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1.
Medicine (Baltimore) ; 98(30): e16581, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31348293

RESUMO

RATIONALE: A number of medicines are associated with edema. However, only 2 cases of edema of both lower legs, associated with levofloxacin, have been reported. PATIENT: We report the case of levofloxacin-associated bilateral leg edema in an 81-year-old male. The patient was referred to the Division of Nephrology due to edema limited to both lower legs, which had developed 1 day before. He had undergone supraglottic laryngectomy due to supraglottic cancer in our institution 6 months ago. He had been admitted to the Department of Otolaryngology due to persistent aspiration and general weakness 5 days ago. DIAGNOSIS: The patient had no underlying diseases that could result in edema. No abnormalities were detected in several diagnostic tests. He strongly denied using other medications including herbal or traditional remedies, recreational drugs, or drugs of abuse. The patient had been intravenously administered levofloxacin at 750 mg per day 5 days earlier; on this basis levofloxacin-induced edema was suspected. INTERVENTIONS AND OUTCOMES: Levofloxacin was immediately withdrawn and conservative management (salt restriction and withdrawal of intravenous fluid) was initiated. His edema was completely restored within 3 weeks after withdrawal of levofloxacin. OUTCOMES: The patient stopped taking levofloxacin and he did not have any recurrent edema until his death due to uncontrolled pneumonia. LESSONS: Levofloxacin should be added to the list of drugs associated with the development of bilateral leg edema. This might obviate the need for time-consuming studies for diagnostic purposes and application of ineffective or harmful treatments.


Assuntos
Antibacterianos/efeitos adversos , Edema/induzido quimicamente , Levofloxacino/efeitos adversos , Idoso de 80 Anos ou mais , Humanos , Levofloxacino/administração & dosagem , Masculino
2.
J Clin Invest ; 130: 3738-3753, 2019 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-31194700

RESUMO

Specific neuronal populations display high vulnerability to pathological processes in Parkinson's disease (PD). The dorsal motor nucleus of the vagus nerve (DMnX) is a primary site of pathological α-synuclein deposition and may play a key role in the spreading of α-synuclein lesions within and outside the CNS. Using in vivo models, we show that cholinergic neurons forming this nucleus are particularly susceptible to oxidative challenges and accumulation of reactive oxidative species (ROS). Targeted α-synuclein overexpression within these neurons triggered an oxidative stress that became significantly more pronounced after exposure to the ROS-generating agent paraquat. A more severe oxidative stress resulted in enhanced production of oxidatively modified forms of α-synuclein, increased α-synuclein aggregation into oligomeric species and marked degeneration of DMnX neurons. Enhanced oxidative stress also affected neuron-to-neuron protein transfer, causing an increased spreading of α-synuclein from the DMnX toward more rostral brain regions. In vitro experiments confirmed a greater propensity of α-synuclein to pass from cell to cell under pro-oxidant conditions, and identified nitrated α-synuclein forms as highly transferable protein species. These findings substantiate the relevance of oxidative injury in PD pathogenetic processes, establish a relationship between oxidative stress and vulnerability to α-synuclein pathology and define a new mechanism, enhanced cell-to-cell α-synuclein transmission, by which oxidative stress could promote PD development and progression.

3.
Ren Fail ; 41(1): 204-210, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30942133

RESUMO

Acute kidney injury (AKI) associated with acute pyelonephritis (APN) rarely has been reported. The aim of this study was to evaluate the incidence and risk factors of AKI associated with APN. We retrospectively reviewed the medical records of 403 patients over 18-year old age hospitalized for APN management from October 2009 to September 2014 in tertiary care referral center. Demographic data, clinical symptoms and signs, and laboratory findings were gathered from the medical records and analyzed. The mean age of patients was 57 years and APN commonly occurred in female (87.6%). AKI occurred in 253 patients (62.8%). As per the RIFLE classification, renal injury was graded as 'Risk' (62.1%), 'Injury' (26.5%), and 'Failure' (11.4%). AKI patients were more likely a male gender and had complicated APN. The AKI group had a significantly higher tendency to present with shock. The prevalence of underlying chronic kidney disease (CKD) was significantly higher in the AKI group. There was no difference in mortality between the AKI and non-AKI groups. Multivariate analysis revealed that age over 65 (OR 1.93, 95% CI 1.18-3.13, p= .008), complicated (OR 2.13, 95% CI 1.35-3.34, p= .001) and bilateral APN (OR 1.71, 95% CI 1.01-2.88, p= .045), and initial shock (OR 2.44, 95% CI 1.05-5.71, p= .039) were independent risk factors for the occurrence of AKI in patients with APN. Physicians should attempt to prevent, detect, and manage AKI associated with APN in patients with above conditions.


