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1.
Case Rep Nephrol Dial ; 14(1): 128-137, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39118826

RESUMEN

Introduction: Drug-induced tubulointerstitial injury is a common cause of renal impairment. Since the mechanisms of drug-induced tubular injury are diverse, various treatment approaches are needed according to the pathogenesis. Renal biopsy is indispensable to determine not only the pathological diagnosis, but also the underlying mechanism, and to guide appropriate treatment. Most recently, one of the red yeast supplements has been widely highlighted as a novel cause of tubular damage, mainly in Japan and Asia. However, neither detailed pathological findings nor the mechanism of renal impairment has been sufficiently reported. Case Presentation: Two cases of renal impairment after taking red yeast supplement internally are presented. Both cases showed renal dysfunction with low uric acid, potassium, and phosphorus levels, characteristic features of Fanconi syndrome. The renal biopsy findings of both cases showed severe injury to the proximal tubules with mild inflammatory cell infiltration. The proximal tubules exhibited diffuse loss of the brush border, flattening, and tubular lumen dilation. Immunofluorescence showed no deposition of immunoglobulin and complement in the glomeruli and tubules. Electron microscopic findings indicated proximal tubular damage without crystal deposition. Moreover, immunohistochemistry using the proximal tubular marker CD10 and a marker for distal tubules including the loop of Henle, E-cadherin, collectively demonstrated that the focus of renal injury in both cases was mainly the proximal tubules. Conclusions: The red yeast rice supplement itself, its metabolized product, or other unknown contaminant components might directly induce proximal tubulopathy rather than an allergic reaction-related tubulointerstitial nephritis.

2.
Reprod Biomed Online ; 49(3): 104110, 2024 09.
Artículo en Inglés | MEDLINE | ID: mdl-38968730

RESUMEN

RESEARCH QUESTION: Is there a relationship between the pronuclear axis and the first cleavage plane formation in human pronuclear-stage embryos, and what are the effects on ploidy and clinical pregnancy rates? DESIGN: Transferred embryos were followed up until their prognoses. A total of 762 embryos formed two cells and reached the blastocyst stage after normal fertilization in a time-lapse incubator. Embryos were classified into three groups: group A: embryos in which the first plane of division was formed parallel to the axis of the pronucleus; group B: embryos in which cases of oblique formation were observed; and group C: embryos in which cases of perpendicular formation were observed. RESULTS: The euploidy rate was significantly higher in groups A and B than those in group C (P < 0.01), whereas the aneuploidy rate was significantly higher in group C (P < 0.01) than in groups A and B. No differences were found between the three groups in frequency of positive HCG-based pregnancy tests, frequency of clinical pregnancies, miscarriage rates or delivery rates. CONCLUSIONS: The formation pattern of the first plane of division relative to the pronuclear axis was a predictor of embryonic ploidy, with a reduced rate of euploidy and a high probability of aneuploidy observed when the first plane of division was perpendicular to the pronuclear axis.


Asunto(s)
Ploidias , Humanos , Femenino , Embarazo , Adulto , Índice de Embarazo , Blastocisto , Aneuploidia , Transferencia de Embrión , Desarrollo Embrionario/fisiología , Fertilización In Vitro , Núcleo Celular
3.
Science ; 385(6704): eadd8394, 2024 Jul 05.
Artículo en Inglés | MEDLINE | ID: mdl-38963856

RESUMEN

Transcribed enhancer maps can reveal nuclear interactions underpinning each cell type and connect specific cell types to diseases. Using a 5' single-cell RNA sequencing approach, we defined transcription start sites of enhancer RNAs and other classes of coding and noncoding RNAs in human CD4+ T cells, revealing cellular heterogeneity and differentiation trajectories. Integration of these datasets with single-cell chromatin profiles showed that active enhancers with bidirectional RNA transcription are highly cell type-specific and that disease heritability is strongly enriched in these enhancers. The resulting cell type-resolved multimodal atlas of bidirectionally transcribed enhancers, which we linked with promoters using fine-scale chromatin contact maps, enabled us to systematically interpret genetic variants associated with a range of immune-mediated diseases.


