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Bryophyllum pinnatum (BP) is a medicinal plant used to treat many conditions when taken as a leaf juice, leaves in capsules, as an ethanolic extract, and as herbal tea. These preparations have been chemically analyzed except for decoctions derived from boiled green leaves. In preparation for a clinical trial to validate BP tea as a treatment for kidney stones, we used NMR and MS analyses to characterize the saturation kinetics of the release of metabolites. During boiling of the leaves, (a) the pH decreased to 4.8 within 14 min and then stabilized; (b) regarding organic acids, citric and malic acid were released with maximum release time (tmax) = 35 min; (c) for glycoflavonoids, quercetin 3-O-α-L-arabinopyranosyl-(1 â 2)-α-L-rhamnopyranoside (Q-3O-ArRh), myricetin 3-O-α-L-arabinopyranosyl-(1 â 2)-α-L-rhamnopyranoside (M-3O-ArRh), kappinatoside, myricitrin, and quercitrin were released with tmax = 5-10 min; and (d) the total phenolic content (TPC) and the total antioxidant capacity (TAC) reached a tmax at 55 min and 61 min, respectively. In summary, 24 g of leaves boiled in 250 mL of water for 61 min ensures a maximal release of key water-soluble metabolites, including organic acids and flavonoids. These metabolites are beneficial for treating kidney stones because they target oxidative stress and inflammation and inhibit stone formation.
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Kalanchoe , Cálculos Renales , Espectroscopía de Resonancia Magnética , Extractos Vegetales , Hojas de la Planta , Kalanchoe/química , Espectroscopía de Resonancia Magnética/métodos , Cálculos Renales/tratamiento farmacológico , Cálculos Renales/metabolismo , Cálculos Renales/química , Extractos Vegetales/química , Extractos Vegetales/farmacología , Hojas de la Planta/química , Cinética , Espectrometría de Masas/métodos , Humanos , Malatos/química , Malatos/metabolismoRESUMEN
Rationale: Imatinib is used in the treatment of Philadelphia chromosome positive (Ph+) leukemias and has been reported to have a direct effect on bone physiology. Presentation: To report on a child with Ph+ acute lymphoblastic leukemia who presented with bilateral flank pain and gross hematuria. Diagnosis: She was diagnosed with obstructive kidney stones 101 days after commencing daily oral imatinib. Stone analysis revealed the presence of calcium phosphate. Interventions and outcome: The patient passed the stones spontaneously with medical therapy that included the use of thiazide, allopurinol, and potassium citrate, but she required temporary insertion of a double-J stent to relieve an obstruction. Novel findings: Imatinib inhibits receptor tyrosine kinases and stimulates the flux of calcium from the extracellular fluid into bone, resulting in hypocalcemia with a compensatory rise in parathyroid hormone that may result in phosphaturia and the formation of calcium phosphate stones. Given that kidney stones are rare events in children, we believe that monitoring for kidney stone formation needs to be performed in children receiving imatinib.
Justification: L'imatinib est utilisé dans le traitement des leucémies à chromosome Philadelphie (Ph+) et a été décrit comme ayant un effet direct sur la physiologie osseuse. Présentation du cas: Une enfant atteinte d'une leucémie lymphoblastique aiguë à Ph+ présentant des douleurs lombaires bilatérales et une hématurie macroscopique. Diagnostic: La patiente a reçu un diagnostic de calculs rénaux obstructifs 101 jours après avoir commencé la prise quotidienne d'imatinib par voie orale. L'analyse des calculs a révélé la présence de phosphate de calcium. Interventions et résultats: La patiente a éliminé spontanément ses calculs grâce à un traitement médical qui comprenait un diurétique thiazidique, de l'allopurinol et du citrate de potassium, mais on a dû lui insérer temporairement une endoprothèse double J pour traiter une obstruction. Nouveaux enseignements: L'imatinib inhibe les récepteurs de la tyrosine kinase et favorise le flux du calcium du liquide extracellulaire vers les os, ce qui entraîne une hypocalcémie avec élévation secondaire de l'hormone parathyroïdienne pouvant provoquer une phosphaturie et la formation de calculs de phosphate de calcium. Puisque la formation de calculs rénaux est rare chez les enfants, nous pensons qu'elle devrait faire l'objet d'une surveillance chez les enfants qui reçoivent de l'imatinib.