Assuntos
Lesão Renal Aguda/epidemiologia , Pielonefrite/complicações , Centros de Atenção Terciária/estatística & dados numéricos , Doença Aguda , Lesão Renal Aguda/diagnóstico , Lesão Renal Aguda/etiologia , Lesão Renal Aguda/prevenção & controle , Adulto , Idoso , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Pielonefrite/terapia , Estudos Retrospectivos , Fatores de Risco , Fatores Sexuais
4.
Clin Ther ; 41(4): 700-713, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30827751

RESUMO

PURPOSE: This study estimated utility weights based on the response to treatment for atopic dermatitis in the general population. METHODS: The Korean general population aged 20-60 years was stratified by using a random sampling method based on age and sex. Two hypothetical health states of atopic dermatitis were developed: response to treatment and no response to treatment. Health utility values were estimated by using time trade-off (TTO) based on a period of 10 years, TTO based on life expectancy, and EuroQol 5-Dimension (EQ-5D) including a visual analog scale (VAS). The mean utility value and 95% CI were derived, and comparisons of subgroups using the t test and ANOVA were performed. We conducted a multilevel analysis after controlling the sociodemographic variables to consider repeated measures. FINDINGS: A total of 155 participants were included in the survey. Their mean age was 39.7 years; 58.7% of participants were women. The mean health utility values for response and no response using TTO based on 10 years were 0.847 and 0.380, respectively. The estimated health utility values of response and no response were 0.865 and 0.476 using TTO based on life expectancy, and 0.814 and 0.279 using EQ-5D. For VAS, the response and no response were 0.744 and 0.322. After controlling the covariates, the important factors that affected utility values were response and no response to treatment (P < 0.001). IMPLICATIONS: This study showed that the utility weights of people with no response to atopic dermatitis treatment were lower compared with response from the general population. Health care providers should therefore consider symptom control as an important factor affecting the quality of life of those with atopic dermatitis.

5.
Ren Fail ; 41(1): 24-33, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30714460

RESUMO

The use of colistin in the treatment of multidrug-resistant Gram-negative bacterial infections is restricted due to nephrotoxicity. We investigated the effects of aged black garlic extract (ABGE) on colistin-induced kidney injury in rats. Rats were assigned to four groups. Normal saline was intraperitoneally and intragastrically injected for control group. ABGE was intragastrically injected for garlic group. Ten mg/kg of colistin was intraperitoneally injected for 6 consecutive days for colistin group. One percent of ABGE was done 30 min prior to colistin injection for treatment group. Rats were sacrificed on the next day after last colistin injection. Colistin injection increased the serum levels of blood urea nitrogen and creatinine; however, ABGE prevented deterioration of these serum levels. ABGE also alleviated tubular damage, including vacuolation and necrosis. TUNEL-positive cells were observed less frequently for the ABGE-treated groups. CD68 positive cells were significantly decreased by pretreatment with ABGE. Levels of oxidative stress biomarkers such as 8-hydroxydeoxyguanosine and malondialdehyde were lower in the ABGE-treated groups. Levels of NF-κB, inducible NO synthase, COX-2, and TGF-ß1 were lower in rats that had been treated with ABGE injection. Renal levels of IL-1ß and TNF-α were increased by colistin administration whereas renal SOD, catalase, and GSH levels were restored by ABGE administration. These results suggest that ABGE, which has antioxidant and anti-inflammatory properties, might be a potential therapeutic agent to prevent renal toxicity of colistin.