Asunto(s)
Linfocitos T CD4-Positivos , Elementos de Facilitación Genéticos , Predisposición Genética a la Enfermedad , Sitio de Iniciación de la Transcripción , Transcripción Genética , Humanos , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Cromatina/metabolismo , Cromatina/genética , Regiones Promotoras Genéticas , Linfocitos T Colaboradores-Inductores/inmunología , Análisis de Expresión Génica de una Sola Célula , Atlas como Asunto
4.
Kidney Int Rep ; 9(7): 2240-2249, 2024 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-39081744

RESUMEN

Introduction: Antineutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis (GN) is characterized by pauci-immune crescentic GN. Myeloperoxidase ANCA-associated GN (MPO-ANCA GN) with membranous nephropathy (MN), where bright granular capillary MPO and IgG staining along the glomerular basement membrane (GBM) is present, has been reported; however, its clinicopathological features remain unclear. Methods: We investigated 7 MPO-ANCA GN with MN and 11 control cases (6 MPO-ANCA GN and 5 primary MN cases). Proteomics of laser microdissected glomeruli followed by immunohistochemical analysis was performed to identify causal antigens in MPO-ANCA GN with MN. We described the clinicopathological features of MPO-associated MN compared with those of MPO-ANCA GN and primary MN. Results: We detected proteomic MPO and granular capillary MPO deposits in all MPO-ANCA GN with MN cases. Confocal microscopy revealed MPO and IgG colocalization along the GBM. MPO-associated MN clinicopathological features include greater proteinuria, a higher fibrous crescent rate, and a lower MPO-ANCA titer than MPO-ANCA GN. The estimated glomerular filtration rate (eGFR) and urinary protein excretion were lower in MPO-associated MN than in primary MN. Conclusion: MPO-associated MN, a unique type of secondary MN where MPO serves as the causal antigen, is a subset of MPO-ANCA GN with MN. Prolonged periods of MPO-ANCA GN and a low MPO-ANCA titer might be related to MPO-associated MN development.

5.
Eur J Obstet Gynecol Reprod Biol ; 300: 12-16, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38972161

RESUMEN

OBJECTIVE: In preimplantation genetic testing for aneuploidy, opinions regarding the handling of mosaic embryos vary. In this study, we aimed to investigate the effects of freeze-thawing, the number of cells obtained, and the number of laser irradiation cycles on the degree of embryonic mosaicism. STUDY DESIGN: This study was conducted in three parts. First, we classified specimens into the normal biopsy (control) (119 patients, 304 blastocysts) and thawed-biopsy (TB group) (26 patients, 72 blastocysts)) groups. The control and TB groups were then classified into three categories (euploidy, mosaic and aneuploidy) according to next-generation sequencing (NGS) results, and the number of cells collected and laser irradiation cycles were compared for each category. Subsequently, the effects of differences in the number of cells collected and laser irradiation cycles on NGS results were investigated in the control and TB groups. Finally, data on cell collection and laser irradiation cycles and NGS analysis results for the groups were compared. RESULTS: The TB group had a significantly higher incidence of chromosomal mosaicism than the control group. Neither the number of cells collected nor the laser irradiation cycles affected the percentage of chromosomal mosaicism. However, the freeze-thaw process increased the occurrence of mosaicism. CONCLUSIONS: This study showed that repeated freeze-thaw cycles increase the incidence of mosaicism, but the embryos are not aneuploid and are therefore suitable for transfer.


Asunto(s)
Aneuploidia , Criopreservación , Mosaicismo , Diagnóstico Preimplantación , Humanos , Mosaicismo/embriología , Diagnóstico Preimplantación/métodos , Femenino , Adulto , Pruebas Genéticas/métodos , Blastocisto/efectos de la radiación , Embarazo , Rayos Láser
7.
Pathol Int ; 74(6): 317-326, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38634742

RESUMEN

Immune checkpoint inhibitors (ICIs) can provide survival benefits to cancer patients; however, they sometimes result in the development of renal immune-related adverse events (irAEs). Tubulointerstitial nephritis (TIN) is the most representative pathological feature of renal irAEs. However, the clinicopathological entity and underlying pathogenesis of ICI-induced TIN are unclear. Therefore, we compared the clinical and histological features of this condition with those of non-ICI drug-induced TIN. Age and C-reactive protein levels were significantly higher in ICI-induced TIN, but there were no significant differences in renal function. Immunophenotyping of ICI-induced TIN showed massive T cell and macrophage infiltration with fewer B cells, plasma cells, neutrophils, and eosinophils. Compared with those in non-ICI drug-induced TIN, CD4+ cell numbers were significantly lower in ICI-induced TIN but CD8+ cell numbers were not significantly different. However, CD8/CD3 and CD8/CD4 ratios were higher in ICI-induced TIN. Moreover, CD25+ and FOXP3+ cells, namely regulatory T cells, were less abundant in ICI-induced TIN. In conclusion, T cell, B cell, plasma cell, neutrophil, and eosinophil numbers proved useful for differentiating ICI-induced and non-ICI drug-induced TIN. Furthermore, the predominant distribution of CD8+ cells and low accumulation of regulatory T cells might be associated with ICI-induced TIN development.


