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mTORC1/2 dual inhibitors may be more effective than mTORC1 inhibitor rapamycin. However, their metabolic impacts on colon cancer cells remain unexplored. We conducted a comparative analysis of the anti-proliferative effects of rapamycin and the novel OSI-027 in colon cancer cells HCT-116, evaluating their metabolic influences through ultra-high performance liquid chromatography-mass spectrometry (UPLC-MS/MS). Our results demonstrate that OSI-027 more effectively inhibits colon cancer cell proliferation than rapamycin. Additionally, we identified nearly 600 metabolites from the spectra, revealing significant differences in metabolic patterns between cells treated with OSI-027 and rapamycin. Through VIP value screening, we pinpointed crucial metabolites contributing to these distinctions. For inhibiting glycolysis and reducing glucose consumption, OSI-027 was likely to be more potent than rapamycin. For amino acids metabolism, although OSI-027 has a broad effect as rapamycin, their effects in degrees were not exactly the same. These findings address the knowledge gap regarding mTORC1/2 dual inhibitors and lay a foundation for their further development and research.
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Neoplasias del Colon , Imidazoles , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 2 de la Rapamicina , Metabolómica , Sirolimus , Triazinas , Humanos , Proliferación Celular/efectos de los fármacos , Neoplasias del Colon/tratamiento farmacológico , Neoplasias del Colon/metabolismo , Células HCT116 , Imidazoles/farmacología , Imidazoles/uso terapéutico , Cromatografía Líquida con Espectrometría de Masas , Diana Mecanicista del Complejo 1 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 2 de la Rapamicina/antagonistas & inhibidores , Diana Mecanicista del Complejo 2 de la Rapamicina/metabolismo , Metabolómica/métodos , Sirolimus/farmacología , Sirolimus/uso terapéutico , Espectrometría de Masas en Tándem , Triazinas/farmacología , Triazinas/uso terapéuticoRESUMEN
OBJECTIVE: Renal safety risk is currently an important factor that hinders the development of uric acid transporter 1 (URAT1) inhibitors. This study aimed to compare the renal safety and uric acid-lowering efficacy of different URAT1 inhibitors and clarify the association between them. METHODS: A systematic review of published randomized controlled trials on URAT1 inhibitors was conducted to investigate the incidence of renal safety events. A model-based analysis was performed to predict the uric acid-lowering efficacy of representative URAT1 inhibitors. RESULTS: The overall renal safety event incidences of lesinurad, verinurad, dotinurad, SHR4640, and benzbromarone in patients with hyperuricemia were 11.2 % (142/1264), 12.0 % (34/284), 0.5 % (2/421), 2.3 % (5/213), and 1.3 % (5/393), respectively. A semi-mechanistic pharmacokinetic/pharmacodynamic model was used to establish the dose-exposure-effect relationship of lesinurad, verinurad, dotinurad, and SHR4640 with or without the combination of xanthine oxidase inhibitors (XOIs). The efficacy ranking of the intermediate dose of URAT1 inhibitors with once-daily dosing was 2 mg dotinurad > 10 mg verinurad > 5 mg SHR4640 > 400 mg lesinurad. The combination of 80 mg febuxostat and 600 mg allopurinol reduced the 24-h cumulative renal uric acid excretion by 48.4 % and 48.3 %, respectively. CONCLUSION: Uric acid-lowering efficacy is not an independent factor for the renal safety risk of different URAT1 inhibitors, and structural differences could be responsible for the difference. The adverse renal effects of URAT1 inhibitors are dose-dependent, and the combination with high doses of XOIs can significantly reduce the renal safety risk by reducing uric acid excretion by the kidneys.