Assuntos
Lesão Renal Aguda/tratamento farmacológico , Antioxidantes/farmacologia , Colistina/efeitos adversos , Alho/química , Extratos Vegetais/farmacologia , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/patologia , Animais , Antioxidantes/uso terapêutico , Modelos Animais de Doenças , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Humanos , Rim/efeitos dos fármacos , Rim/patologia , Masculino , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/uso terapêutico , Ratos , Ratos Sprague-Dawley , Resultado do Tratamento , Água/química
6.
Nephrol Dial Transplant ; 34(9): 1481-1498, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-30544214

RESUMO

BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor critical for T-cell function. Although inhibition of the Janus kinase 2 (JAK2)/STAT3 pathway has been reported to be protective against ischemia-reperfusion injury (IRI), the role of T cell-associated STAT3 in the pathogenesis of renal IRI has not been specifically defined. METHODS: We induced renal IRI in both mice with T cell-specific STAT3 knockout (Lck-Cre;STAT3flox/flox) and wild-type controls (C57BL/6) and assessed renal damage and inflammation at 48 h after IRI. Human proximal tubular epithelial cells grown under hypoxia were treated with a JAK2 inhibitor, caffeic acid 3,4-dihydroxy-phenylethyl ester, to determine the effect of JAK2/STAT3 inhibition on renal epithelia. Independently, we disrupted Cln 3-requiring 9 (Ctr9) to inhibit T helper 17 (Th17) activation via RNA interference and determined if Ctr9 inhibition aggravates renal injury through upregulated Th17 activation. RESULTS: The Lck-Cre;STAT3flox/flox mice exhibited significantly reduced kidney damage compared with controls. This protective effect was associated with reduced intrarenal Th17 infiltration and proinflammatory cytokines. Human proximal tubular epithelial cells under hypoxia exhibited significant upregulation of interleukin 17 receptors, and pharmacologic inhibition of JAK2 significantly ameliorated this change. RNA interference with Ctr9 in splenocytes enhanced differentiation into Th17 cells. In vivo knockdown of Ctr9 in mice with renal IRI further aggravated Th17-associated inflammation and kidney injury. CONCLUSIONS: STAT3 in T cells contributes to renal IRI through Th17 activation. Inhibition of Ctr9 further enhances Th17 activation and aggravates kidney injury, further supporting the role of Th17 cells in renal IRI.

7.
BMC Nephrol ; 19(1): 306, 2018 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-30400882

RESUMO

BACKGROUND: The number of elderly patients with end-stage renal disease is increasing rapidly. The higher prevalence of comorbidities and shorter life expectancy in these patients make it difficult to decide on the type of vascular access (VA). We explored the optimal choice for VA in elderly hemodialysis patients. METHODS: We included elderly patients (> 65 years) visiting our VA clinic and divided them into three groups as follows: radiocephalic arteriovenous fistula (AVF), brachiocephalic AVF, and prosthetic arteriovenous graft (AVG). The primary outcomes were VA abandonment and all-cause mortality. The secondary outcome was maturation failure (MF). RESULTS: Of 529 patients, 61.2% were men. The mean age was 73.6 ± 6.0 years. The VA types were as follows: 49.9% radiocephalic AVF, 31.8% brachiocephalic AVF, and 18.3% AVG. Patients with an AVG tended to be older, female, and have a lower body mass index. More than half of patients (n = 302, 57.1%) started dialysis with central catheters, but the proportion of predialysis central catheter placement was not different among the VA types. Radiocephalic AVF was significantly superior to AVG in terms of VA abandonment (P = 0.005) and all-cause mortality (P < 0.001) in spite of a higher probability of MF. Brachiocephalic AVF was associated with a shorter time to the first needling and fewer interventions before maturation than radiocephalic AVF. CONCLUSIONS: Autologous AVF was suggested as the preferred VA choice in terms of long-term outcomes in elderly patients.

8.
Nat Commun ; 9(1): 3465, 2018 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-30150626

RESUMO

Propagation of α-synuclein aggregates has been suggested as a contributing factor in Parkinson's disease (PD) progression. However, the molecular mechanisms underlying α-synuclein aggregation are not fully understood. Here, we demonstrate in cell culture, nematode, and rodent models of PD that leucine-rich repeat kinase 2 (LRRK2), a PD-linked kinase, modulates α-synuclein propagation in a kinase activity-dependent manner. The PD-linked G2019S mutation in LRRK2, which increases kinase activity, enhances propagation efficiency. Furthermore, we show that the role of LRRK2 in α-synuclein propagation is mediated by RAB35 phosphorylation. Constitutive activation of RAB35 overrides the reduced α-synuclein propagation phenotype in lrk-1 mutant C. elegans. Finally, in a mouse model of synucleinopathy, administration of an LRRK2 kinase inhibitor reduced α-synuclein aggregation via enhanced interaction of α-synuclein with the lysosomal degradation pathway. These results suggest that LRRK2-mediated RAB35 phosphorylation is a potential therapeutic target for modifying disease progression.