Asunto(s)
Linfocitos T CD8-positivos , Inhibidores de Puntos de Control Inmunológico , Nefritis Intersticial , Linfocitos T Reguladores , Humanos , Nefritis Intersticial/inducido químicamente , Nefritis Intersticial/patología , Nefritis Intersticial/inmunología , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Masculino , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/patología , Linfocitos T Reguladores/efectos de los fármacos , Femenino , Anciano , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/inmunología , Persona de Mediana Edad , Adulto , Anciano de 80 o más Años
8.
J Clin Med ; 13(8)2024 Apr 10.
Artículo en Inglés | MEDLINE | ID: mdl-38673446

RESUMEN

Background/Objectives: Expansive open-door laminoplasty results in favorable clinical outcomes for cervical myelopathy. However, some postoperative complications associated with surgical invasiveness, such as axial neck pain and kyphosis, have not been resolved. The use of an exoscope, which is a recently introduced novel magnification tool, allows for traditional open-door laminoplasty with minimal invasiveness. Therefore, we propose the use of exoscopic minimally invasive open-door laminoplasty (exLAP) and present its clinical outcomes during the acute postoperative period. Methods: A total of 28 patients who underwent open-door laminoplasty at C3-C6 were reviewed. Of these patients, 17 underwent exLAP (group M) and 11 underwent conventional Hirabayashi open-door laminoplasty (group H). Outcomes were evaluated using numerical rating scale (NRS) scores for neck pain and the frequency of oral analgesic use from postoperative day 1 to 7. Results: The NRS score for neck pain was significantly lower for patients in group M than for those in group H. Conclusions: ExLAP is a novel, practical, and minimally invasive surgical technique that may alleviate the postoperative axial pain of patients with cervical myelopathy.

9.
Commun Biol ; 7(1): 488, 2024 Apr 22.
Artículo en Inglés | MEDLINE | ID: mdl-38649462

RESUMEN

Antibody responses, involving B cells, CD4 + T cells, and macrophages, are implicated in autoimmune diseases and organ transplant rejection. We have previously shown that inhibiting FROUNT with disulfiram (DSF) suppresses macrophage activation and migration, effectively treating inflammatory diseases. In this study, we investigated the effectiveness of DSF in antibody-producing reactions. Using a heart transplantation mouse model with antibody-mediated rejection, we administered anti-CD8 antibody to exclude cellular rejection. DSF directly inhibited B cell responses in vitro and significantly reduced plasma donor-specific antibodies and graft antibody deposition in vivo, resulting in prolonged survival of the heart graft. DSF also mediated various effects, including decreased macrophage infiltration and increased Foxp3+ regulatory T-cells in the grafts. Additionally, DSF inhibited pyrimidine metabolism-related gene expression induced by B-cell stimulation. These findings demonstrate that DSF modulates antibody production in the immune response complexity by regulating B-cell and macrophage responses.


Asunto(s)
Linfocitos B , Disulfiram , Activación de Macrófagos , Pirimidinas , Animales , Disulfiram/farmacología , Ratones , Linfocitos B/inmunología , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Activación de Macrófagos/efectos de los fármacos , Pirimidinas/farmacología , Ratones Endogámicos C57BL , Trasplante de Corazón/efectos adversos , Masculino , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Macrófagos/metabolismo , Formación de Anticuerpos/efectos de los fármacos , Rechazo de Injerto/prevención & control , Rechazo de Injerto/inmunología , Ratones Endogámicos BALB C
10.
Syst Biol Reprod Med ; 70(1): 52-58, 2024 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-38426509