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BACKGROUND: HLX02, the first China-manufactured trastuzumab biosimilar, is approved in Europe (EU) and China. This study evaluated bioequivalence between HLX02 and US-approved trastuzumab (US-trastuzumab). METHOD: In this double-blind, parallel-group, Phase I study, healthy Chinese men were randomized (1:1:1) to receive a single 6 mg/kg dose of HLX02, reference US-trastuzumab, or reference EU-approved trastuzumab (EU-trastuzumab). Equivalence in PK profiles was demonstrated if the 90% confidence intervals (CIs) for the geometric mean ratio (GMR) for the difference between the least square means of the area under the curve (AUC) from time 0 to infinity (AUC∞) were 0.8-1.25. RESULTS: Pharmacokinetic profiles of the three trastuzumab products were similar in 111 Chinese men. Equivalence was confirmed between HLX02 and US-trastuzumab (GMR for AUC∞ 1.009, 90% CI 0.950-1.072); HLX02 and EU-trastuzumab (GMR for AUC∞ 1.068, 90% CI 1.005-1.135); and EU- and US-trastuzumab (GMR for AUC∞ 0.945, 90% CI 0.889-1004). Exploratory analysis of all other PK parameters also demonstrated equivalence between any two of the three trastuzumab products. HLX02 had similar safety and immunogenicity profiles to US- and EU-trastuzumab. CONCLUSION: HLX02 is bioequivalent to US-trastuzumab and EU-trastuzumab, with similar safety and immunogenicity profiles. US- and EU-trastuzumab were also bioequivalent to each other.
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Biosimilares Farmacéuticos , Pueblos del Este de Asia , Trastuzumab , Humanos , Masculino , Área Bajo la Curva , Biosimilares Farmacéuticos/efectos adversos , Biosimilares Farmacéuticos/metabolismo , Biosimilares Farmacéuticos/farmacocinética , Biosimilares Farmacéuticos/uso terapéutico , Método Doble Ciego , Equivalencia Terapéutica , Trastuzumab/efectos adversos , Trastuzumab/inmunología , Trastuzumab/farmacocinética , China , Estados Unidos , Unión Europea , Voluntarios SanosRESUMEN
Introduction: Intrahepatic cholangiocarcinoma (iCCA) is a heterogeneous entity with diverse etiologies, morphologies, and clinical outcomes, but our knowledge of its epidemiology and carcinogenesis is very limited. Materials and methods: The expression patterns of circRNAs were explored in iCCA tissues and corresponding adjacent normal ones, denoted by (iCCA) and (iCCAP), respectively, using high-throughput sequencing. Results: A total of 117 differential expressed (DE) circRNAs were identified. Based on the parental transcripts of circRNAs, these DE circRNAs were related to several important GO terms and were enriched in important pathways. Two circRNA-mediated ceRNA networks were constructed and many important metabolic pathways related to mRNAs were regulated by DE circRNAs via miRNAs. Conclusion: Our study revealed the DE circRNAs in the iCCA tissues compared with iCCAP ones, suggesting that circRNAs may play crucial roles in the pathogenesis of iCCA.
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AIMS: This multicenter, open-label, randomized study (Registration No. ChiCTR-OCH-14004528) aimed to compare the efficacy and effects of oxcarbazepine (OXC) with levetiracetam (LEV) as monotherapies on patient quality of life and mental health for patients with newly diagnosed focal epilepsy from China. METHODS: Patients with newly diagnosed focal epilepsy who had experienced 2 or more unprovoked seizures at greater than a 24-h interval during the previous year were recruited. Participants were randomly assigned to the OXC group or LEV group. Efficacy, safety, quality of life, and mental health were evaluated over 12-week and 24-week periods. RESULTS: In total, we recruited 271 newly diagnosed patients from 23 centers. Forty-four patients were excluded before treatment for reasons. The rate of seizure freedom of OXC was significantly superior to that of LEV at 12 weeks and 24 weeks (p < 0.05). The quality of life (except for the seizure worry subsection) and anxiety scale scores also showed significant differences from before to after treatment in the OXC and LEV groups. CONCLUSIONS: OXC monotherapy may be more effective than LEV monotherapy in patients with newly diagnosed focal epilepsy. Both OXC and LEV could improve the quality of life and anxiety state in adult patients with focal epilepsy.
