusion weighted images and two revealed focal brain oedema. In conclusion, NIID accounts for 19.9% (32/161) of patients with adult-onset genetically undiagnosed nonvascular leukoencephalopathies in Taiwan. Half of the NIID patients developed encephalitis-like episodes with restricted diffusion in the cortical regions on diffusion weighted images at the acute stage. Corticomedullary junction hyperintense lesions, white matter hyperintensities in the paravermis or middle cerebellar peduncles, bladder dysfunction and visual disturbance are useful hints to diagnosing NIID.
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Encefalitis , Leucoencefalopatías , Enfermedades Neurodegenerativas , Regiones no Traducidas 5' , Adulto , Anciano , Encefalitis/patología , Humanos , Cuerpos de Inclusión Intranucleares/patología , Leucoencefalopatías/diagnóstico por imagen , Leucoencefalopatías/genética , Leucoencefalopatías/patología , Persona de Mediana Edad , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/genéticaRESUMEN
Introduction: In this study, simvastatin-incorporated poly(D,L-lactide-co-glycolide) (PLGA) nanofibrous mats were fabricated via electrospinning, and their efficacy in the repair of the Achilles tendon was evaluated. Methods: The morphology of spun nanofibers and the in vitro drug release kinetics were assessed, while the in vivo efficacy in tendon repair was tested using a rat model. Results: Images obtained by scanning electron microscopy revealed that spun nanofibers exhibit a porous structure with a fiber diameter of approximately 350 nm. Fourier-transform infrared spectrometry and differential scanning calorimetry demonstrated successful incorporation of pharmaceutical agents into the PLGA nanofibers. The drug-loaded nanofibrous membranes sustainably discharged high concentrations of simvastatin for >28 days at the target site, and drug concentrations in blood were low. Tendons repaired using simvastatin-eluting nanofibers exhibited superior mechanical strength and animal activities to those repaired without nanofibers or with pure PLGA nanofibers. Discussion: Simvastatin-loaded nanofibers demonstrated effectiveness and sustainable capability for the repair of Achilles tendons. Eventually biodegradable drug-eluting nanofibrous mats may be used in humans for the treatment of tendon ruptures.
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Tendón Calcáneo , Nanofibras , Animales , Liberación de Fármacos , Membranas , Nanofibras/química , Ratas , Simvastatina/farmacologíaRESUMEN
Plasma galectin-3 (Gal-3) is associated with organ fibrosis, but whether urinary Gal-3 is a potential biomarker of kidney disease progression has never been explored. Between 2018 and 2021, we prospectively enrolled 280 patients who underwent renal biopsy and were divided into three groups based on their urinary Gal-3 levels (<354.6, 354.6−510.7, and ≥510.8 pg/mL) to assess kidney disease progression (defined as ≥40% decline in the estimated glomerular filtration rate or end-stage renal disease) and renal histology findings. Patients in the highest urinary Gal-3 tertile had the lowest eGFRs and highest proteinuria levels. In multivariate Cox regression models, patients in the highest tertile had the highest risk of kidney disease progression (adjusted hazard ratio, 4.60; 95% confidence interval, 2.85−7.71) compared to those in the lowest tertile. Higher urinary Gal-3 levels were associated with more severe renal fibrosis. Intrarenal mRNA expression of LGALS3 (Gal-3-encoded gene) was most correlated with the renal stress biomarkers (IGFBP7 and TIMB2), renal function biomarkers (PTGDS) and fibrosis-associated genes (TGFB1). The urinary Gal-3 level may be useful for the identification of patients at high risk of kidney disease progression and renal fibrosis, and for the early initiation of treatments for these patients.