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OBJECTIVE: Dosimetric sparing of critical swallowing structures like constrictor muscles and larynx can lead to improved functional outcomes in head and neck cancer patients treated by chemoradiation. METHODS: A total of 50 Patients with newly diagnosed, biopsy proven AJCC stage II-IV head and neck squamous cell cancers (HNSCC) were prospectively studied. 25 patients were randomized in each arm of Dysphagia-optimized Intensity Modulated Radiotherapy (Do-IMRT) arm and Standard Intensity Modulated Radiotherapy (SIMRT) arm. Additional dose constraints were applied to the dysphagia/aspiration at risk structures (DARS) in Do-IMRT arm. The impact of using Do-IMRT was assessed by the difference in mean scores of MD Anderson Dysphagia Inventory (MDADI), University of Washington-Quality of Life (UW-QOL), and 100 ml Water Swallow Test (WST). RESULTS: Patients in both arms showed significant (P <0.01 or P < 0.001) improvement in MDADI (global and composite), UW-QOL and Water Swallow Test scores. However, the improvements were found significantly higher in Do-IMRT as compared to S-IMRT. Significant improvements i.e. mean change from baseline to 12 months (P <0.05 or P <0.01 or P <0.001) were 19. 2, 8.6, 14.3, 7.4, 18.6 and 22.0% higher respectively in Do-IMRT as compared to S-IMRT in MDADI global and composite scores, UW-QOL swallowing scores, and 100 ml Water Swallow (swallowing volume, swallowing capacity and swallowing speed) test scores. CONCLUSION: The Do-IMRT improves swallowing functions compared to S-IMRT in HNSCC patients treated with radical chemoradiation.
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Trastornos de Deglución , Neoplasias de Cabeza y Cuello , Radioterapia de Intensidad Modulada , Humanos , Trastornos de Deglución/etiología , Carcinoma de Células Escamosas de Cabeza y Cuello , Calidad de Vida , Neoplasias de Cabeza y Cuello/radioterapia , AguaRESUMEN
BACKGROUND: In cervical cancer treatment, overall treatment time (OTT) is an important prognostic factor. This study compares the clinical outcomes when High-Dose-Rate Intracavitary-Brachytherapy(HDR-ICRT) is interdigitated with external beam radiotherapy(EBRT) versus sequential HDR-ICRT after EBRT in the treatment of locally advanced carcinoma cervix. METHODS: Histologically confirmed carcinoma cervix patients [FIGO Stage IIB-IVA (except IIIC-2)] were included and randomized into two groups. The study group received EBRT 50Gy in 25 fractions with interdigitated HDR-ICRT 7Gy per fraction weekly for three fractions starting after completion of 3 weeks of EBRT or as soon as cervical os became negotiable thereafter. Patients in the control group received EBRT 50Gy in 25 fractions with sequential HDR-ICRT 7Gy per fraction weekly for three fractions starting one week after completion of EBRT. All patients were regularly followed up during and after radiotherapy for local toxicity and disease control. RESULTS: This study enrolled 102 patients; 51 in each arm. Median OTT in study and control arm were 46 and 60 days, respectively. Median follow-up duration was 24 months (two years). Loco-regional control after two years of follow-up was 84.31 % and 72.54% of patients in study arm control arm respectively (p-value 0.148). Two (3.92%) patients from study arm and eight (15.68%) from control arm had residual disease. Two patients in study arm and one from control arm had local recurrence. Two patients from study arm three patients from control arm developed distant metastases. RTOG mucosal grade III acute mucosal toxicity in either arm. Cervical-os negotiability was limiting factor for interdigitated HDR-ICRT. CONCLUSIONS: Interdigitated HDR-ICRT with EBRT may give local control with manageable toxicities as compared to sequential HDR-ICRT, with the advantage of significant reduction in OTT.