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Epilepsias Parciales , Calidad de Vida , Adulto , Anticonvulsivantes/uso terapéutico , Epilepsias Parciales/tratamiento farmacológico , Humanos , Levetiracetam/uso terapéutico , Oxcarbazepina/uso terapéutico , Convulsiones/tratamiento farmacológico , Resultado del TratamientoRESUMEN
A growing body of evidence suggests that gut microbiota could participate in the progression of depression via the microbiota-gut-brain axis. However, the detailed microbial metabolic profile changes in the progression of depression is still not fully elucidated. In this study, a liquid chromatography coupled to mass spectrometry-based untargeted serum high-throughput metabolomics method was first performed to screen for potential biomarkers in a depressive-like state in a chronic unpredictable mild stress (CUMS)-induced mouse model. Our results identified that the bile acid and energy metabolism pathways were significantly affected in CUMS progression. The detailed bile acid profiles were subsequently quantified in the serum, liver, and feces. The results showed that CUMS significantly promoted the deconjugation of conjugated bile acid and secondary bile acid biosynthesis. Furthermore, 16S rRNA gene sequencing revealed that the increased secondary bile acid levels in the feces positively correlated with Ruminococcaceae_UCG-010, Ruminococcus, and Clostridia_UCG-014 abundance. Taken together, our study suggested that changes in family Ruminococcaceae abundance following chronic stress increased biosynthesis of deoxycholic acid (DCA), a unconjugated secondary bile acid in the intestine. Aberrant activation of secondary bile acid biosynthesis pathway thereby increased the hydrophobicity of the bile acid pool, which might, in turn, promoted metabolic disturbances and disease progression in CUMS mice.
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OBJECTIVE: To characterize the intestinal flora of patients with epilepsy and its correlation with epilepsy. METHODS: Patients with ages > 18 years were consecutively enrolled from the outpatient department, Affiliated Hospital of Guizhou Medical University from January 2018 to December 2019. A total of 71 subjects were recruited, including epilepsy patients (n = 41) as an observation group and patient family members (n = 30) as a control group. Fresh stool specimens of all the subjects were collected. The 16S ribosomal RNA sequencing was analyzed to determine changes in intestinal flora composition and its correlation with epilepsy. Subgroup analysis was then conducted. All patients with epilepsy were divided into an urban group (n = 21) and a rural group (n = 20) according to the region, and bioinformatics analyses were repeated between subgroups. RESULTS: LEfSe analysis showed that Fusobacterium, Megasphaera, Alloprevotella, and Sutterella had relatively increased abundance in the epilepsy group at the genus level. Correlation analysis suggested that Fusobacterium sp. (r = 0.584, P < 0.01), Fusobacterium mortiferum (r = 0.560, P < 0.01), Ruminococcus gnavus (r = 0.541, P < 0.01), and Bacteroides fragilis (r = 0.506, P < 0.01) were significantly positively correlated with the occurrence of epilepsy (r ≥ 0.5, P < 0.05). PICRUSt function prediction analysis showed that there were significant differences in 16 pathways between the groups at level 3. Comparing the rural group with the urban group, Proteobacteria increased at the phylum level and Escherichia coli, Fusobacterium varium, Prevotella stercorea, and Prevotellaceae bacterium DJF VR15 increased at the species level in the rural group. CONCLUSION: There were significant differences in the composition and functional pathways of gut flora between epilepsy patients and patient family members. The Fusobacterium may become a potential biomarker for the diagnosis of epilepsy.
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Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder characterized by headache, seizures, confusion and visual disturbances, as well as potentially reversible neuroimaging findings in most patients after proper treatment. Seizures is one of the most common clinical presentations of PRES. This review summarizes the potential pathophysiology and clinical features of PRES, as well as a multimodal approach to imaging and also briefly discusses the phenomenon of seizures in paediatric population.