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BACKGROUND: Common demographic risk factors are identified in colorectal cancer (CRC) and type 2 diabetes mellitus (DM), nevertheless, the molecular link and mechanism for CRC-DM comorbidity remain elusive. Dysregulated glycogen synthase kinase-3 beta under metabolic imbalance is suggested to accelerate CRC pathogenesis/progression via regulating collpasin response mediator protein-2 (CRMP2). Accordingly, roles of CRMP2 in CRC and CRC-DM patients were investigated for elucidating the molecular convergence of CRC and DM. METHODS: CRMP2 profile in tumor tissues from CRC and CRC-DM patients was investigated to explore the link between CRC and DM etiology. Meanwhile, molecular mechanism of glucose to regulate CRMP2 profile and CRC characteristics was examined in vitro and in vivo. RESULTS: CRMP2 was significantly lower in tumor lesions and associated with advanced tumor stage in CRC-DM patients. Physiological hyperglycemia suppressed CRMP2 expression/activity and augmented malignant characteristics of CRC cells. Hyperglycemia promotes actin de-polymerization, cytoskeleton flexibility and cell proliferation/metastasis by downregulating CRMP2 profile and thus contributes to CRC disease progression. CONCLUSIONS: This study uncovers molecular evidence to substantiate and elucidate the link between CRC and T2DM, as well as characterizing the roles of CRMP2 in CRC-DM. Accordingly, altered metabolic adaptations are promising targets for anti-diabetic and cancer strategies.
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Neoplasias Colorrectales , Diabetes Mellitus Tipo 2 , Hiperglucemia , Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Neoplasias Colorrectales/complicaciones , Comorbilidad , Diabetes Mellitus Tipo 2/complicaciones , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Proteínas del Tejido Nervioso/genética , FosforilaciónRESUMEN
BACKGROUND AND OBJECTIVES: The GGC repeat expansion in the 5' untranslated region of NOTCH2NLC was recently identified as the cause of neuronal intranuclear inclusion disease (NIID), which may manifest with peripheral neuropathy. The aim of this study is to investigate its contribution to inherited neuropathy. METHODS: This cohort study screened patients with molecularly undiagnosed Charcot-Marie-Tooth disease (CMT) and healthy controls for the GGC repeat expansion in NOTCH2NLC using repeat-primed PCR and fragment analysis. The clinical and electrophysiologic features of the patients harboring the GGC repeat expansion were scrutinized. Skin biopsy with immunohistochemistry staining and electric microscopic imaging were performed. RESULTS: One hundred twenty-seven unrelated patients with CMT, including 66 cases with axonal CMT (CMT2), and 200 healthy controls were included. Among them, 7 patients with CMT carried a variant NOTCH2NLC allele with GGC repeat expansion, but it was absent in controls. The sizes of the expanded GGC repeats ranged from 80 to 104 repeats. All 7 patients developed sensory predominant neuropathy with an average age at disease onset of 37.1 years (range 21-55 years). Electrophysiologic studies revealed mild axonal sensorimotor polyneuropathy. Leukoencephalopathy was absent in the 5 patients who received a brain MRI. Skin biopsy from 2 patients showed eosinophilic, ubiquitin- and p62-positive intranuclear inclusions in the sweat gland cells and dermal fibroblasts. Two of the 7 patients had a family history of NIID. DISCUSSION: The NOTCH2NLC GGC repeat expansions are an underdiagnosed and important cause of inherited neuropathy. The expansion accounts for 10.6% (7 of 66) of molecularly unassigned CMT2 cases in the Taiwanese CMT cohort. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in Taiwanese patients with genetically undiagnosed CMT, 10.6% of the CMT2 cases have the GGC repeat expansion in NOTCH2NLC.