RESUMEN

The aim of this study was to non-invasively investigate euploid embryos using methods other than pre-implantation genetic testing for aneuploidy. The study focused on direct cleavage (DC) observed during early embryo development. We also investigated the relationship between the mode of early embryo division and embryo ploidy. Embryos were divided into the normal cleavage (NC) and DC groups, and the DC group was further subdivided into the DC-First (DC-F) and DC-Second (DC-S) groups, depending on whether DC was observed at the first or second cleavage, respectively. The acquisition rates of euploid embryos and embryos appropriate for transfer were compared between the groups. Our results revealed that the timing of the first division did not differ between blastocyst grades or in embryos with varying degrees of ploidy. Further, the timing of the first cleavage did not affect the acquisition rate of embryos appropriate for transfer and euploid embryo formation rate did not significantly differ between the DC and NC groups. We also noted that for embryos appropriate for transfer, euploidy acquisition rate did not differ significantly between the DC and NC groups. Further, the euploidy acquisition rate of embryos did not differ between the DC-F and DC-S groups. However, the acquisition rate of embryos appropriate for transfer, including those with low mosaicism, was significantly higher in the DC-S group than in the DC-F group. These findings indicated that the number of good-quality blastocysts formed was significantly higher in the NC group than in the DC group and the acquisition rate of embryos appropriate for transfer, including those with low mosaicism, was significantly higher in the DC-S group than in the DC-F group.


Asunto(s)
Diagnóstico Preimplantación , Embarazo , Femenino , Humanos , Diagnóstico Preimplantación/métodos , Estudios Retrospectivos , Implantación del Embrión , Desarrollo Embrionario , Aneuploidia , Pruebas Genéticas , Blastocisto , Mosaicismo
11.
CEN Case Rep ; 2024 Jan 27.
Artículo en Inglés | MEDLINE | ID: mdl-38280123

RESUMEN

Recently, several target antigens of membranous nephropathy (MN), such as phospholipase A2 receptor (PLA2R) and exostosin 1/exostosin 2 (EXT1/2), have been discovered. A 30-year-old woman was referred to our hospital with nephrotic range proteinuria and microscopic hematuria. She was first noted to have proteinuria before pregnancy, and her proteinuria worsened in the postpartum period. A renal biopsy showed MN. Immunofluorescence microscopy showed IgG, IgA, IgM, C3, C4, and C1q depositions in the mesangial area and glomerular capillary walls (GCWs). Regarding the IgG subclass, IgG1 and IgG3 were detected on glomeruli. Electron microscopy showed subepithelial electron-dense deposits (EDDs). EDDs were also detected in paramesangial and subendothelial areas. The diagnosis of membranous lupus nephritis (MLN) was suspected, but she did not fulfill the criteria for systemic lupus erythematosus. Neither anti-nuclear antibody nor hypocomplementemia were detected. We further evaluated glomerular EXT1/2 expressions, which were evident on GCWs. In addition, PLA2R was also detected on GCWs, although serum antibody for PLA2R was negative. She responded to immunosuppressive therapy with decreased proteinuria. In the present case, glomerular PLA2R expression implied the possibility of primary MN. However, pathological findings with a full-house staining pattern and glomerular EXT1/2 expressions were very similar to those of lupus-associated MN. Glomerular PLA2R expression appeared not to reflect immunocomplexes of PLA2R and autoantibody when considering the results for glomerular IgG subclass and the absence of serum anti-PLA2R antibody. Collectively, it is plausible that this was a case of a relatively young postpartum female who developed latent MLN rather than primary MN.

12.
Blood ; 143(3): 243-257, 2024 Jan 18.
Artículo en Inglés | MEDLINE | ID: mdl-37922454

RESUMEN

ABSTRACT: Regulation of lineage biases in hematopoietic stem and progenitor cells (HSPCs) is pivotal for balanced hematopoietic output. However, little is known about the mechanism behind lineage choice in HSPCs. Here, we show that messenger RNA (mRNA) decay factors regnase-1 (Reg1; Zc3h12a) and regnase-3 (Reg3; Zc3h12c) are essential for determining lymphoid fate and restricting myeloid differentiation in HSPCs. Loss of Reg1 and Reg3 resulted in severe impairment of lymphopoiesis and a mild increase in myelopoiesis in the bone marrow. Single-cell RNA sequencing analysis revealed that Reg1 and Reg3 regulate lineage directions in HSPCs via the control of a set of myeloid-related genes. Reg1- and Reg3-mediated control of mRNA encoding Nfkbiz, a transcriptional and epigenetic regulator, was essential for balancing lymphoid/myeloid lineage output in HSPCs in vivo. Furthermore, single-cell assay for transposase-accessible chromatin sequencing analysis revealed that Reg1 and Reg3 control the epigenetic landscape on myeloid-related gene loci in early stage HSPCs via Nfkbiz. Consistently, an antisense oligonucleotide designed to inhibit Reg1- and Reg3-mediated Nfkbiz mRNA degradation primed hematopoietic stem cells toward myeloid lineages by enhancing Nfkbiz expression. Collectively, the collaboration between posttranscriptional control and chromatin remodeling by the Reg1/Reg3-Nfkbiz axis governs HSPC lineage biases, ultimately dictating the fate of lymphoid vs myeloid differentiation.