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Braquiterapia , Carcinoma de Células Escamosas , Neoplasias del Cuello Uterino , Femenino , Humanos , Cuello del Útero/patología , Carcinoma de Células Escamosas/patología , Dosificación Radioterapéutica , Neoplasias del Cuello Uterino/radioterapia , Neoplasias del Cuello Uterino/patologíaRESUMEN
Salivary glands consist of highly specialized epithelial cells that secrete the fluid, saliva, and/or transport saliva into the oral cavity. Saliva is essential to lubricate the oral cavity for food consumption and to maintain the hygiene of the oral cavity. In this review, we will focus on the formation of the epithelial cell lineage and the cell junctions that are essential for formation of saliva and maintenance of the epithelial barrier between the ducts that transport saliva and the extracellular environment.
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Glándula Submandibular , Uniones Estrechas , Glándulas Salivales , Células Epiteliales , Uniones IntercelularesRESUMEN
Claudins are a family of tight junction proteins expressed in epithelial tissues during development and in postnatal life. We hypothesized that claudins are required for branching morphogenesis in the developing chick lung. To test this hypothesis, we exposed cultured chick lung explants at embryonic day 5 to a truncated non-toxic form of the Clostridium perfringens enterotoxin known as C-CPE that removes C-CPE-sensitive claudins from tight junctions. Using in situ hybridization and immunofluorescence studies, we established that only one C-CPE-sensitive claudin, Claudin-3, was expressed in the chick lung at this stage. C-CPE treated lung explants did not exhibit any defect in lung branching compared to controls. However, they did exhibit a significantly smaller lumen area, suggesting that paracellular permeability was perturbed. The decrease in lumen area was associated with a loss of Claudin-3 expression within tight junctions of the respiratory epithelium and an increase in permeability of the respiratory epithelium. When C-CPE-treated lung explants were treated with forskolin, lumen area was restored. In summary, removal of a sealing claudin, Claudin-3, from tight junctions in embryonic lung epithelium results in a decrease in lumen area and in hydrostatic pressure needed for lung development.
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Pollos , Claudinas , Animales , Claudina-3/genética , Claudinas/genética , Epitelio , PulmónRESUMEN
The extracellular matrix of the bladder consists mostly of type I and III collagen, which are required during loading. During bladder injury, there is an accumulation of collagen that impairs bladder function. Little is known about the genes that regulate production of collagens in the bladder. We demonstrate that the transcription factor Odd-skipped related 1 (Osr1) is expressed in the bladder mesenchyme and epithelium at the onset of development. As development proceeds, Osr1 is mainly expressed in mesenchymal progenitors and their derivatives. We hypothesized that Osr1 regulates mesenchymal cell differentiation and production of collagens in the bladder. To test this hypothesis, we examined newborn and adult mice heterozygous for Osr1, Osr1+/-. The bladders of newborn Osr1+/- mice had a decrease in collagen I by western blot analysis and a global decrease in collagens using Sirius red staining. There was also a decrease in the cellularity of the lamina propria, where most collagen is synthesized. This was not due to decreased proliferation or increased apoptosis in this cell population. Surprisingly, the bladders of adult Osr1+/- mice had an increase in collagen that was associated with abnormal bladder function; they also had a decrease in bladder capacity and voided more frequently. The results suggest that Osr1 is important for the differentiation of mesenchymal cells that give rise to collagen-producing cells.
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Colágeno Tipo I/biosíntesis , Células Madre Mesenquimatosas/metabolismo , Transducción de Señal/genética , Factores de Transcripción/metabolismo , Vejiga Urinaria/metabolismo , Animales , Animales Recién Nacidos , Diferenciación Celular/genética , Proliferación Celular/genética , Células Cultivadas , Matriz Extracelular/metabolismo , Regulación del Desarrollo de la Expresión Génica , Células Madre Mesenquimatosas/citología , Mesodermo/metabolismo , Ratones , Ratones Transgénicos , Membrana Mucosa/citología , Membrana Mucosa/metabolismo , Organogénesis/genética , Factores de Transcripción/genéticaRESUMEN
OBJECTIVES: Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria. METHOD: Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. RESULTS: Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected. CONCLUSION: In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.