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Síndrome de Leucoencefalopatía Posterior , Niño , Cefalea , Humanos , Imagen por Resonancia Magnética , Neuroimagen , Síndrome de Leucoencefalopatía Posterior/diagnóstico por imagen , Convulsiones/diagnóstico por imagen , Convulsiones/etiologíaRESUMEN
Abstract Fluoroquinolones are an important class of antimicrobial agents to manage infectious diseases. However, knowledge about how host bile acids are modified by fluoroquinolones is limited. We investigated and compared the impact of fluoroquinolones on circulating bile acid profiles and gut microbiota from in vivo studies. We administered ciprofloxacin (100 mg/kg/day) or moxifloxacin (40 mg/kg/day) orally to male Wistar rats for seven days. Fifteen bile acids (BAs) from the serum and large intestine were quantified by HPLC-MS/MS. The diversity of gut microbiota after ciprofloxacin and moxifloxacin treatment was analyzed using high-throughput, next-generation sequencing technology. The two fluoroquinolone-treated groups had different BA profiles. Ciprofloxacin significantly reduced the hydrophobicity index of the BA pool, reduced secondary BAs, and increased taurine-conjugated primary BAs in both the serum and large intestine as compared with moxifloxacin. Besides, ciprofloxacin treatment altered intestinal microbiota with a remarkable increase in Firmicutes to Bacteroidetes ratio, while moxifloxacin exerted no effect. What we found suggests that different fluoroquinolones have a distinct effect on the host BAs metabolism and intestinal bacteria, and therefore provide guidance on the selection of fluoroquinolones to treat infectious diseases.
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Animales , Masculino , Ratas , Ácidos y Sales Biliares , Estudio Comparativo , Ciprofloxacina/análisis , Ratas Wistar , Microbioma Gastrointestinal , Moxifloxacino/análisis , Cromatografía Líquida de Alta Presión/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Interacciones Hidrofóbicas e Hidrofílicas , Intestino Grueso/anomalías , Antiinfecciosos/farmacologíaRESUMEN
Patients with diabetes mellitus have a higher risk of developing Parkinson's disease (PD). However, the molecular links between PD and diabetes remain unclear. In this study, we investigated the roles of thioredoxin-interacting protein (TXNIP) in Parkin/PINK1-mediated mitophagy in dopaminergic (DA) cells under high-glucose (HG) conditions. In streptozotocin-induced diabetic mice, TXNIP was upregulated and autophagy was inhibited in the midbrain, while the loss of DA neurons was accelerated by hyperglycemia. In cultured PC12 cells under HG, TXNIP expression was upregulated and the intracellular reactive oxygen species (ROS) levels increased, leading to cell death. Autophagic flux was further blocked and PINK1 expression was decreased under HG conditions. Parkin expression in the mitochondrial fraction and carbonyl cyanide 3-chlorophenylhydrazone (CCCP)-induced co-localization of COX IV (marker for mitochondria) and LAMP1 (marker for lysosomes) were also significantly decreased by HG. Overexpression of TXNIP was sufficient to decrease the expression of both PINK1 and Parkin in PC12 cells, while knockdown of the expression of TXNIP by siRNA decreased intracellular ROS and attenuated cellular injury under HG. Moreover, inhibition of TXNIP improved the CCCP-induced co-localization of COX IV and LAMP1 in PC12 cells under HG. Together, these results suggest that TXNIP regulates Parkin/PINK1-mediated mitophagy under HG conditions, and targeting TXNIP may be a promising therapeutic strategy for reducing the risk of PD under hyperglycemic conditions.