9.
BMC Nephrol ; 19(1): 104, 2018 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-29724179

RESUMO

BACKGROUND: Urinothorax is defined as the presence of urine in the pleural space and is a rather rare cause of transudate pleural effusion. The potential etiologies are urinary tract obstruction and trauma. Diagnosis requires a high index of clinical suspicion and the condition is completely reversible following relief of underlying disease. CASE PRESENTATION: We report a 27-year-old man who developed urinothorax after renal biopsy. Urine leakage was confirmed with 99mTc DTPA (diethylenetriaminepentacetate) and single-photon emission computed tomography scans and retrograde pyelography. The pleural effusion was completely resolved by removing the leakage with a Foley catheter and a double J stent. CONCLUSIONS: Urinothorax has not been reported in patients doing renal biopsy in the literature. Based on our experience, urinothorax should be suspected, diagnosed, and managed appropriately when pleural effusion occurred after renal biopsy.

10.
Arch Gerontol Geriatr ; 76: 175-181, 2018 May - Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29525605

RESUMO

Idiopathic membranous nephropathy (MN) is the most common glomerulonephritis in elderly patients showing nephrotic syndrome. However, little is known about its treatment options and outcomes in elderly MN patients at long term follow-up. We retrospectively enrolled patients with biopsy-proven MN between April 1990 and December 2015 from eight tertiary hospitals in Korea. Among them, we excluded patients who had secondary causes of MN and subnephrotic-range proteinuria. We evaluated the presenting features and clinical outcomes and analyzed the all-cause mortality, renal outcomes, infection, and remission with respect to age. During the median follow-up at 77.2 months, 198 younger patients (<65 years) and 133 elderly patients (≥65 years) were enrolled. Age was an independent risk factor for all-cause mortality, renal outcome, and infection (for all P < 0.05) except remission. In elderly patients, there was no significant factor associated with mortality rate. The use of angiotensin-converting enzyme inhibitor (ACEI) or angiotensin II receptor blocker (ARB) was significantly associated with renal outcome and infection (renal outcome, hazard ration [HR] 0.06, 95% confidence intervals [CI] 0.01-0.36, P = 0.003; infection, HR 0.20, 95% CI 0.04-0.94, P = 0.041). Immunosuppressant therapy significantly increased renal outcome (P = 0.045) and infection (P = 0.029) compared with conservative therapy. In conclusion, old age is one of the clinically important predictors for MN patients. Among the treatment of elderly MN patients, only ACEI or ARB was associated with beneficial effects on renal outcome and infection. Elderly MN patients need a more tailored regimen considering their comorbidities and condition.

11.
Sci Rep ; 8(1): 1687, 2018 01 26.
Artigo em Inglês | MEDLINE | ID: mdl-29374217

RESUMO

The objective of the study was to investigate the pharmacokinetic drug-drug interactions between tacrolimus (TAC) and mycophenolate mofetil (MMF) in healthy Korean male volunteers. Seventeen volunteers participated in a three-period, single-dose, and fixed sequence study. They sequentially received MMF, TAC, and the combination. Concentrations of TAC, mycophenolic acid (MPA), and its metabolites MPA 7-O-glucuronide and MPA acyl glucuronide were measured. The variants of CYP3A4, CYP3A5, SLCO1B1, SLCO1B3, ABCC2, UGT1A9, and UGT2B7 were genotyped. Drug interaction was evaluated with a non-compartmental analysis and population pharmacokinetic modelling to quantify the interaction effect. A total of 1,082 concentrations of those analytes were analysed. AUC0-inf of TAC increased by 22.1% (322.4 ± 174.1 to 393.6 ± 121.7 ng·h/mL; P < 0.05) when co-administered with MMF, whereas the pharmacokinetic parameters of MPA and its metabolites were not changed by TAC. Apparent clearance (CL/F) of TAC was 17.8 L/h [relative standard error (RSE) 11%] or 13.8 L/h (RSE 11%) without or with MMF, respectively. Interaction was explained by the exponential model. The CYP3A5 genotype was the only significant covariate. The population estimate of CL/F of TAC was 1.48-fold (RSE 16%) in CYP3A5 expressers when compared to nonexpressers. CL/F of TAC was decreased when co-administered with MMF in these subjects.