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Secuencia de Bases , Exones , Hipercalcemia/genética , Hipercalciuria/genética , Eliminación de Secuencia , Proteínas Cotransportadoras de Sodio-Fosfato de Tipo IIa/genética , Vitamina D3 24-Hidroxilasa/genética , Canadá , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Estudios RetrospectivosRESUMEN
Claudins are a family of tight junction proteins that are expressed during mouse kidney development. They regulate paracellular transport of solutes along the nephron and contribute to the final composition of the urinary filtrate. To understand their roles during development, we used a protein reagent, a truncated version of the Clostridium perfringens enterotoxin (C-CPE), to specifically remove a subset of claudin family members from mouse embryonic kidney explants at embryonic day 12. We observed that treatment with C-CPE decreased the number and the complexity of ureteric bud tips that formed: there were more single and less bifid ureteric bud tips when compared to control-treated explants. In addition, C-CPE-treated explants exhibited ureteric bud tips with larger lumens when compared to control explants (p < .05). Immunofluorescent analysis revealed decreased expression and localization of Claudin-3, -4, -6, and -8 to tight junctions of ureteric bud tips following treatment with C-CPE. Interestingly, Claudin-7 showed higher expression in the basolateral membrane of the ureteric bud lineage and poor localization to the tight junctions of the ureteric bud lineage both in controls and in C-CPE-treated explants. Taken together, it appears that claudin proteins may play a role in ureteric bud branching morphogenesis through changes in lumen formation that may affect the efficiency by which ureteric buds emerge and branch.
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Claudinas/metabolismo , Riñón/metabolismo , Morfogénesis , Animales , Riñón/embriología , Ratones , Uniones Estrechas/metabolismoRESUMEN
Congenital anomalies of the kidneys and urinary tracts (CAKUT) are disorders caused by defects in the development of the kidneys and their outflow tracts. The formation of the kidneys begins at week 3 and nephrogenesis continues until week 36, therefore, the kidneys and outflow tracts are susceptible to environmental risk factors that perturb development throughout gestation. Many genes have been implicated in kidney and outflow tract development, and mutations have been identified in patients with CAKUT. In severe cases of CAKUT, when the kidneys do not form, the fetus will not survive. However, in less severe cases, the baby can survive with combined kidney and outflow tract defects or they may only be identified in adulthood. In this review, we will cover the clinical presentation of CAKUT, its epidemiology, and its long-term outcomes. We will then discuss risk factors for CAKUT, including genetic and environmental contributions. Although severe CAKUT is rare, low nephron number is a much more common disorder with its effect on kidney function increasingly apparent as a person ages. Low nephron number appears to arise by the same mechanisms as CAKUT, but it differs in terms of the magnitude of the insult and the timing of when it occurs during gestation. By understanding the causes of CAKUT and low nephron number, we can begin to identify preventive treatments and establish clinical guidelines for how these patients should be followed.
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Riñón/anomalías , Anomalías Urogenitales , Reflujo Vesicoureteral , Animales , Modelos Animales de Enfermedad , Muerte Fetal , Predisposición Genética a la Enfermedad , Humanos , Riñón/fisiopatología , Fenotipo , Pronóstico , Medición de Riesgo , Factores de Riesgo , Índice de Severidad de la Enfermedad , Anomalías Urogenitales/diagnóstico , Anomalías Urogenitales/genética , Anomalías Urogenitales/fisiopatología , Anomalías Urogenitales/terapia , Reflujo Vesicoureteral/diagnóstico , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/fisiopatología , Reflujo Vesicoureteral/terapiaRESUMEN
INTRODUCTION: To consider alternative mechanisms that give rise to a refluxing ureterovesical junction (UVJ), we hypothesized that children with a common heritable urinary tract defect, vesicoureteric reflux (VUR), may have a defect in the extracellular matrix composition of the UVJ and other tissues that would be revealed by assessment of the peripheral joints. Hypermobile joints can arise from defects in the extracellular matrix within the joint capsule that affect proteins, including tenascin XB (TNXB). METHODS: We performed an observational study of children with familial and non-familial VUR to determine the prevalence of joint hypermobility, renal scarring, and DNA sequence variants in TNXB. RESULTS: Most children (27/44) exhibited joint hypermobility using the Beighton scoring system. This included 15/26 girls (57.7%) and 12/18 boys (66.7%), which is a significantly higher prevalence for both sexes when compared to population controls (p<0.005). We found no association between joint hypermobility and renal scarring. Seven of 49 children harbored rare pathogenic sequence variants in TNXB, and two also exhibited joint hypermobility. No sequence variants in TNXB were identified in 25/27 children with VUR and joint hypermobility. Due to the observational design of the study, there was missing data for joint hypermobility scores in six children and for dimercaptosuccinic acid (DMSA) scans in 17 children. CONCLUSIONS: We observed a high prevalence of VUR and joint hypermobility in children followed within a tertiary care pediatric urology clinic. While mutations in TNXB have been reported in families with VUR and joint hypermobility, we identified only two children with these phenotypes and pathogenic variants in TNXB. We, therefore, speculate that VUR and joint hypermobility may be due to mutations in other extracellular matrix genes.