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Proteínas Portadoras/metabolismo , Neuronas Dopaminérgicas/metabolismo , Mitofagia , Proteínas Quinasas/metabolismo , Tiorredoxinas/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Animales , Diabetes Mellitus Experimental , Glucosa , Masculino , Ratones , Células PC12 , Enfermedad de Parkinson , RatasRESUMEN
OBJECTIVES: The goal of this study was to investigate alterations of white matter (WM) network in patients with left non-lesional temporal lobe epilepsy (nl-TLE) and right nl-TLE to assess the relationship between the white matter network properties and clinical parameters. METHODS: T1 magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) were acquired for 45 participants, including 30 nl-TLE patients (13 left, 17 right) and 15 healthy controls. Diffusion tensor tractography was computed to model the WM structural network. The topologic properties of the WM network were obtained by graph theoretical analysis, and the between-group differences in global and nodal properties of the WM network were examined by network-based statistical analysis (NBS). The relationship between WM network properties and clinical parameters was assessed by Pearson's correlation analysis. RESULTS: NBS results indicated that patients with left and right nl-TLE experienced distinct changes of WM nodal and global network properties compared with HCs. Positive correlation coefficients were found in several regions. The structural disruptions of networks in the two nl-TLE groups were observed to be different in distribution and severity. CONCLUSIONS: This study provides evidence for changes of the WM network topological properties and structural connectivity in nl-TLE patients, which provide useful insights for the understanding of disease mechanisms of TLE and improving treatment outcomes for nl-TLE. KEY POINTS: ⢠This study aims to investigate alterations of white matter (WM) network in patients with non-lesional temporal lobe epilepsy (nl-TLE). ⢠Network-based statistical analysis results indicated that patients with left and right nl-TLE experienced distinct changes of WM nodal and global network properties compared with healthy controls. ⢠This study provides useful insights for the understanding of disease mechanisms of TLE and improving treatment outcomes for nl-TLE.
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Epilepsia del Lóbulo Temporal/diagnóstico , Epilepsia del Lóbulo Temporal/patología , Imagen por Resonancia Magnética/métodos , Sustancia Blanca/diagnóstico por imagen , Sustancia Blanca/patología , Adulto , Imagen de Difusión Tensora/métodos , Femenino , Humanos , MasculinoRESUMEN
BACKGROUND: Childhood absence epilepsy is a common generalized epilepsy syndrome characterized by childhood onset of frequent sporadic absence seizures. During onset, the electroencephalogram exhibits bilateral, symmetric, and synchronous discharges of approximately 3 Hz of generalized spike-and-wave complexes. Focal spikes are often found in children with focal epilepsy but are not common in absence epilepsy. CASE DESCRIPTION: In the case patient, focal spikes were observed during active onset of absence epilepsy and at 5 years after the first hospital visit, at which time absence epilepsy was controlled and medication was withdrawn without focal seizure attack in the interim. CONCLUSIONS: This case demonstrates that focal spikes associated with childhood absence epilepsy do not require specific treatment in the absence of focal seizures.
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Epilepsia Tipo Ausencia/fisiopatología , Potenciales de Acción , Anticonvulsivantes/uso terapéutico , Niño , Sustitución de Medicamentos , Electroencefalografía , Epilepsia Tipo Ausencia/diagnóstico por imagen , Epilepsia Tipo Ausencia/tratamiento farmacológico , Estudios de Seguimiento , Humanos , Lamotrigina/uso terapéutico , Imagen por Resonancia Magnética , Masculino , Neuroimagen , Trastornos Intrínsecos del Sueño/fisiopatología , Ácido Valproico/uso terapéutico , Grabación en VideoRESUMEN
BACKGROUND: Mixed cerebrovascular disease is a diagnostic entity that presents with hemorrhagic and ischemic stroke clinically and/or subclinically. Here, we report a patient with mixed vascular risk factors, who presented with multiple intracerebral hemorrhages and a simultaneously occurring cerebral infarction with hemorrhagic transformation. CASE PRESENTATION: A 63-year-old male with no history of trauma or prior neurological disease presented with a sudden onset of weakness in his right limbs, followed by an episode of focal seizure without impaired awareness. The patient had a 4-year history of deep vein thrombosis in the lower limbs, and a 2-year history of Raynaud's phenomenon in the hands. He also had a family history of hypertension and thrombophilia. Head computed tomography plain scans showed two high densities in the bilateral parietal lobes and one mixed density in the left frontal lobe. The patient was diagnosed with mixed cerebrovascular disease. In this report, we make a systematic clinical reasoning regarding the etiological diagnosis, and discuss the possible pathogenic mechanisms leading to mixed cerebrovascular disease. We exclude coagulopathy, endocarditis, atrial fibrillation, patent foramen ovale, brain tumor, cerebral venous thrombosis, cerebral vascular malformation, cerebral amyloid angiopathy and vasculitis as causative factors. We identify hypertension, hereditary protein S deficiency, hypercholesteremia and hyperhomocysteinemia as contributing etiologies in this case. CONCLUSION: This case presents complex underlying mechanisms of mixed cerebrovascular disease, in which hypertension and hyperhomocysteinemia are considered to play a central role.