Asunto(s)
Médula Ósea , Células Madre Hematopoyéticas , Linaje de la Célula/genética , Células Madre Hematopoyéticas/metabolismo , Médula Ósea/metabolismo , Hematopoyesis/genética , ARN Mensajero/metabolismo , Diferenciación Celular/genética
13.
Front Endocrinol (Lausanne) ; 14: 1277873, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38027155

RESUMEN

Introduction: The delayed-start gonadotropin-releasing hormone antagonist protocol seems effective for patients who are poor ovarian responders, but there are insufficient data on whether it is also effective for patients with poor-quality embryos and low rates of good blastocyst formation. Specifically, the effectiveness of delayed-start gonadotropin-releasing hormone antagonists with progesterone has not been adequately investigated. Therefore, we compared the efficacy of the original delayed-start gonadotropin-releasing hormone antagonist protocol using medroxyprogesterone acetate (MPA) and high-dose gonadotropin in patients with poor ovarian response. Methods: Overall, 156 patients with recurrent assisted reproductive technology failure who underwent the original protocol were included. They received cetrorelix acetate (3 mg) and MPA (10 mg) on cycle day 3, and high-dose gonadotropin was initiated on day 11. When the leading follicle reached 14 mm, ganirelix acetate (0.25 mg) was administered until the trigger day. The number of oocytes retrieved, metaphase II (MII) oocytes, two pronuclear (2PN) zygotes, and good blastocysts and live birth rates were compared between the previous (Cycle A) and original (Cycle B) cycles in three groups (Group A, all patients; Group B, poor responders; and Group C, patients with poor-quality embryos). Results: In Group A (n=156), the number of MII oocytes (3.6 ± 3.3 versus 4.5 ± 3.6), 2PN zygotes (2.8 ± 2.9 versus 3.8 ± 3.1), good blastocysts (0.5 ± 0.9 versus 1.2 ± 1.6), and live birth rates (0.6 versus 24.4) significantly increased in Cycle B. Similar results were obtained in Group B (n=83; 2PN zygotes [1.7 ± 1.7 versus 2.3 ± 1.8], good blastocysts [0.4 ± 0.7 versus 0.9 ± 1.3], live birth rates [0 versus 18.1]) and Group C (n=73; MII oocytes [5.1 ± 3.8 versus 6.6 ± 4.0], 2PN zygotes [4.0 ± 3.4 versus 5.4 ± 3.4], good blastocysts [0.7 ± 1.1 versus 1.6 ± 1.9], and live birth rates [1.4 versus 31.5]). Conclusion: This original protocol increased the number of MII oocytes retrieved, 2PN zygotes, good blastocysts, and live birth rates in both poor responders and in patients with poor-quality embryos.


Asunto(s)
Gonadotropinas , Acetato de Medroxiprogesterona , Embarazo , Femenino , Humanos , Índice de Embarazo , Hormona Liberadora de Gonadotropina , Inducción de la Ovulación/métodos , Antagonistas de Hormonas
14.
BMC Nephrol ; 24(1): 218, 2023 07 24.
Artículo en Inglés | MEDLINE | ID: mdl-37488532

RESUMEN

BACKGROUND: Recent developments in mass spectrometry (MS) have revealed target antigens for membranous nephropathy (MN), including phospholipase A2 receptor and exostosin 1/exostosin 2 (EXT1/2). EXT1/2 are known antigens of autoimmune disease-related MN, especially membranous lupus nephritis. We describe the case of an elderly man who developed nephrotic syndrome followed by progressive renal dysfunction. CASE PRESENTATION: A 78-year-old man presented with rapidly progressive renal dysfunction with proteinuria and hematuria. Three years previously, he had developed leg edema but did not receive any treatment. Laboratory tests showed elevated anti-nuclear antibody (Ab), anti-dsDNA Ab titer, and hypocomplementemia, indicating systemic lupus erythematous. Myeloperoxidase anti-neutrophil cytoplasmic Ab (ANCA) and anti-glomerular basement membrane (GBM) Ab were also detected. The renal pathologic findings were compatible with crescentic glomerulonephritis (GN), whereas non-crescentic glomeruli exhibited MN without remarkable endocapillary or mesangial proliferative change. Immunofluorescence microscopy revealed glomerular IgG, C3, and C1q deposition. All IgG subclasses were positive in glomeruli. Anti-PLA2R Ab in serum was negative. MS analysis was performed to detect the antigens of MN, and EXT1/2 was detected in glomeruli. Therefore, we reached a diagnosis of membranous lupus nephritis concurrent with both ANCA-associated vasculitis and anti-GBM-GN. The simultaneous occurrence of these three diseases is extremely rare. CONCLUSIONS: This is the first report of EXT1/2-related membranous lupus nephritis concurrent with ANCA-associated vasculitis and anti-GBM-GN. This case demonstrates the usefulness of MS in diagnosing complicated cases of MN.


Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos , Glomerulonefritis Membranoproliferativa , Glomerulonefritis Membranosa , Glomerulonefritis , Lupus Eritematoso Sistémico , Nefritis Lúpica , Anciano , Humanos , Masculino , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Anticuerpos Anticitoplasma de Neutrófilos , Glomerulonefritis/patología , Glomerulonefritis Membranoproliferativa/complicaciones , Glomerulonefritis Membranosa/complicaciones , Glomerulonefritis Membranosa/diagnóstico , Inmunoglobulina G , Lupus Eritematoso Sistémico/complicaciones , Nefritis Lúpica/complicaciones , Nefritis Lúpica/diagnóstico , Espectrometría de Masas , N-Acetilglucosaminiltransferasas
15.
Elife ; 122023 07 18.
Artículo en Inglés | MEDLINE | ID: mdl-37461309

RESUMEN

Ossification of the posterior longitudinal ligament of the spine (OPLL) is an intractable disease leading to severe neurological deficits. Its etiology and pathogenesis are primarily unknown. The relationship between OPLL and comorbidities, especially type 2 diabetes (T2D) and high body mass index (BMI), has been the focus of attention; however, no trait has been proven to have a causal relationship. We conducted a meta-analysis of genome-wide association studies (GWASs) using 22,016 Japanese individuals and identified 14 significant loci, 8 of which were previously unreported. We then conducted a gene-based association analysis and a transcriptome-wide Mendelian randomization approach and identified three candidate genes for each. Partitioning heritability enrichment analyses observed significant enrichment of the polygenic signals in the active enhancers of the connective/bone cell group, especially H3K27ac in chondrogenic differentiation cells, as well as the immune/hematopoietic cell group. Single-cell RNA sequencing of Achilles tendon cells from a mouse Achilles tendon ossification model confirmed the expression of genes in GWAS and post-GWAS analyses in mesenchymal and immune cells. Genetic correlations with 96 complex traits showed positive correlations with T2D and BMI and a negative correlation with cerebral aneurysm. Mendelian randomization analysis demonstrated a significant causal effect of increased BMI and high bone mineral density on OPLL. We evaluated the clinical images in detail and classified OPLL into cervical, thoracic, and the other types. GWAS subanalyses identified subtype-specific signals. A polygenic risk score for BMI demonstrated that the effect of BMI was particularly strong in thoracic OPLL. Our study provides genetic insight into the etiology and pathogenesis of OPLL and is expected to serve as a basis for future treatment development.


Asunto(s)
Diabetes Mellitus Tipo 2 , Osificación del Ligamento Longitudinal Posterior , Animales , Ratones , Osteogénesis , Estudio de Asociación del Genoma Completo , Diabetes Mellitus Tipo 2/patología , Columna Vertebral/patología , Osificación del Ligamento Longitudinal Posterior/genética , Osificación del Ligamento Longitudinal Posterior/patología
16.
Int J Mol Sci ; 24(9)2023 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-37176142