12.
Ren Fail ; 40(1): 693-699, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30741615

RESUMO

Alcoholic ketoacidosis (AKA) is occasionally associated with multiple complications leading to death. However, no study has yet evaluated prognostic factors in patients with AKA. It is known that the logistic organ dysfunction system (LODS) score is an objective and useful index to predict the prognosis. We used LODS score to predict prognosis of AKA. We retrospectively reviewed the medical records of 46 patients who were diagnosed as AKA in our hospital. The mean LODS score was 6.3. The probability of mortality based on the LODS score was 36.6%, and 16 patients (34.5%) did, in fact, die. The total LODS score and lactate dehydrogenase (LDH) were significantly higher in the non-survival group. Prothrombin activity, serum platelet number, and the serum albumin levels were significantly higher in the survival group. We found significant correlations between the LODS score and arterial pH, the albumin level, and the LDH concentration. Multivariate analysis showed that the serum albumin and LDH levels were independently associated with survival in AKA patients. AKA patients suffered high-level mortality and the LODS score was an accurate predictor of prognosis. Clinicians may use the LODS score to this end.


Assuntos
Alcoolismo/complicações , Cetose/mortalidade , Insuficiência de Múltiplos Órgãos/mortalidade , Adulto , Feminino , Mortalidade Hospitalar , Humanos , Unidades de Terapia Intensiva , Cetose/sangue , Cetose/diagnóstico , Cetose/etiologia , L-Lactato Desidrogenase/sangue , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/diagnóstico , Insuficiência de Múltiplos Órgãos/etiologia , Análise Multivariada , Prognóstico , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida
13.
Ren Fail ; 40(1): 687-692, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30741619

RESUMO

Intravenous (IV) acyclovir is commonly administered medication for viral infection but is well known for its nephrotoxicity. However, there was no study for incidence, risk factors, and clinical outcomes of acute kidney injury (AKI) associated with IV acyclovir administration. We retrospectively reviewed the medical records of 287 patients who were medicated IV acyclovir from January 2008 to May 2013 in Gyeongsang National University Hospital. All had documented medical histories and underwent medical review. Demographic data, risk factors, concomitant drugs, laboratory findings and outcome were gathered from the medical records and analyzed. AKI occurred in 51 patients (17.8%). As per RIFLE classification, renal injury was graded as either at risk of renal dysfunction (62.7%), renal injury (15.6%), and renal failure (21.6%). There was no significant difference in age, sex, total dose, drug duration, and presence of hydration between AKI and non-AKI group. However, systolic pressure, underlying diabetes, concomitant vancomycin and non-steroidal anti-inflammatory drugs (NSAIDs) use was positively correlated with AKI occurrence (p = .04, p < .001, 0.01, and 0.04, respectively). Two patients underwent hemodialysis and these patients died. Higher mortality was observed in AKI patients (p < .001). Multivariate analysis also presented that presence of diabetes, concomitant NSAIDs, and vancomycin use was independent risk factor of acyclovir associated with AKI (p = .001, OR 3.611 (CI: 1.708-7.633), p = .050, OR 2.630 (CI: 1.000-6.917), and p = .009, OR 4.349 (CI: 1.452-13.022), respectively). AKI is relatively common in patients administrating acyclovir injection. Physicians should attempt to prevent, detect, and manage acyclovir associated AKI in patients prescribing acyclovir due to possible association of poor prognosis.


Assuntos
Lesão Renal Aguda/epidemiologia , Aciclovir/efeitos adversos , Antivirais/efeitos adversos , Rim/efeitos dos fármacos , Diálise Renal/estatística & dados numéricos , Lesão Renal Aguda/induzido quimicamente , Lesão Renal Aguda/terapia , Aciclovir/administração & dosagem , Administração Intravenosa , Adulto , Idoso , Antivirais/administração & dosagem , Feminino , Taxa de Filtração Glomerular , Infecções por Herpesviridae/tratamento farmacológico , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Prognóstico , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Taxa de Sobrevida
14.
J Korean Med Sci ; 33(53): e298, 2018 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-30595680

RESUMO

Background: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4ß-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. Methods: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6ß-OH-cortisol/cortisol, 6ß-OH-cortisone/cortisone, 4ß-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4ß-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. Results: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone as well as plasma 4ß-OH-cholesterol and 4ß-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. Conclusion: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.