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Hipercolesterolemia/complicaciones , Hiperhomocisteinemia/complicaciones , Hipertensión/complicaciones , Deficiencia de Proteína S/complicaciones , Accidente Cerebrovascular/etiología , Isquemia Encefálica/etiología , Hemorragia Cerebral/etiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
AIMS: Changes in cardiac autonomic nervous function have been evaluated by studying the related indexes of heart rate variability (HRV) in patients with focal epilepsy (FE) in the interictal period. MAIN METHODS: A total of 30 FE patients who were treated in our department from July 2015 to May 2017, were included into this study. These patients were divided into three pairs of groups: less frequent seizure group and more frequent seizure group; medication group and non-medication group; <10â¯years disease group and ≥10â¯years disease group. In addition, 16 normal healthy subjects were enrolled as the control group. The time domain and frequency domain indexes of HRV indexes between subgroups and the control group were retrospectively analyzed. KEY FINDINGS: The low-frequency/high-frequency ratio (LF/HF) in the interictal period was higher in the more frequent seizure group than in the control group and less frequent seizure group (Pâ¯<â¯0.05). Furthermore, differences in interictal LF/HF and very low frequency (VLF) between the medication group and non-medication group and control group were statistically significant (Pâ¯<â¯0.05). SIGNIFICANCE: In interictal period FE patients who present with an imbalance in autonomic nervous function, LF/HF can serve as an indicator to evaluate the interictal cardiac sympathetic activity of FE patients. Furthermore, the dynamic observation of changes in the HRV-related indexes of FE patients can prevent the choice of antiepileptic drugs that affect heart function, which is of guiding significance for evaluating autonomic nervous function.
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Epilepsias Parciales/complicaciones , Frecuencia Cardíaca , Convulsiones/etiología , Adolescente , Adulto , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de Tiempo , Adulto JovenRESUMEN
As a brain disorder, epilepsy is characterized with abnormal hypersynchronous neural firings. It is known that seizures initiate and propagate in different brain regions. Long-term intracranial multichannel electroencephalography (EEG) reflects broadband ictal activity under seizure occurrence. Network-based techniques are efficient in discovering brain dynamics and offering finger-print features for specific individuals. In this study, we adopt link prediction for proposing a novel workflow aiming to quantify seizure dynamics and uncover pathological mechanisms of epilepsy. A dataset of EEG signals was enrolled that recorded from 8 patients with 3 different types of pharmocoresistant focal epilepsy. Weighted networks are obtained from phase locking value (PLV) in subband EEG oscillations. Common neighbor (CN), resource allocation (RA), Adamic-Adar (AA), and Sorenson algorithms are brought in for link prediction performance comparison. Results demonstrate that RA outperforms its rivals. Similarity, matrix was produced from the RA technique performing on EEG networks later. Nodes are gathered to form sequences by selecting the ones with the highest similarity. It is demonstrated that variations are in accordance with seizure attack in node sequences of gamma band EEG oscillations. What is more, variations in node sequences monitor the total seizure journey including its initiation and termination.