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Péptidos y Proteínas de Señalización Intercelular , Proteínas del Tejido Nervioso , Enfermedades Neurodegenerativas , Enfermedades del Sistema Nervioso Periférico , Adulto , Estudios de Casos y Controles , Estudios de Cohortes , Humanos , Péptidos y Proteínas de Señalización Intercelular/genética , Cuerpos de Inclusión Intranucleares/patología , Persona de Mediana Edad , Proteínas del Tejido Nervioso/genética , Enfermedades Neurodegenerativas/patología , Enfermedades del Sistema Nervioso Periférico/patología , Expansión de Repetición de Trinucleótido , Adulto JovenRESUMEN
Background: Galectin-3 (Gal-3) is a multifunctional glycan-binding protein shown to be linked to chronic inflammation and fibrogenesis. Plasma Gal-3 is associated with proteinuria and renal dysfunction, but its role has never been confirmed with kidney biopsy results. In our study, we aimed to explore the expression of Gal-3 in biopsy-proven patients, and we tested the hypothesis that chronic kidney disease (CKD) leads to upregulation of plasma Gal-3 expression in corresponding biopsy findings and RNA sequencing analysis. Method: In 249 patients (male/female: 155/94, age: 57.2 ± 16.3 years) who underwent kidney biopsy, plasma levels of Gal-3 were measured to estimate the association of renal fibrosis. Relationships between plasma Gal-3 levels, estimated glomerular filtration rate (eGFR) and renal histology findings were also assessed. We further examined the gene expression of Gal-3 in RNA-sequencing analysis in biopsy-proven patients. Results: Compared to patients without CKD, CKD patients had higher levels of plasma Gal-3 (1,016.3 ± 628.1 pg/mL vs. 811.6 ± 369.6 pg/ml; P = 0.010). Plasma Gal-3 was inversely correlated with eGFR (P = 0.005) but not with proteinuria. Higher Gal-3 levels were associated with interstitial fibrosis, tubular atrophy and vascular intimal fibrosis. RNA-sequencing analysis showed the upregulation of Gal-3 in fibrotic kidney biopsy samples, and the differentially expressed genes were mainly enhanced in immune cell activation and the regulation of cell-cell adhesion. Conclusions: Plasma Gal-3 levels are inverse correlated with eGFR but positively correlated with renal fibrosis, which may be involved in the immune response and associated pathways. These findings support the role of Gal-3 as a predictive marker of renal fibrosis.
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BACKGROUND: Acute kidney injury (AKI) is an emerging global healthcare issue without effective therapy yet. Autophagy recycles damaged organelles and helps maintain tissue homeostasis in acute renal ischemia-reperfusion (I/R) injury. Hypoxic mesenchymal stem cells (HMSCs) represent an innovative cell-based therapy in AKI. Moreover, the conditioned medium of HMSCs (HMSC-CM) rich in beneficial trophic factors may serve as a cell-free alternative therapy. Nonetheless, whether HMSCs or HMSC-CM mitigate renal I/R injury via modulating tubular autophagy remains unclear. METHODS: Renal I/R injury was induced by clamping of the left renal artery with right nephrectomy in male Sprague-Dawley rats. The rats were injected with either PBS, HMSCs, or HMSC-CM immediately after the surgery and sacrificed 48 h later. Renal tubular NRK-52E cells subjected to hypoxia-reoxygenation (H/R) injury were co-cultured with HMSCs or treated with HMSC-CM to assess the regulatory effects of HSMCs on tubular autophagy and apoptosis. The association of tubular autophagy gene expression and renal recovery was also investigated in patients with ischemic AKI. RESULT: HMSCs had a superior anti-oxidative effect in I/R-injured rat kidneys as compared to normoxia-cultured mesenchymal stem cells. HMSCs further attenuated renal macrophage infiltration and inflammation, reduced tubular apoptosis, enhanced tubular proliferation, and improved kidney function decline in rats with renal I/R injury. Moreover, HMSCs suppressed superoxide formation, reduced DNA damage and lipid peroxidation, and increased anti-oxidants expression in renal tubular epithelial cells during I/R injury. Co-culture of HMSCs with H/R-injured NRK-52E cells also lessened tubular cell death. Mechanistically, HMSCs downregulated the expression of pro-inflammatory interleukin-1ß, proapoptotic Bax, and caspase 3. Notably, HMSCs also upregulated the expression of autophagy-related LC3B, Atg5 and Beclin 1 in renal tubular cells both in vivo and in vitro. Addition of 3-methyladenine suppressed the activity of autophagy and abrogated the renoprotective effects of HMSCs. The renoprotective effect of tubular autophagy was further validated in patients with ischemic AKI. AKI patients with higher renal LC3B expression were associated with better renal recovery. CONCLUSION: The present study describes that the enhancing effect of MSCs, and especially of HMCSs, on tissue autophagy can be applied to suppress renal tubular apoptosis and attenuate renal impairment during renal I/R injury in the rat. Our findings provide further mechanistic support to HMSCs therapy and its investigation in clinical trials of ischemic AKI.