Assuntos
Citocromo P-450 CYP3A/metabolismo , Fígado/metabolismo , Insuficiência Renal/patologia , Adulto , Idoso , Biomarcadores/sangue , Biomarcadores/urina , Colesterol/sangue , Cromatografia Líquida de Alta Pressão , Cortisona/química , Cortisona/urina , Feminino , Cromatografia Gasosa-Espectrometria de Massas , Taxa de Filtração Glomerular , Humanos , Hidrocortisona/química , Hidrocortisona/urina , Indicã/sangue , Rim/metabolismo , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Insuficiência Renal/metabolismo , Índice de Gravidade de Doença
15.
Cell Rep ; 21(10): 2952-2964, 2017 Dec 05.
Artigo em Inglês | MEDLINE | ID: mdl-29212038

RESUMO

Triple-negative breast cancer (TNBC) is considered incurable with currently available treatments, highlighting the need for therapeutic targets and predictive biomarkers. Here, we report a unique role for Bcl-2-associated athanogene 2 (BAG2), which is significantly overexpressed in TNBC, in regulating the dual functions of cathepsin B as either a pro- or anti-oncogenic enzyme. Silencing BAG2 suppresses tumorigenesis and lung metastasis and induces apoptosis by increasing the intracellular mature form of cathepsin B, whereas BAG2 expression induces metastasis by blocking the auto-cleavage processing of pro-cathepsin B via interaction with the propeptide region. BAG2 regulates pro-cathepsin B/annexin II complex formation and facilitates the trafficking of pro-cathespin-B-containing TGN38-positive vesicles toward the cell periphery, leading to the secretion of pro-cathepsin B, which induces metastasis. Collectively, our results uncover BAG2 as a regulator of the oncogenic function of pro-cathepsin B and a potential diagnostic and therapeutic target that may reduce the burden of metastatic breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Catepsina B/metabolismo , Chaperonas Moleculares/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Apoptose/genética , Apoptose/fisiologia , Catepsina B/genética , Linhagem Celular Tumoral , Feminino , Humanos , Chaperonas Moleculares/genética , Neoplasias de Mama Triplo Negativas/genética
16.
Medicine (Baltimore) ; 96(40): e8251, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28984784

RESUMO

RATIONALE: Severe hypokalemia can be a potentially life-threatening disorder and is associated with variable degrees of skeletal muscle weakness. PATIENT CONCERNS: We report a case of severe hypokalemic paralysis and rhabdomyolysis in a 28-year-old bodybuilder. He was admitted to the emergency room due to progressive paralysis in both lower extremities, which had begun 12 hours earlier. He was a bodybuilder trainer and had participated in a regional competition 5 days earlier. He went on a binge, consuming large amounts of carbohydrates over 4 days, resulting in a gain of 10 kg in weight. DIAGNOSES: He had no family history of paralysis and this was his first attack. He strongly denied drug abuse, such as anabolic steroids, thyroid and growth hormone, and diuretics. Neurological examinations revealed symmetrical flaccid paralysis in his lower extremities, but the patient was alert and his sensory system was intact. His initial serum potassium and phosphate level was 1.8 mmol/L and 1.4 mg/dL, respectively. The calculated transtubular potassium gradient (TTKG) was 2.02. His thyroid function was normal. INTERVENTIONS AND OUTCOMES: Serum potassium levels increased to 3.8 mmol/L with intravenous infusion of about 50 mmol of potassium chloride over 20 hours. OUTCOMES: His muscular symptoms improved progressively and he was discharged from the hospital 7 days after admission on foot. He was followed in our outpatient clinic, without recurrence. LESSONS: Physicians should keep in mind that large intakes of food during short periods can provoke hypokalemic paralysis and rhabdomyolysis, especially in bodybuilders.