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Bacterial urinary tract infections (UTIs) are one of the most common reasons for children to be admitted to hospital. Bacteria infect and invade the bladder (the lower urinary tract) and if the infection disseminates to the upper urinary tract, significant inflammation in the kidneys may arise. Inflammation is a double-edged sword: it is needed to clear bacteria, but if excessive, kidney tissue is injured. During injury, nephrons are destroyed and replaced with deposition of extracellular matrix and a renal scar. In this review, we explore the pathogenesis of UTIs and discuss the risk factors that result in dissemination of bladder infection to the kidneys. Three major risk factors predispose to kidney infections: the presence of vesicoureteric reflux, the presence of bladder and bowel dysfunction, and defects in the ability of the host immune response to clear bacteria. In this review, we will discuss these factors, their relationship to renal scarring, and potential treatments that might be beneficial to prevent renal scar formation in children.
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Cicatriz/inmunología , Riñón/patología , Pielonefritis/inmunología , Reflujo Vesicoureteral/complicaciones , Inmunidad Adaptativa , Animales , Antibacterianos/uso terapéutico , Niño , Cicatriz/epidemiología , Cicatriz/patología , Cicatriz/prevención & control , Inhibidores de la Ciclooxigenasa 2/uso terapéutico , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Glucocorticoides/uso terapéutico , Humanos , Riñón/inmunología , Riñón/microbiología , Inhibidores de la Metaloproteinasa de la Matriz/uso terapéutico , Pielonefritis/tratamiento farmacológico , Pielonefritis/epidemiología , Pielonefritis/microbiología , Factores de Riesgo , Vejiga Urinaria/inmunología , Vejiga Urinaria/microbiología , Reflujo Vesicoureteral/inmunologíaRESUMEN
: Kidney stones affect 10% of the population. Yet, there is relatively little known about how they form or how to prevent and treat them. The claudin family of tight junction proteins has been linked to the formation of kidney stones. The flavonoid quercetin has been shown to prevent kidney stone formation and to modify claudin expression in different models. Here we investigate the effect of quercetin on claudin expression and localization in MDCK II cells, a cation-selective cell line, derived from the proximal tubule. For this study, we focused our analyses on claudin family members that confer different tight junction properties: barrier-sealing (Cldn1, -3, and -7), cation-selective (Cldn2) or anion-selective (Cldn4). Our data revealed that quercetin's effects on the expression and localization of different claudins over time corresponded with changes in transepithelial resistance, which was measured continuously throughout the treatment. In addition, these effects appear to be independent of PI3K/AKT signaling, one of the pathways that is known to act downstream of quercetin. In conclusion, our data suggest that quercetin's effects on claudins result in a tighter epithelial barrier, which may reduce the reabsorption of sodium, calcium and water, thereby preventing the formation of a kidney stone.