RESUMEN

Recently, the comprehensive concept of "infection-related glomerulonephritis (IRGN)" has replaced that of postinfectious glomerulonephritis (PIGN) because of the diverse infection patterns, epidemiology, clinical features, and pathogenesis. In addition to evidence of infection, hypocomplementemia particularly depresses serum complement 3 (C3), with endocapillary proliferative and exudative GN developing into membranoproliferative glomerulonephritis (MPGN); also, C3-dominant or co-dominant glomerular immunofluorescence staining is central for diagnosing IRGN. Moreover, nephritis-associated plasmin receptor (NAPlr), originally isolated from the cytoplasmic fraction of group A Streptococci, is vital as an essential inducer of C3-dominant glomerular injury and is a key diagnostic biomarker for IRGN. Meanwhile, "C3 glomerulopathy (C3G)", also showing a histological pattern of MPGN due to acquired or genetic dysregulation of the complement alternative pathway (AP), mimics C3-dominant IRGN. Initially, C3G was characterized by intensive "isolated C3" deposition on glomeruli. However, updated definitions allow for glomerular deposition of other complement factors or immunoglobulins if C3 positivity is dominant and at least two orders of magnitude greater than any other immunoreactant, which makes it challenging to quickly distinguish pathomorphological findings between IRGN and C3G. As for NAPlr, it was demonstrated to induce complement AP activation directly in vitro, and it aggravates glomerular injury in the development of IRGN. A recent report identified anti-factor B autoantibodies as a contributing factor for complement AP activation in pediatric patients with PIGN. Moreover, C3G with glomerular NAPlr deposition without evidence of infection was reported. Taken together, the clinico-pathogenic features of IRGN overlap considerably with those of C3G. In this review, similarities and differences between the two diseases are highlighted.


Asunto(s)
Glomerulonefritis Membranoproliferativa , Glomerulonefritis , Humanos , Niño , Glomerulonefritis/patología , Glomerulonefritis Membranoproliferativa/etiología , Glomérulos Renales/patología , Autoanticuerpos
17.
BMC Nephrol ; 24(1): 48, 2023 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-36894873

RESUMEN

BACKGROUND: Immune checkpoint inhibitors (ICIs) have provided significant benefits in cancer treatment, but they could develop immune-related adverse events (irAE). ICI-associated renal adverse effects are rare and tubulointerstitial nephritis (TIN) is the most common in the renal irAE. However, only a few case reports of renal vasculitis associated with ICI have been reported. In addition, the characteristics of infiltrating inflammatory cells of ICI-associated TIN and renal vasculitis have been uncertain. CASE PRESENTATION: A 65-year-old man received immune checkpoint inhibitors (ICIs), anti-CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) and anti-PD-1 (programmed cell death 1) antibodies for aggravated metastatic malignant melanoma. About 1 week after the second administration of nivolumab and ipilimumab, acute kidney injury developed. A renal biopsy was performed that showed TIN and non-necrotizing granulomatous vasculitis in interlobular arteries. Massive CD3+ T cells and CD163+ macrophages infiltrated both tubulointerstitium and interlobular arteries. Many infiltrating cells tested positive for Ki-67 and PD-1 ligand (PD-L1), but negative for PD-1. In CD3+ T cells, CD8+ T cells were predominantly infiltrated, and these cells were positive for Granzyme B (GrB) and cytotoxic granule TIA-1, but negative for CD25, indicating antigen-independent activated CD8+ T cells. Infiltration of CD4+ T cells was noted without obvious CD4+ CD25+ regulatory T (Treg) cells. His renal dysfunction recovered within 2 months of treatment with prednisolone in addition to discontinuation of nivolumab and ipilimumab. CONCLUSIONS: We herein reported a case of ICI-related TIN and renal granulomatous vasculitis with infiltration of massive antigen-independent activated CD8+ T cells and CD163+ macrophages, and none or few CD4+ CD25+ Treg cells. These infiltrating cells might be a characteristic of the development of renal irAE.


Asunto(s)
Antineoplásicos Inmunológicos , Nefritis Intersticial , Vasculitis del Sistema Nervioso Central , Anciano , Humanos , Masculino , Antineoplásicos Inmunológicos/efectos adversos , Linfocitos T CD8-positivos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Ipilimumab/efectos adversos , Nefritis Intersticial/inducido químicamente , Nivolumab/efectos adversos , Vasculitis del Sistema Nervioso Central/inducido químicamente
18.
Acta Med Okayama ; 77(1): 45-55, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-36849145

RESUMEN

Novel deep learning image reconstruction (DLIR) reportedly changes the image quality characteristics based on object contrast and image noise. In clinical practice, computed tomography image noise is usually controlled by tube current modulation (TCM) to accommodate changes in object size. This study aimed to evaluate the image quality characteristics of DLIR for different object sizes when the in-plane noise was controlled by TCM. Images acquisition was performed on a GE Revolution CT system to investigate the impact of the DLIR algorithm compared to the standard reconstructions of filtered-back projection (FBP) and hybrid iterative reconstruction (hybrid-IR). The image quality assessment was performed using phantom images, and an observer study was conducted using clinical cases. The image quality assessment confirmed the excellent noise- reduction performance of DLIR, despite variations due to phantom size. Similarly, in the observer study, DLIR received high evaluations regardless of the body parts imaged. We evaluated a novel DLIR algorithm by replicating clinical behaviors. Consequently, DLIR exhibited higher image quality than those of FBP and hybrid-IR in both phantom and observer studies, albeit the value depended on the reconstruction strength, and proved itself capable of providing stable image quality in clinical use.