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Encéfalo/diagnóstico por imagen , Electrocorticografía , Epilepsia/diagnóstico por imagen , Convulsiones/diagnóstico por imagen , Procesamiento de Señales Asistido por Computador , Adolescente , Adulto , Algoritmos , Área Bajo la Curva , Femenino , Humanos , Procesamiento de Imagen Asistido por Computador , Masculino , Monitoreo Fisiológico , Oscilometría , Reproducibilidad de los Resultados , Adulto JovenRESUMEN
Neurofibromatosis type 1 (NF1) is a rare autosomal dominant disorder that primarily affects the skin and the nervous system. This condition is called segmental NF1 (also called neurofibromatosis type V) when clinical features are limited to one area of the body. Segmental NF1 is generally thought to result from somatic mosaicism due to a postzygotic mutation in the NF1 gene, thus a test for NF1 gene abnormalities in peripheral blood is usually negative. Here we report a 31-year-old male presenting with epileptic seizures, who had a history of neurofibromas confirmed by biopsy, but lacked a family history of neurofibromatosis. Multiple signs highly suggestive of NF1 and cerebrovascular abnormities were seen, including distended scalp vessels, gingival hyperplasia, cutaneous masses, skin nodules, and café-au-lait macules. Cerebral computed tomography angiography and venography revealed multiple intracranial arteriovenous fistula. However, NF1 genetic testing of peripheral blood failed to detect mutations, deletions or rearrangements in any of the coding exons or neighboring splice sites. A diagnosis of segmental NF1 was still warranted. To the best of our knowledge, this is the first case study of segmental NF1 complicated with multiple intracranial arteriovenous fistulas.
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Neurofibromatosis/patología , Neurofibromatosis 1/genética , Neoplasias Cutáneas/genética , Piel/patología , Adulto , Fístula Arteriovenosa/diagnóstico , Fístula Arteriovenosa/genética , Humanos , Masculino , Mosaicismo , Mutación/genética , Neurofibromatosis/diagnóstico , Neurofibromatosis 1/diagnóstico , Neurofibromatosis 1/patología , Neoplasias Cutáneas/patologíaRESUMEN
RATIONALE: Idiopathic hypoparathyroidism (IHP) is a rare endocrine condition, which is frequently represented by neuropsychiatric disorders. Hence, the misdiagnosis rate of the disease is rather high, especially for neurologists. PATIENT CONCERNS: We reported a case of misdiagnosed, atypical IHP. In addition, the literature on IHP and the misdiagnosis published in China in the past 2 decades has been reviewed and summarized. DIAGNOSES: Blood testing confirmed that parathyroid hormone (PTH) = 0âpg/mL and the final diagnosis was IHP. INTERVENTIONS AND OUTCOMES: With calcium and vitamin D supplementation, the patient's myasthenia improved significantly, and muscle enzymes returned to normal gradually. One-year follow-up demonstrated that the patient's myasthenia disappeared, and the blood calcium and PTH levels were normal. In addition, the literature on IHP and the misdiagnosis published in China in the past 2 decades has been reviewed and summarized. LESSONS: The misdiagnosis rate of IHP in China was high in the past 2 decades, which might be attributed to the misdiagnosis as epilepsy or mental diseases. A clinician should be able to understand the disease and emphasize the screening of high-risk population, especially for those patients with hypocalcemia, hyperphosphatemia, and increased blood creatine kinase with unknown causes or nontypical clinical symptoms.