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Claudinas/genética , Claudinas/metabolismo , Expresión Génica , Quercetina/metabolismo , Uniones Estrechas/metabolismo , Animales , Biomarcadores , Membrana Celular/metabolismo , Perros , Células de Riñón Canino Madin Darby , Fosfatidilinositol 3-Quinasas/metabolismo , Transporte de Proteínas , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de SeñalRESUMEN
Genome-wide association study (GWAS) loci for several immunity-mediated diseases (early onset asthma, inflammatory bowel disease (IBD), primary biliary cholangitis, and rheumatoid arthritis) map to chromosomal region 17q12-q21. The predominant view is that association between 17q12-q21 alleles and increased risk of developing asthma or IBD is due to regulatory variants. ORM sphingolipid biosynthesis regulator (ORMDL3) residing in this region is the most promising gene candidate for explaining association with disease. However, the relationship between 17q12-q21 alleles and disease is complex suggesting contributions from other factors, such as trans-acting genetic and environmental modifiers or circadian rhythms. Circadian rhythms regulate expression levels of thousands of genes and their dysregulation is implicated in the etiology of several common chronic inflammatory diseases. However, their role in the regulation of the 17q12-q21 genes has not been investigated. Moreover, the core clock gene nuclear receptor subfamily 1, group D, member 1 (NR1D1) resides about 200 kb distal to the GWAS region. We hypothesized that circadian rhythms influenced gene expression levels in 17q12-q21 region and conversely, regulatory elements in this region influenced transcription of the core clock gene NR1D1 in cis. To test these hypotheses, we examined the diurnal expression profiles of zona pellucida binding protein 2 (ZPBP2/Zpbp2), gasdermin B (GSDMB), and ORMDL3/Ormdl3 in human and mouse tissues and analyzed the impact of genetic variation in the ZPBP2/Zpbp2 region on NR1D1/Nr1d1 expression. We found that Ormdl3 and Zpbp2 were controlled by the circadian clock in a tissue-specific fashion. We also report that deletion of the Zpbp2 region altered the expression profile of Nr1d1 in lungs and ileum in a time-dependent manner. In liver, the deletion was associated with enhanced expression of Ormdl3. We provide the first evidence that disease-associated genes Zpbp2 and Ormdl3 are regulated by circadian rhythms and the Zpbp2 region influences expression of the core clock gene Nr1d1.
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Cromosomas Humanos Par 17/genética , Relojes Circadianos/genética , Proteínas del Huevo/genética , Proteínas de la Membrana/genética , Animales , Línea Celular Tumoral , Conjuntos de Datos como Asunto , Proteínas del Huevo/metabolismo , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/fisiología , Variación Genética , Estudio de Asociación del Genoma Completo , Humanos , Íleon/metabolismo , Hígado/metabolismo , Pulmón/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Ratones , Ratones Noqueados , Proteínas de Neoplasias/metabolismo , Miembro 1 del Grupo D de la Subfamilia 1 de Receptores Nucleares/metabolismo , Elementos Reguladores de la Transcripción/genética , Factores de TiempoRESUMEN
Although sequence variants in CD2-associated protein (CD2AP) have been identified in patients with focal segmental glomerulosclerosis (FSGS), definitive proof of causality in human disease is meager. By whole-exome sequencing, we identified a homozygous frame-shift mutation in CD2AP (p.S198fs) in three siblings born of consanguineous parents who developed childhood-onset FSGS and end stage renal disease. When the same frameshift mutation was introduced in mice by gene editing, the mice developed FSGS and kidney failure. These results provide conclusive evidence that homozygous mutation of CD2AP causes FSGS in humans.