Asunto(s)
Aprendizaje Profundo , Humanos , Fantasmas de Imagen , Algoritmos , Tomografía Computarizada por Rayos X , Procesamiento de Imagen Asistido por Computador
19.
Sci Rep ; 13(1): 1849, 2023 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-36725891

RESUMEN

To evaluate the radiological differences between diffuse idiopathic skeletal hyperostosis (DISH) and ankylosing spondylitis (AS) using whole spine computed tomography (CT), including the spine and sacroiliac joint (SIJ). The ossification and bridging of spinal ligament and fusion of the facet joint and SIJ were evaluated in 111 patients who were diagnosed with DISH and 27 patients with AS on the whole spine CT. The number of anterior bridging and shape of bridging (candle-wax-type/ smooth-type) were also evaluated. We further evaluated patients with DISH and AS by matching their age and sex. Complete SIJ fusion was more common in AS, whereas anterior and posterior bony bridging around SIJ was more common in DISH. However, 63% of patients with DISH had a partial or complete fusion. In spinal anterior bony bridging, the majority of patients with AS had the smooth-type, whereas those with DISH had the candle-wax-type. However, some of the patients with DISH (11%) had smooth-type. Intervertebral facet joint fusion is more common in AS. The number of anterior spinal bony bridging was greater in AS than in DISH, especially in the lumbar spine. These results are useful in differentiating DISH from AS and should therefore be considered when making a diagnosis.


Asunto(s)
Hiperostosis Esquelética Difusa Idiopática , Espondilitis Anquilosante , Humanos , Hiperostosis Esquelética Difusa Idiopática/diagnóstico por imagen , Espondilitis Anquilosante/diagnóstico por imagen , Articulación Sacroiliaca/diagnóstico por imagen , Tomografía Computarizada por Rayos X/métodos , Vértebras Lumbares/diagnóstico por imagen
20.
Arch Gynecol Obstet ; 307(5): 1607-1612, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36799921

RESUMEN

PURPOSE: We examined the impacts of the smooth endoplasmic reticulum cluster (sERC) presence on embryonic development and blastocyst ploidy. METHODS: Patients who underwent oocyte retrieval from January 2019 to November 2021 were included in the study. We classified the oocytes into three groups: normal oocytes in the sERC ( -) cycle, normal oocytes in the sERC ( +) cycle, and sERC ( +) oocytes. Next, the levels of serum estradiol, progesterone, anti-Mullerian hormone, follicle-stimulating hormone, and human menopausal gonadotropin were compared between the groups. Moreover, fertilization, degeneration, and abnormal fertilization rates were compared between groups. To investigate developmental outcomes, the blastocyst and good-quality blastocyst rates after intracytoplasmic sperm injection were compared. The quality of the transferred blastocysts was evaluated at follow-up. Additionally, embryos were submitted for next-generation sequencing analysis to examine the effect of sERC presence on ploidy. RESULTS: The sERC ( +) group had significantly higher serum estradiol, serum progesterone, and serum anti-Mullerian hormone concentrations compared to those in the sERC ( -) group (P < 0.01). The abnormal fertilization rate was higher in the sERC ( +) cycle-sERC ( +) oocyte group (16.1%; 37/230) than in the sERC ( +) cycle-normal oocyte (6.2%; 63/971) and sERC ( -) cycle-normal oocyte groups (7.1%; 174/2467) (P < 0.01). After embryo transfer, nine women gave birth, and no confirmed congenital anomalies were observed. There was no significant difference in ploidy between the sERC ( +) and sERC ( -) groups. CONCLUSION: The occurrence rates of embryos with euploidy were similar between the sERC ( +) and sERC ( -) groups.


Asunto(s)
Hormona Antimülleriana , Progesterona , Embarazo , Humanos , Masculino , Femenino , Índice de Embarazo , Betahistina , Semen , Ploidias , Oocitos , Blastocisto , Estradiol , Retículo Endoplásmico Liso , Fertilización In Vitro
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