Assuntos
Bulimia/complicações , Paralisia Periódica Hiperpotassêmica/etiologia , Rabdomiólise/etiologia , Levantamento de Peso , Adulto , Humanos , Masculino
17.
Nat Cell Biol ; 19(10): 1260-1273, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28892081

RESUMO

Although the ubiquitin-editing enzyme A20 is a key player in inflammation and autoimmunity, its role in cancer metastasis remains unknown. Here we show that A20 monoubiquitylates Snail1 at three lysine residues and thereby promotes metastasis of aggressive basal-like breast cancers. A20 is significantly upregulated in human basal-like breast cancers and its expression level is inversely correlated with metastasis-free patient survival. A20 facilitates TGF-ß1-induced epithelial-mesenchymal transition (EMT) of breast cancer cells through multi-monoubiquitylation of Snail1. Monoubiquitylated Snail1 has reduced affinity for glycogen synthase kinase 3ß (GSK3ß), and is thus stabilized in the nucleus through decreased phosphorylation. Knockdown of A20 or overexpression of Snail1 with mutation of the monoubiquitylated lysine residues into arginine abolishes lung metastasis in mouse xenograft and orthotopic breast cancer models, indicating that A20 and monoubiquitylated Snail1 are required for metastasis. Our findings uncover an essential role of the A20-Snail1 axis in TGF-ß1-induced EMT and metastasis of basal-like breast cancers.


Assuntos
Neoplasias da Mama/enzimologia , Movimento Celular , Neoplasias Pulmonares/enzimologia , Fatores de Transcrição da Família Snail/metabolismo , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/metabolismo , Ubiquitinação , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Resistencia a Medicamentos Antineoplásicos , Transição Epitelial-Mesenquimal , Feminino , Regulação Neoplásica da Expressão Gênica , Glicogênio Sintase Quinase 3 beta/metabolismo , Células HEK293 , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/prevenção & controle , Lisina , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células-Tronco Neoplásicas/enzimologia , Células-Tronco Neoplásicas/patologia , Fosforilação , Estabilidade Proteica , Interferência de RNA , Transdução de Sinais , Fatores de Transcrição da Família Snail/genética , Fatores de Tempo , Transfecção , Fator de Crescimento Transformador beta1/farmacologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/farmacologia , Ubiquitinação/efeitos dos fármacos
18.
Medicine (Baltimore) ; 96(19): e6666, 2017 May.
Artigo em Inglês | MEDLINE | ID: mdl-28489742

RESUMO

Cardiovascular disease (CVD) is the main public health problem in patients with chronic kidney disease (CKD); however, there is no established biomarker for predicting CVD morbidity and mortality in CKD. The aim of this study was to evaluate the role of circulating tumor necrosis factor receptors (cTNFRs) in predicting CVD risk in CKD patients.We prospectively recruited 984 patients with CKD from 11 centers between 2006 and 2012. The levels of cTNFR1 and cTNFR2 were determined by performing an enzyme-linked immunosorbent assay. During the mean follow-up period of 4 years, 36 patients experienced a CVD event. The median serum concentrations of cTNFR1 and cTNFR2 were 2703.4 (225.6-13,057.7) and 5661.0 (634.9-30,599.6) pg/mL, respectively, and the cTNFR1 level was closely correlated with the cTNFR2 level (r = 0.86, P < .0001). The urinary protein-to-creatinine ratio (UPCR) and estimated glomerular filtration rate (eGFR) were significantly correlated with the cTNFR2 level (r = 0.21 for UPCR, r = -0.67 for eGFR; P < .001 for all). Similar correlations were observed for serum cTNFR1 (r = 0.21 for UPCR, r = -0.75 for eGFR; P < .001 for all). In the Cox proportional hazard analyses, cTNFR1 (hazard ratio [HR] 2.506, 95% confidence interval [CI] 1.186-5.295, P = .016) and cTNFR2 (HR 4.156, 95% CI 1.913-9.030, P < .001) predicted CVD risk even after adjustment for clinical covariates, such as UPCR, eGFR, and high-sensitivity C-reactive protein. cTNFR1 and 2 are associated with CVD and other risk factors in CKD, independently of eGFR and UPCR. Furthermore, cTNFRs could be relevant predictors of CVD in CKD patients.


Assuntos
Doenças Cardiovasculares/sangue , Doenças Cardiovasculares/complicações , Receptores Tipo II do Fator de Necrose Tumoral/sangue , Receptores Tipo I de Fatores de Necrose Tumoral/sangue , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/complicações , Adulto , Idoso , Análise Química do Sangue , Doenças Cardiovasculares/mortalidade , Doenças Cardiovasculares/urina , Creatinina/urina , Porocarcinoma Écrino , Ensaio de Imunoadsorção Enzimática , Feminino , Seguimentos , Taxa de Filtração Glomerular , Humanos , Masculino , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Estudos Prospectivos , Insuficiência Renal Crônica/mortalidade , Insuficiência Renal Crônica/urina , Fatores de Risco
19.
Exp Mol Med ; 49(4): e314, 2017 04 07.
Artigo em Inglês | MEDLINE | ID: mdl-28386127