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Lesión Renal Aguda , Células Madre Mesenquimatosas , Daño por Reperfusión , Lesión Renal Aguda/terapia , Animales , Apoptosis , Autofagia , Humanos , Hipoxia , Isquemia , Riñón , Masculino , Ratas , Ratas Sprague-Dawley , Reperfusión , Daño por Reperfusión/terapiaRESUMEN
BACKGROUND: Immunoglobulin M (IgM) mesangial deposition in pediatric minimal change disease (MCD) has been reported to be associated with steroid dependence and poor renal outcomes. However, the evidence linking the impacts of IgM mesangial deposition to the treatment prognosis in adult-onset MCD is still elusive. METHODS: In this retrospective cohort study, 37 adult patients with MCD received kidney biopsies from January 2010 to May 2020. Immunofluorescence microscopy was performed and the patients dichotomized according to IgM mesangial deposition (12 patients with positive IgM deposition; 25 patients with negative IgM deposition). We analyzed the clinical features, the dosage of immunosuppressive agents, and the response to treatment for 2 years between the two groups. RESULTS: Analysis of the clinical symptoms, the dosage of immunosuppressive treatment, and the time to remission revealed no statistical difference between the groups. However, compared to the negative IgM group, the frequency of relapses was significantly higher in the positive IgM group during the two-year follow-up period (the negative IgM group 0.25 episodes/year; the positive IgM group 0.75 episodes/year, p = 0.029). Furthermore, multivariate linear regression revealed that the positivity of IgM mesangial deposition is independently associated with the frequency of relapses (regression coefficient B 0.450, 95% CI 0.116-0.784, p = 0.010). CONCLUSIONS: Our findings indicated that adult-onset MCD patients with IgM mesangial deposition have a high risk of relapses. Therefore, intensive monitoring of disease activity should be considered in MCD adults with IgM mesangial deposition.
Asunto(s)
Mesangio Glomerular/metabolismo , Inmunoglobulina M/metabolismo , Nefrosis Lipoidea/etiología , Adulto , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , Recurrencia , Estudios Retrospectivos , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: Diabetic nephropathy (DN) is the most prevalent cause of renal disease in type 2 diabetic patients and is usually diagnosed clinically. A kidney biopsy is considered when non-diabetic renal disease (NDRD) is suspected, such as rapid progression in renal function impairment and severe proteinuria. Still, there is yet no consensus on the timing of kidney biopsy in type 2 diabetic patients. This study aims to identify markers that can help differentiate between DN and NDRD and guide the decision of kidney biopsy. METHODS: We retrospectively reviewed patients with type 2 diabetes who received kidney biopsy from 2008 to 2017 at Taipei Veterans General Hospital. Ophthalmologist consultation and outpatient records, diagnosis of kidney biopsy, laboratory data, and clinical characteristics were collected. RESULTS: This study enrolled 160 type 2 diabetic patients, among which 120 (75%) had isolated DN and 40 (25%) had NDRD ± DN (26 had isolated NDRD, and 14 had NDRD superimposed on DN). In multivariate logistic regression analysis, DM duration (odds ratio [OR]: 0.907; 95% confidence interval [CI]: 0.842-0.977; P = 0.01), diabetic retinopathy (OR: 0.196; 95% CI: 0.061-0.627; P = 0.006), and urinary RBC (OR: 1.068; 95% CI: 1.024-1.115; P = 0.002) were independent predictors of NDRD. In patients with diabetic retinopathy (n = 112, 70%), the presence of proliferative diabetic retinopathy, pan-retinal photocoagulation, and hematuria were factors predicting NDRD; and in patients without diabetic retinopathy (n = 48, 30%), short DM duration and hematuria were factors predicting NDRD. CONCLUSIONS: Using diabetic retinopathy, DM duration, and hematuria, we developed a 3-step approach to stratify patients into three categories with the different likelihoods of having NDRD. Then different strategies could be taken accordingly. Our stepwise approach is easy to follow and may serve as an appropriate and useful tool to help clinicians in making decisions of kidney biopsy in type 2 DM patients presenting with kidney diseases.