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Errores Diagnósticos/efectos adversos , Hipoparatiroidismo/diagnóstico , Adulto , Femenino , Humanos , Hipoparatiroidismo/tratamiento farmacológico , Hormona Paratiroidea/sangreRESUMEN
AIMS: Thioredoxin-interacting protein (TXNIP) is associated with activation of oxidative stress through inhibition of thioredoxin (Trx). However, some evidences point out that TXNIP acts as a scaffolding protein in signaling complex independent of cellular redox regulation. The autophagy-lysosomal pathway plays important roles in the clearance of misfolded proteins and dysfunctional organelles. Lysosomal dysfunction has been involved in several neurodegenerative disorders including Parkinson's disease (PD). Although researchers have reported that TXNIP inhibited autophagic flux, the specific mechanism is rarely studied. METHODS: In this study, we investigated the effects of TXNIP on autophagic flux and α-synuclein accumulation by Western blot in HEK293 cells transfected with TXNIP plasmid. Further, we explored the influence of TXNIP on DA neuron survival in substantia nigra by IHC. RESULTS: We found that TXNIP induced LC3-II expression, but failed to degrade p62, a substrate of autophagy. Also, TXNIP aggravated α-synuclein accumulation. We also found that TXNIP inhibited the expression of ATP13A2, a lysosomal membrane protein. Moreover, we found that overexpression of ATP13A2 attenuated the impairment of autophagic flux and α-synuclein accumulation induced by TXNIP. Furthermore, overexpression of TXNIP in substantia nigra resulted in loss of DA neuron. CONCLUSION: Our data suggested that TXNIP blocked autophagic flux and induced α-synuclein accumulation through inhibition of ATP13A2, indicating TXNIP was a disease-causing protein in PD.
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Autofagia/genética , Proteínas Portadoras/metabolismo , Mesencéfalo/metabolismo , alfa-Sinucleína/metabolismo , Quinasas de la Proteína-Quinasa Activada por el AMP , Adenosina Trifosfatasas/metabolismo , Animales , Proteínas Portadoras/genética , Muerte Celular/genética , Línea Celular Transformada , Neuronas Dopaminérgicas/metabolismo , Regulación de la Expresión Génica/genética , Humanos , Lentivirus/genética , Proteínas de la Membrana/metabolismo , Mesencéfalo/citología , Ratones , Ratones Endogámicos C57BL , Proteínas Asociadas a Microtúbulos/metabolismo , Mutación/genética , Péptidos/metabolismo , Proteínas Quinasas/metabolismo , ATPasas de Translocación de Protón , TransfecciónRESUMEN
The aim of the study was to develop a population pharmacokinetic (PPK) model of oxcarbazepine and optimize the treatment of oxcarbazepine in Chinese patients with epilepsy. A total of 108 oxcarbazepine therapeutic drug monitoring samples from 78 patients with epilepsy were collected in this study. The pharmacologically active metabolite 10,11-dihydro-10-hydrocarbamazepine (MHD) was used as the analytical target for monitoring therapy of oxcarbazepine. Patients' clinical data were retrospectively collected. The PPK model for MHD was developed using Phoenix NLME 1.2 with a non-linear mixed-effect model. MHD pharmacokinetics obeys a one-compartment model with first-order absorption and elimination. The effect of age, gender, red blood cell count, red blood cell specific volume, hemoglobin (HGB), alanine aminotransferase (ALT), aspartate aminotransferase (AST), blood urea nitrogen (BUN), and serum creatine were analyzed. Bootstrap and data splitting were used simultaneously to validate the final PPK models. The mean values of volume of distribution and clearance of MHD in the patients were 14.2 L and 2.38 L h(-1), respectively. BUN and HGB influenced the MHD volume of distribution according to the following equation: V = tvV × (BUN/4.76)(-0.007) × (HGB/140)(-0.001) × e (ηV) . The MHD clearance was dependent on ALT and gender as follows: CL = tvCL × (ALT/30)(0.181) × (gender) × 1.083 × e (ηCL). The final PPK model was demonstrated to be suitable and effective and it can be used to evaluate the pharmacokinetic parameters of MHD in Chinese patients with epilepsy and to choose an optimal dosage regimen of oxcarbazepine on the basis of these parameters.