RESUMO

Amyloid fibril formation has been implicated in the pathogenesis of neurodegenerative diseases. Fibrillation generates numerous conformers. Presumably, the conformers may possess specific biological properties, thus providing a biochemical framework for strains of prions. However, the precise relationship between various fibril conformers and their pathogenic functions has not been determined because of limited accessibility to adequate amounts of fibrils from tissue samples. α-Synuclein is one such protein, and it has been implicated in Parkinson disease. Using a technique known as protein misfolding cyclic amplification, originally developed for amplifying prions, we established a procedure through which the amplification of α-synuclein fibrils is possible. With a trace amount of seeds, we succeeded in amplifying α-synuclein fibrils. The replication of the seeds was faithful in terms of conformation even after multiple rounds of cyclic amplification. Moreover, two transgenic mouse strains each representing a distinct synucleinopathy were used to investigate different conformers by using this technique. The amplified α-synuclein fibrils derived from the tissue extracts of these two strains led to the production of two different fibril conformers with distinct proteinase K digestion profiles. Together, our results demonstrated that a trace amount of α-synuclein fibrils in tissue extracts could be amplified with their conformations conserved. This procedure should be useful in amplifying α-synuclein fibrils from the brains and body fluids of patients afflicted with synucleinopathies and may serve as a potential diagnostic tool for Parkinson disease and other synucleinopathies.


Assuntos
Amiloide/metabolismo , Agregação Patológica de Proteínas/metabolismo , alfa-Sinucleína/metabolismo , Amiloide/química , Animais , Encéfalo/metabolismo , Humanos , Camundongos , Conformação Proteica , Dobramento de Proteína , alfa-Sinucleína/química
20.
BMJ Open ; 7(3): e013882, 2017 03 15.
Artigo em Inglês | MEDLINE | ID: mdl-28298367

RESUMO

OBJECTIVES: Renal involvement in scrub typhus ranges from simple urinary abnormalities to acute kidney injury (AKI) leading to death. This study evaluated the incidence, predictors and prognosis of AKI associated with scrub typhus according to the RIFLE (risk, injury, failure, loss, end-stage kidney disease) criteria. METHODS: We retrospectively evaluated the medical records of patients diagnosed with scrub typhus from January 2001 to November 2013 in Gyeongsang National University Hospital. RESULTS: During the study period, 510 patients were diagnosed with scrub typhus and the incidence of AKI was 35.9%. There were 132 (25.9%) patients at risk, 37 (7.3%) with injury and 14 (2.7%) with failure. In comparison with the non-AKI group, the AKI group was older (73.9 vs 63.4 years, p<0.001) and had more comorbidities such as hypertension, diabetes mellitus and chronic kidney disease (CKD). AKI frequently occurs in hypertensive patients taking angiotensin receptor blockers or ACE inhibitors (p=0.002), and in patients with diabetes with higher glycated haemoglobin levels (p=0.033). Haematuria and proteinuria were more frequent in the AKI group. There was no relationship between the severity of proteinuria and occurrence of AKI. Intensive care unit admission and death were more frequent in the AKI group. The renal function of most patients with AKI recovered without sequelae, except for 1 patient who had underlying CKD. Multivariate analysis showed that age, presence of CKD, serum albumin level and time to hospital presentation after symptom onset were independent predictors of AKI in patients with scrub typhus. CONCLUSIONS: Our current results suggest that the presence of underlying CKD, older age, lower serum albumin level and time to hospital presentation after symptom onset were important risk factors to determine occurrence of AKI. Whether earlier diagnosis and treatment in patients with the above risk factors reduce the incidence and severity of AKI deserves to be investigated.


Assuntos
Lesão Renal Aguda/etiologia , Rim , Tifo por Ácaros/complicações , Lesão Renal Aguda/epidemiologia , Adulto , Fatores Etários , Idoso , Comorbidade , Feminino , Hospitalização , Hospitais , Humanos , Incidência , Unidades de Terapia Intensiva , Rim/patologia , Rim/fisiopatologia , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Renal Crônica/complicações , República da Coreia/epidemiologia , Estudos Retrospectivos , Fatores de Risco , Tifo por Ácaros/patologia
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