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Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas del Citoesqueleto/genética , Glomeruloesclerosis Focal y Segmentaria/genética , Fallo Renal Crónico/patología , Animales , Consanguinidad , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Mutación del Sistema de Lectura , Edición Génica , Técnicas de Sustitución del Gen , Glomeruloesclerosis Focal y Segmentaria/patología , Homocigoto , Humanos , Fallo Renal Crónico/genética , Masculino , Ratones , Ratones Transgénicos , Linaje , Secuenciación del ExomaRESUMEN
Ethylmalonic encephalopathy (EE) is caused by mutations in the ETHE1 gene. ETHE1 is vital for the catabolism of hydrogen sulfide (H2S). Patients with pathogenic mutations in ETHE1 have markedly increased thiosulfate, which is a reliable index of H2S levels. Accumulation of H2S is thought to cause the characteristic metabolic derangement found in EE. Recently introduced treatment strategies in EE, such as combined use of metronidazole (MNZ) and N-acetylcysteine (NAC), are aimed at lowering chronic H2S load. Experience with treatment strategies directed against acute episodes of metabolic decompensation (e.g., hemodialysis) is limited. Here we present an unusually mild, molecularly confirmed, case of EE in a 19-year-old male on chronic treatment with MNZ and NAC. During an acute episode of metabolic decompensation, we employed continuous renal replacement therapy (CRRT) to regain metabolic control. On continuous treatment with NAC and MNZ during the months preceding the acute event, plasma thiosulfate levels ranged from 1.6 to 4 µg/mL (reference range up to 2 µg/mL) and had a mean value of 2.5 µg/mL. During the acute decompensation, thiosulfate levels were 6.7 µg/mL, with hyperlactatemia and perturbed organic acid, acylglycine, and acylcarnitine profiles. CRRT decreased thiosulfate within 24 h to 1.4 µg/mL. Following discontinuation of CRRT, mean thiosulfate levels were 3.2 µg/mL (range, 2.4-3.7 µg/mL) accompanied by clinical improvement with metabolic stabilization of blood gas, acylcarnitine, organic acid, and acylglycine profiles. In conclusion, CRRT may help to regain metabolic control in patients with EE who have an acute metabolic decompensation on chronic treatment with NAC and MNZ.
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Renal tubular dysgenesis (RTD) is a developmental abnormality of the nephron characterized by fetal anuria, oligohydramnios, and severe postnatal hypotension. Genetic forms have an autosomal recessive inheritance and are caused by mutations in genes encoding key components of the renin-angiotensin pathway. We report three patients from two unrelated families with RTD due to pathogenic variants of the angiotensin-converting enzyme (ACE) gene, in whom RTD was associated with microcolon. We also detail key variations of the renin-angiotensin system in one of these infants. The severe intestinal developmental abnormality culminating in microcolon and early terminal ileum perforation/necrotizing enterocolitis is a novel finding not previously associated with RTD, which points to a role of the renin-angiotensin system in gut development.
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Anomalías Múltiples/genética , Íleon/anomalías , Túbulos Renales/anomalías , Peptidil-Dipeptidasa A/genética , Fenotipo , Anomalías Múltiples/patología , Femenino , Humanos , Recién Nacido , MasculinoRESUMEN
The claudin family of tetraspan transmembrane proteins is essential for tight junction formation and regulation of paracellular transport between epithelial cells. Claudins also play a role in apical-basal cell polarity, cell adhesion and link the tight junction to the actin cytoskeleton to exert effects on cell shape. The function of claudins in paracellular transport has been extensively studied through loss-of-function and gain-of-function studies in cell lines and in animal models, however, their role in morphogenesis has been less appreciated. In this review, we will highlight the importance of claudins during morphogenesis by specifically focusing on their critical functions in generating epithelial tubes, lumens, and tubular networks during organ formation.
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Claudinas/fisiología , Epitelio/crecimiento & desarrollo , Morfogénesis/fisiología , Animales , HumanosRESUMEN
Odd-skipped related 1 (Osr1) is a transcriptional repressor that plays critical roles in maintaining the mesenchymal stem cell population within the developing kidney. Here, we report that newborn pups with a heterozygous null mutation in Osr1 exhibit a 21% incidence of vesicoureteric reflux and have hydronephrosis and urinary tract duplications. Newborn pups have a short intravesical ureter, resulting in a less competent ureterovesical junction which arises from a delay in urinary tract development. We describe a new domain of Osr1 expression in the ureteral mesenchyme and within the developing bladder in the mouse. OSR1 was sequenced in 186 children with primary vesicoureteric reflux, and 17 have single nucleotide polymorphisms. Fifteen children have a common synonymous variant, rs12329305, one child has a rare nonsynonymous variant, rs3440471, and one child has a rare 5'-UTR variant, rs45535040 The impact of these SNPs is not clear; therefore, the role of OSR1 in human disease remains to be elucidated. Osr1 is a candidate gene implicated in the pathogenesis of vesicoureteric reflux and congenital abnormalities of the kidney and urinary tract in mice.